Cannabidiol in Gliomas: Therapeutic Potential and Nanocarrier Strategies, with an Emphasis on Vesicular Delivery Systems.
1/5 보강
Cannabidiol (CBD), a nonpsychoactive phytocannabinoid extracted from , has emerged as a compound of considerable therapeutic interest across numerous medical disciplines, including pain management, an
APA
Szkudlarek J, Piwowarczyk L, Jelińska A (2026). Cannabidiol in Gliomas: Therapeutic Potential and Nanocarrier Strategies, with an Emphasis on Vesicular Delivery Systems.. Molecular pharmaceutics, 23(1), 28-42. https://doi.org/10.1021/acs.molpharmaceut.5c00853
MLA
Szkudlarek J, et al.. "Cannabidiol in Gliomas: Therapeutic Potential and Nanocarrier Strategies, with an Emphasis on Vesicular Delivery Systems.." Molecular pharmaceutics, vol. 23, no. 1, 2026, pp. 28-42.
PMID
41288593 ↗
Abstract 한글 요약
Cannabidiol (CBD), a nonpsychoactive phytocannabinoid extracted from , has emerged as a compound of considerable therapeutic interest across numerous medical disciplines, including pain management, anti-inflammatory therapy, and oncology. This review critically examines the potential of CBD in the treatment of glioblastoma multiforme (GBM), one of the most aggressive and treatment-resistant primary brain tumors. Particular emphasis is placed on the molecular mechanisms underlying CBD's antitumor activity, including the modulation of key signaling pathways, inhibition of tumor proliferation, and enhancement of chemosensitivity. Furthermore, the review highlights the increasing role of nanotechnology in overcoming the intrinsic pharmacokinetic limitations of CBD, particularly its low oral bioavailability, which presents a significant challenge to its clinical application. Advanced nanocarrier platforms, including nanoemulsions, nanoparticles, nanoparticle-based transdermal systems, nanocapsules, and liposomes, have shown promise in optimizing CBD delivery to the central nervous system (CNS). Notably, the integration of CBD into lipid-based drug delivery systems (LBDDS) is highlighted as a particularly promising strategy to potentiate its therapeutic efficacy. This approach enhances bioavailability and may amplify synergistic effects when combined with conventional chemotherapeutics or targeted agents. Overall, the synergistic use of nanotechnological approaches and CBD-based therapies may open new avenues for research, offering the potential to significantly advance treatment efficacy in glioblastoma and other diseases.
🏷️ 키워드 / MeSH 📖 같은 키워드 OA만
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Introduction
1
Introduction
Cannabis has been used
medicinally since the 16th century in Asia
for pain relief, reducing inflammation, and treating various conditions
like seizures and insomnia. In 1840, William O’Shaughnessy
highlighted its potential for ailments like asthma, sleep disorders,
and opium withdrawal, paving the way for its therapeutic exploration.
Over 560 compounds have been identified in cannabis, many with unique
properties that could make them viable drug candidates. Many studies have investigated the anticancer
effects of plant-derived natural compounds, utilizing both in vitro
and in vivo models. Among these, CBD stands
out as the second most abundant compound in Cannabis, with promising
therapeutic effects, including sedation, anti-inflammation, antioxidation,
and neuroprotection.
,
CBD is notable in that it lacks
psychoactive properties such as hallucinations and addiction, making
it of growing interest.
,
However, its medical use is limited
by poor water solubility, low bioavailability, and unstable pharmacokinetics.
,
Despite these challenges, CBD is widely consumed in unapproved over-the-counter
products of unknown composition. The chemical
formula of the CBD is shown in Figure
.
CBD’s effects are believed to result from
multiple molecular
mechanisms involving G protein-coupled receptors (GPCRs) and ion channels. Additionally, CBD exhibits anticancer effects
by interacting with the endocannabinoid system, leading to tumor cell
inhibition, pain relief, and reduced chemotherapy-related side effects
such as nausea and vomiting. Furthermore,
CBD has the potential to enhance the effectiveness of conventional
cancer therapies like chemotherapy and radiation while protecting
against neurological and organ damage.
,
Significant
milestones in the medical use of CBD include the approval of Sativex
and Epidiolex. A combination of two compounds found in Cannabis sativa, the psychotropic Δ9‑tetrahydrocannabinol (Δ9‑THC, THC) and CBD
in Sativex (27 mg/mL Δ9‑THC; 25 mg/mL CBD),
became the first CBD-based drug that the Medicines and Healthcare
Products Regulatory Agency accepted for multiple sclerosis spasticity
treatment (2010). Through an oromucosal spray, a significant portion
of its CBD is absorbed through the gastrointestinal tract. Eight years
later, Epidiolex (100 mg/mL CBD), the first drug with CBD as the sole
active ingredient for treating rare epilepsy forms, was approved by
the Food and Drug Administration.
CBD has shown remarkable potential in inhibiting the progression
of various cancers, including glioblastoma, lung, breast, colon, prostate,
and melanoma, as demonstrated in numerous animal studies. However, CBD’s therapeutic potential
is significantly impeded by its low oral bioavailability (about 6%
in humans). Reasons for low bioavailability can include significant
first-pass metabolism in the liver, instability in the acidic gastric
pH, and poor water solubility. Interestingly, coadministration with
a high-fat meal may increase CBD’s bioavailability by up to
4-fold.
,
CBD’s high hydrophobicity, resulting
in extremely low water solubility (approximately 2.3 × 10–2 μg/mL), further restricts its practical use. To overcome these challenges, advanced delivery
systems are essential for improving the solubility and bioavailability
of lipophilic substances, such as CBD.
One promising approach to overcoming these limitations is
nanotechnology,
a rapidly advancing field that offers a promising, secure, cost-effective,
and efficient approach to revolutionizing cancer treatment strategies.
,
Nanoparticle-based drug delivery systems (DDS) enhance anticancer
therapy by targeting drugs directly to cancer cells, reducing systemic
toxicity, and improving therapeutic outcomes. Encapsulation protects
drugs from degradation, ensures controlled release, and maximizes
effectiveness while minimizing side effects. Nanoscale formulations have been widely studied to enhance lipophilic
compounds’ solubility, release profiles, and bioavailability. Nanovesicles, a subcategory of lipid-based drug
delivery systems (LBDDS), are widely used as carriers in DDS and stand
out as one of the most prevalent choices. Among these, liposomes, a well-known representative of nanovesicles,
are recognized as the first nanomedical delivery system to achieve
clinical use and gain widespread acceptance.
This review includes studies on the role of CBD in GBM. It
proposes
the use of CBD in LBDDS as a promising strategy to oppose GBM, addressing
a significant gap in existing research. To our knowledge, no one has
yet described or comprehensively summarized the research on the use
of CBD in nanovesicles
Introduction
Cannabis has been used
medicinally since the 16th century in Asia
for pain relief, reducing inflammation, and treating various conditions
like seizures and insomnia. In 1840, William O’Shaughnessy
highlighted its potential for ailments like asthma, sleep disorders,
and opium withdrawal, paving the way for its therapeutic exploration.
Over 560 compounds have been identified in cannabis, many with unique
properties that could make them viable drug candidates. Many studies have investigated the anticancer
effects of plant-derived natural compounds, utilizing both in vitro
and in vivo models. Among these, CBD stands
out as the second most abundant compound in Cannabis, with promising
therapeutic effects, including sedation, anti-inflammation, antioxidation,
and neuroprotection.
,
CBD is notable in that it lacks
psychoactive properties such as hallucinations and addiction, making
it of growing interest.
,
However, its medical use is limited
by poor water solubility, low bioavailability, and unstable pharmacokinetics.
,
Despite these challenges, CBD is widely consumed in unapproved over-the-counter
products of unknown composition. The chemical
formula of the CBD is shown in Figure
.
CBD’s effects are believed to result from
multiple molecular
mechanisms involving G protein-coupled receptors (GPCRs) and ion channels. Additionally, CBD exhibits anticancer effects
by interacting with the endocannabinoid system, leading to tumor cell
inhibition, pain relief, and reduced chemotherapy-related side effects
such as nausea and vomiting. Furthermore,
CBD has the potential to enhance the effectiveness of conventional
cancer therapies like chemotherapy and radiation while protecting
against neurological and organ damage.
,
Significant
milestones in the medical use of CBD include the approval of Sativex
and Epidiolex. A combination of two compounds found in Cannabis sativa, the psychotropic Δ9‑tetrahydrocannabinol (Δ9‑THC, THC) and CBD
in Sativex (27 mg/mL Δ9‑THC; 25 mg/mL CBD),
became the first CBD-based drug that the Medicines and Healthcare
Products Regulatory Agency accepted for multiple sclerosis spasticity
treatment (2010). Through an oromucosal spray, a significant portion
of its CBD is absorbed through the gastrointestinal tract. Eight years
later, Epidiolex (100 mg/mL CBD), the first drug with CBD as the sole
active ingredient for treating rare epilepsy forms, was approved by
the Food and Drug Administration.
CBD has shown remarkable potential in inhibiting the progression
of various cancers, including glioblastoma, lung, breast, colon, prostate,
and melanoma, as demonstrated in numerous animal studies. However, CBD’s therapeutic potential
is significantly impeded by its low oral bioavailability (about 6%
in humans). Reasons for low bioavailability can include significant
first-pass metabolism in the liver, instability in the acidic gastric
pH, and poor water solubility. Interestingly, coadministration with
a high-fat meal may increase CBD’s bioavailability by up to
4-fold.
,
CBD’s high hydrophobicity, resulting
in extremely low water solubility (approximately 2.3 × 10–2 μg/mL), further restricts its practical use. To overcome these challenges, advanced delivery
systems are essential for improving the solubility and bioavailability
of lipophilic substances, such as CBD.
One promising approach to overcoming these limitations is
nanotechnology,
a rapidly advancing field that offers a promising, secure, cost-effective,
and efficient approach to revolutionizing cancer treatment strategies.
,
Nanoparticle-based drug delivery systems (DDS) enhance anticancer
therapy by targeting drugs directly to cancer cells, reducing systemic
toxicity, and improving therapeutic outcomes. Encapsulation protects
drugs from degradation, ensures controlled release, and maximizes
effectiveness while minimizing side effects. Nanoscale formulations have been widely studied to enhance lipophilic
compounds’ solubility, release profiles, and bioavailability. Nanovesicles, a subcategory of lipid-based drug
delivery systems (LBDDS), are widely used as carriers in DDS and stand
out as one of the most prevalent choices. Among these, liposomes, a well-known representative of nanovesicles,
are recognized as the first nanomedical delivery system to achieve
clinical use and gain widespread acceptance.
This review includes studies on the role of CBD in GBM. It
proposes
the use of CBD in LBDDS as a promising strategy to oppose GBM, addressing
a significant gap in existing research. To our knowledge, no one has
yet described or comprehensively summarized the research on the use
of CBD in nanovesicles
Current Treatment Strategies and Challenges in GBM
2
Current Treatment Strategies and Challenges
in GBM
Glioma, a type of primary brain tumor, includes GBM,
the most common
malignant tumor of the human CNS, and is characterized by a median
survival of fewer than 15 months.
,
The GBM’s
aggressive nature is marked by pronounced heterogeneity and uncontrolled
cell growth, significantly contributing to its poor prognosis. The intricate tumor microenvironment (TME) and
its interaction with cancer cells significantly influence GBM growth
and persistence. Adding to this challenge,
glioma-initiating cells, known as GBM stem cells (GSCs), are among
the most therapy-resistant cancer cells, further complicating treatment
outcomes.
Current therapeutic approaches,
including surgery, radiotherapy,
and chemotherapy with agents such as Temozolomide (TMZ), doxorubicin
(DOXO), and carmustine (BCNU), have demonstrated only limited effectiveness
in improving patient survival. Most GBM patients receive the Stupp
regimen, the standard since 2005, which entails maximal safe resection;
radiotherapy to 60 Gy in 2-Gy fractions, 5 days/week; concurrent TMZ
75 mg/m2; then up to six 28-day adjuvant cycles of TMZ
150–200 mg/m2 on days 1–5. Despite this standard approach, TMZ’s benefit is
limited by resistance driven by tumor-intrinsic factors (such as MGMT
expression and enhanced DNA-repair capacity) and microenvironmental
influences (including hypoxia-induced signaling and immune evasion). Beyond surgery, RT, and chemotherapy, Tumor
Treating Fields (TTFields) is a noninvasive, regional therapy for
newly diagnosed GBM (with maintenance TMZ) and for recurrent GBM (monotherapy).
Following the EF-14 trial, the U.S. FDA authorized TTFields after
chemoradiation with maintenance TMZ. TTFields deliver low-intensity
alternating electric fields that disrupt mitosis, improving progression-free
and overall survival, although real-world adoption remains modest.
,
Given GBM’s hyperemic biology with upregulated VEGFA and
HIF, VEGFA is a rational target. Bevacizumab (BEV) is a humanized
anti-VEGFA antibody with established activity in various cancers,
including colorectal, cervical, renal cell carcinoma, and nonsquamous
nonsmall cell lung cancer (NSCLC). Improves progression-free survival
in GBM but has not demonstrated an overall-survival advantage. In
recurrent GBM, combination regimens, particularly with lomustine and
radiotherapy, outperform BEV monotherapy. Additionally, predictive
factors for a better response include IDH mutation status, high tumor
burden, and the double-positive sign. The dendritic cell (DC) vaccine is an emerging immunotherapy with
supportive evidence for its use in treating glioblastoma. The Phase
III DC-vaccine trial and meta-analysis showed that the DC vaccine,
combined with standard care, was associated with significantly improved
overall survival (HR = 0.71; 95% CI, 0.57–0.88) and progression-free
survival (HR = 0.65; 95% CI, 0.43–0.98). In the subgroup of
newly diagnosed glioblastoma patients, the DC vaccine was associated
with improved progression-free survival (HR = 0.59; 95% CI, 0.39–0.90). The paucity of T cells limits the efficacy of
immunotherapy in GBM within the tumor bed, resulting from both systemic
and local immunosuppression. However, most research prioritizes the
local immunosuppressive TME, overlooking the concurrent systemic immune
suppression.
Adoptive T-cell therapy
with CAR-T cells remains a promising yet
experimental approach in GBM. These engineered T cells target defined
surface antigens and have transformed hematologic oncology since 2017;
however, translation to solid tumors is limited by antigen heterogeneity
and escape, suboptimal trafficking/penetration, and an immunosuppressive
TME.
Frustration with conventional
therapies often drives patients with
cancer to online sources touting cannabis benefits. They then trial
heterogeneous products, ranging from whole-plant extracts to purified
oils, and typically self-determine dosing. Numerous anecdotal favorable
outcomes have been described, perpetuating interest in cannabis-based
interventions.
This highlights
the urgent need to discover new therapies that
enhance chemosensitivity and improve GMB patients’ results.
,
The schematic of GBM selected characteristics is shown in Figure
.
Current Treatment Strategies and Challenges
in GBM
Glioma, a type of primary brain tumor, includes GBM,
the most common
malignant tumor of the human CNS, and is characterized by a median
survival of fewer than 15 months.
,
The GBM’s
aggressive nature is marked by pronounced heterogeneity and uncontrolled
cell growth, significantly contributing to its poor prognosis. The intricate tumor microenvironment (TME) and
its interaction with cancer cells significantly influence GBM growth
and persistence. Adding to this challenge,
glioma-initiating cells, known as GBM stem cells (GSCs), are among
the most therapy-resistant cancer cells, further complicating treatment
outcomes.
Current therapeutic approaches,
including surgery, radiotherapy,
and chemotherapy with agents such as Temozolomide (TMZ), doxorubicin
(DOXO), and carmustine (BCNU), have demonstrated only limited effectiveness
in improving patient survival. Most GBM patients receive the Stupp
regimen, the standard since 2005, which entails maximal safe resection;
radiotherapy to 60 Gy in 2-Gy fractions, 5 days/week; concurrent TMZ
75 mg/m2; then up to six 28-day adjuvant cycles of TMZ
150–200 mg/m2 on days 1–5. Despite this standard approach, TMZ’s benefit is
limited by resistance driven by tumor-intrinsic factors (such as MGMT
expression and enhanced DNA-repair capacity) and microenvironmental
influences (including hypoxia-induced signaling and immune evasion). Beyond surgery, RT, and chemotherapy, Tumor
Treating Fields (TTFields) is a noninvasive, regional therapy for
newly diagnosed GBM (with maintenance TMZ) and for recurrent GBM (monotherapy).
Following the EF-14 trial, the U.S. FDA authorized TTFields after
chemoradiation with maintenance TMZ. TTFields deliver low-intensity
alternating electric fields that disrupt mitosis, improving progression-free
and overall survival, although real-world adoption remains modest.
,
Given GBM’s hyperemic biology with upregulated VEGFA and
HIF, VEGFA is a rational target. Bevacizumab (BEV) is a humanized
anti-VEGFA antibody with established activity in various cancers,
including colorectal, cervical, renal cell carcinoma, and nonsquamous
nonsmall cell lung cancer (NSCLC). Improves progression-free survival
in GBM but has not demonstrated an overall-survival advantage. In
recurrent GBM, combination regimens, particularly with lomustine and
radiotherapy, outperform BEV monotherapy. Additionally, predictive
factors for a better response include IDH mutation status, high tumor
burden, and the double-positive sign. The dendritic cell (DC) vaccine is an emerging immunotherapy with
supportive evidence for its use in treating glioblastoma. The Phase
III DC-vaccine trial and meta-analysis showed that the DC vaccine,
combined with standard care, was associated with significantly improved
overall survival (HR = 0.71; 95% CI, 0.57–0.88) and progression-free
survival (HR = 0.65; 95% CI, 0.43–0.98). In the subgroup of
newly diagnosed glioblastoma patients, the DC vaccine was associated
with improved progression-free survival (HR = 0.59; 95% CI, 0.39–0.90). The paucity of T cells limits the efficacy of
immunotherapy in GBM within the tumor bed, resulting from both systemic
and local immunosuppression. However, most research prioritizes the
local immunosuppressive TME, overlooking the concurrent systemic immune
suppression.
Adoptive T-cell therapy
with CAR-T cells remains a promising yet
experimental approach in GBM. These engineered T cells target defined
surface antigens and have transformed hematologic oncology since 2017;
however, translation to solid tumors is limited by antigen heterogeneity
and escape, suboptimal trafficking/penetration, and an immunosuppressive
TME.
Frustration with conventional
therapies often drives patients with
cancer to online sources touting cannabis benefits. They then trial
heterogeneous products, ranging from whole-plant extracts to purified
oils, and typically self-determine dosing. Numerous anecdotal favorable
outcomes have been described, perpetuating interest in cannabis-based
interventions.
This highlights
the urgent need to discover new therapies that
enhance chemosensitivity and improve GMB patients’ results.
,
The schematic of GBM selected characteristics is shown in Figure
.
Progress and Perspectives in CBD Studies on GBM
3
Progress and Perspectives in CBD Studies on
GBM
Despite promising pharmacology, cannabinoids’
clinical use
is constrained by psychoactivity and marked lipophilicity. However,
nonpsychoactive CBD has been shown to alleviate cancer-related symptoms
and exert antitumor actions by inducing reactive oxygen species (ROS)-mediated
apoptosis, modulating autophagy, regulating immune checkpoints, inhibiting
angiogenesis, and reducing cell migration. Emerging evidence further
indicates that CBD can sensitize tumors to standard therapies, enhancing
the efficacy of chemotherapy and radiotherapy, and may act synergistically
with existing treatments in malignant brain tumors.
,
Given the therapeutic resistance of GBM and its persistently poor
survival outcomes, plant-derived agents, notably CBD, warrant evaluation
as adjuncts, or where appropriate, alternatives to current modalities.
Prospective research and rigorously designed clinical trials are necessary
to validate these observations, optimize delivery strategies (including
nanomedicine formulations), and define the therapeutic role of CBD
in glioma, with the aim of improving patient outcomes and survival.
3.1
Anticancer Molecular Pathways Modulated by
CBD in Glioma
At the molecular level, CBD’s impact
on GBM is profound. The transcription factor NF-κB promotes
cancer progression, while CBD can transform NF-κB into a tumor
suppressor. Volmar et al. discovered that CBD enhances DNA binding
of the NF-κB subunit v-rel avian reticuloendotheliosis viral
oncogene homologue A (RELA) while inhibiting its phosphorylation at
serine-311, a critical site for genetic transactivation. Additionally,
CBD sensitivity was prominent in human primary GBM stem-like cells
(hGSC) with low ROS levels. In contrast, high ROS levels in other
tumors inhibited CBD-induced hGSC death, making ROS a predictive marker
for CBD responsiveness. The transcriptional
regulator Id-1 is present in GBM cell lines and primary cultures,
and its expression is associated with heightened invasiveness. In
U251 cells, CBD concentration-dependently reduced Id-1, which correlated
with inhibition of cell invasion, with similar effects seen in primary
GBM cells. CBD altered the phosphorylation of key kinases, including
AKT, in U251 cells. CBD suppresses GBM invasion by organotypic brain
slice and decreases Id-1 expression and GBM progression in vivo. Similarly, CBD increased ROS levels in GSCs,
reducing cell survival, phosphorylated (p)-AKT, self-renewal, and
enhancing survival in GSC-bearing mice. CBD-inhibited self-renewal
was linked to p-p38 pathway activation and reduced pivotal stem cell
regulators p-STAT3, Sox2, and Id1. However, some GSCs adapted, causing
tumor regrowth. Combining CBD with system Xc (key in antioxidant response)
inhibition increased ROS, significantly reducing GSC survival, self-renewal,
and invasion. Kim et al. demonstrated
that in GBM cells (U87, U373), CBD enhanced autophagy-related protein
(LC3 II, Atg7, Beclin-1) and altered ferroptosis-related proteins
(GPX4, SLC7A11, TFRC). CBD also raised endoplasmic reticulum (ER)
stress, ROS levels, and iron accumulation while reducing Glutathione
(GSH) levels. In vitro studies showed
that CBD reduced U87-MG and T98G cell proliferation and invasiveness
by downregulating proteins linked to growth, invasion, and angiogenesis.
In U87-MG cells, CBD suppressed ERK and Akt prosurvival pathways in
a dose-dependent manner and decreased hypoxia-inducible factor (HIF-1α)
expression.
The role of TRPV channels
in mediating CBD’s effects has gained increasing attention.
The activation of transient receptor potential vanilloid type 2 (TRPV2)
has been demonstrated to reduce the growth of GBM cells and mitigate
their resistance to chemotherapy agents. Nabissi et al. showed that
CBD-induced TRPV2 activation affects glioma cell (U87MG cell line
and primary glioblastoma cells from a patient with grade IV GBM) sensitivity
to TMZ, BCNU, and DOXO. CBD enhances TRPV2 expression and activity,
modulates Ca2+ influx, increases drug uptake, and synergizes
with cytotoxic agents to apoptosis in glioma cells without affecting
normal astrocytes. In another study,
CBD upregulates acute myeloid leukemia (Aml-1) expression, crucial
in GBM growth and differentiation, through a TRPV2 and PI3K/AKT-dependent
mechanism. CBD-induced TRPV2 activation triggers autophagy, promoting
Aml-1a-dependent GSC differentiation and overcoming BCNU resistance
in GSCs. Huang et al. demonstrated that
CBD-induced calcium flux via transient receptor potential cation channel
subfamily V member 4 (TRPV4) activation was crucial for initiating
mitophagy. High TRPV4 levels were linked to more aggressive tumors
and poorer survival in patients with glioma. ER stress and the ATF4-DDIT3-TRIB3-AKT-MTOR
axis (downstream of TRPV4) contribute to CBD-induced mitophagy.
In another study, Lah et al. reported
that CBD and phytocannabinoids’
precursor in the biosynthesis, cannabigerol (CBG), affect GBM, showing
that both individually and combined induce caspase-dependent apoptosis.
They identified GPR55 and TRPV1 receptors as key targets for CBD and
CBG to remove GSCs. In patient-derived GSCs, the most effective cytotoxicity
was observed with a 3:1 molar ratio of CBG to CBD.
Marcu et al. demonstrated that CBD was more effective
than Δ9-THC
in inhibiting cell growth in SF126, U251, and U87 GBM cells, with
lower IC50 values (CBD: 1.2, 0.6, and 0.6 μmol/L,
respectively; Δ9-THC: 2.5, 3.3, and 3.3 μmol/L, respectively).
Combined treatment of CBD with Δ9-THC significantly modulated
the cell cycle, induced ROS and apoptosis, and specifically modulated
ERK and caspase activities. Δ9-THC and CBD synergistically inhibited
proliferation in U251 and SF126 cell lines, with unique effects on
signal transduction pathways not seen with either compound alone. Adding a mechanistic perspective, Kolbe et al.
investigated the effect of CBD and the GPR55 antagonist CID16020046
(CID) in effectively decreasing the reduction in Ki67 (a proliferation
marker) caused by lysophosphatidylinositol (LPI), thereby confirming
LPI’s binding to GPR55. They highlighted THC’s ability
to bind to GPR55 and suggested that CBD may act as a potential antagonist
at GPR55.
Massi et al. conducted
a study to assess the in vitro antiproliferative
effects of CBD on U87 and U373 human glioma cell lines. CBD treatment
led to a significant reduction in mitochondrial oxidative metabolism
and cell viability, in a concentration-dependent manner, with an IC50 of 25 μM (after 24 h). This effect was partially mitigated
by the CB2 receptor antagonist (SR144528; SR2) and alpha-tocopherol,
but not by the CB1 receptor antagonist (SR141716; SR1), capsazepine,
ceramide inhibitors, or pertussis toxin. CBD induced apoptosis, independent
of cannabinoid receptor antagonists. In vivo, CBD administration (0.5
mg/mouse) significantly suppressed the growth of U87 glioma cells
in nude mice. Turizo Smith et al. report
that CBD, evaluated alongside Cannabichromene, cannabigerol, and Piper nigrum derivatives, shows high-affinity binding
to glioblastoma-relevant targets GPR55 and PINK1. In in vitro assays,
CBD exerted cytotoxic effects in glioblastoma cell lines (U87MG, T98G,
CCF-STTG1), as well as in neuroblastoma (SH-SY5Y) and oligodendroglial
(MO3.13) cells, with evidence of interactions among these compounds.
The tumor-vs-normal differential expression of GPR55 and PINK1 further
underscores their value as therapeutic targets and biomarkers.
In studies with mice, the researchers
highlight the potential of
inhalation delivery of CBD for treating GBM. Khodadadi et al. exhibited
that inhaled CBD inhibited GBM tumor growth and also modified the
TME by reducing P-selectin, apelin, interleukin IL-8 and blocking
indoleamine 2,3-dioxygenase (IDO), a key immune checkpoint. Additionally,
CBD increased the expression of cluster of differentiation (CD) 103,
suggesting enhanced antigen presentation, strengthened CD8 immune
responses, and decreased the presence of innate Lymphoid Cells within
the tumor. Wang et al. underscored that
CBD treatment notably enhanced the volume of T-cell intracellular
antigen-related proteins (TIAR-1), which was closely associated with
an increase in eukaryotic translation initiation factor 2 alpha (eIF2α)
expression and phosphorylation of eIF2α (p-eIF2α)
in tissues treated with CBD compared to the placebo group (p < 0.05). Inhaled CBD markedly promoted the upregulation
of stress granules (SGs) in GBM.
CBD may modulate treatment responsiveness in cancer by altering
the PI3K/AKT/mTOR and ERK signaling pathways. Studies indicate that
combining CBD with standard chemotherapies can augment anticancer
activity via these pathway effects.
Translationally, these mechanisms map onto actionable biomarkers,
RAD51 suppression, TRPV2 activity, NF-κB/STAT3 and Wnt/β-catenin
signatures, that can guide patient selection and pharmacodynamic readouts
in early phase GBM trials.
3.2
CBD in Supportive Therapy for GBM
In clinical settings, CBD has shown promising outcomes when used
alongside standard GBM therapies. Likar et al. explored CBD as a supportive
treatment for GBM alongside standard care (surgery and radiochemotherapy).
In 2019, they demonstrated a case series of 9 brain tumor patients,
including 6 with GBM, with longer survival rates with CBD (twice daily,
dose: 100 mg, later usually increased to 200 mg). By 2021, the cohort expanded to 15 GBM patients, including
the original 6. Patients received 400–600 mg of CBD daily,
with two also taking 7.5 mg of THC. Among these patients, 46.7% (7
patients) survived for at least 24 months, and 26.7% (4 patients)
lived for at least 36 months. In 2023,
a follow-up of the same 15 GBM patients demonstrated a median survival
of 28 months and an average of 30.9 months, which is 3–5 times
longer than expected. Higher doses of CBD (400–600 mg/day)
were linked to significantly longer survival, while lower doses (200
mg/day) corresponded with survival time less than the median value.
One of the most compelling aspects of
CBD research in GBM is its ability to enhance the efficacy of standard
chemotherapies, particularly TMZ. TMZ resistance is often caused by
methylguanine DNA-methyltransferase (MGMT) overexpression and DNA
mismatch repair (MMR) deficiency. CBD and its derivative, 4′-Fluoro-cannabidiol
(4′-F-CBD), which has demonstrated enhanced activity in vivo
behavioral studies, have been shown to overcome these mechanisms in
GBM. Brookes et al. identified methylated DNA as a previously unrecognized
anticancer mechanism of CBD. Additionally, in vitro studies using
human GBM cell lines U373–V (−MGMT, +MMR) and U373-M
(+MGMT, +MMR) demonstrated synergy among imidazotetrazines (TMZ and
its analog: T25) and cannabinoids (CBD and 4′-F-CBD). CBD improved TMZ’s effectiveness in U251
and U87MG cell lines and patient-derived GBM163 cells by increasing
ROS levels, activating the ROS sensor AMP-activated protein kinase
(AMPK), and elevating the autophagy marker LC3A. CBD sensitized U87
and GBM163 intracranial tumors to TMZ and showed a considerable increase
in survival in tumor-bearing mice (the effect was absent in orthotopic
GBM models with intact MGMT expression). CBD suppressed RAD51 expression
in MGMT-methylated GBM models, suggesting a potential mechanism for
its ability to enhance tumor sensitivity to TMZ. Deng et al. investigated that CBD dose-dependently reduced
cell proliferation and viability across human GBM cell lines (T98G,
U251, U87MG), PDGF-GBM cells from a mouse model, and cultured mouse
neural progenitor cells (NPCs), exhibiting similar potency and lacking
cancer-cell selectivity, through an allosteric mechanism in all tested
cells. Combining CBD with DNA-damaging agents (TMZ, BCNU, cisplatin)
resulted in synergistic antiproliferative and cytotoxic effects within
a specific concentration range in the used cell lines. However, low
concentrations caused antagonistic effects in some human and mouse
GBM cells. Kosgodage et al. exhibited
that CBD with TMZ increased antioncogenic miR126 while decreasing
pro-oncogenic miR21 expression in GBM cells and GBM-derived extracellular
vesicles (EVs), in comparison with treatment with only TMZ. CBD treatment
reduced prohibitin (PHB), a protein involved in mitochondrial protection
and chemoresistance in GBM cells. Additionally,
combining CBD with TMZ synergistically inhibited tumor growth in patient-derived
GBM cultures and glioma cell lines (U251, U87 MG, LN18, and GL261).
In U87MG, U118MG, and T98G cell lines,
CBD with γ-irradiation
and KU60019 (ATM kinase inhibitor) increased apoptosis, G2/M cell
cycle arrest, inhibited proliferation, and induced pro-inflammatory
cytokine production, leading to apoptotic and inflammation-linked
cell death. CBD-activated JNK-AP1, which has active NF-κB pathways,
increased DR5/TRAIL-R2 gene and protein expression and enhanced GBM
cell sensitivity to TRAIL-induced apoptosis. CBD significantly reduced
PD-L1 surface levels in GBM cells, a key T-lymphocyte immune checkpoint.
TS543 human proneural glioma neurospheres showed significant sensitivity
to CBD-induced cell death, which was further enhanced when combined
with γ-irradiation and KU60019.
Scott et al. studied the effects of THC and CBD, alone and
combined
with radiotherapy, on human GBM cell lines (T98G, U87MG) and the mouse
glioma cell line (GL261). Cannabinoids were tested as pure (P) and
botanical drug substances (BDS). THC-BDS was more effective than THC-P,
while CBD-P outperformed CBD-BDS. Pretreating cells with CBD-P and
THC-P together preirradiation enhanced radiosensitivity compared to
pretreating the cannabinoids individually. The enhanced radiosensitivity
was linked with increased autophagy and apoptosis markers. In vivo,
the combination of CBD, THC, and irradiation notably restrained tumor
progression in an orthotopic syngeneic model. Using GBM cell lines (U87MG, U118MG, and T98G), scientists exhibited
that CBD-mediated signaling can amplify γ-irradiation-induced
cell death in GBM while having minimal impact on neural stem/progenitor
cells and astrocytes. MAPK p38 was a major driver of CBD-induced cell
death, whereas death levels after CBD + radiation treatment depended
on MAPK p38 and JNK, which regulate endogenous TRAIL expression. CBD
upregulated TNF/TNFR1 and TRAIL/TRAIL-R2 signaling (via ligand and
receptor modulation) and apoptosis. NF-κB p65-P(Ser536) was
not a primary CBD target level of this factor, which was high in CBD-treated
GBM cells, but its inhibition enhanced CBD-induced apoptosis.
Scientists noticed that CBD significantly
amplifies THC-induced
autophagy, indicating its role in supporting THC’s autophagy
activation pathway. CBD, in combination with THC, potentiates the
antitumor effects of THC, thus potentially resulting in a reduced
THC dose and a diminished incidence of psychoactive side effects in
cannabinoid-based therapeutic regimens. Additionally, Sativex, currently
used for palliative care in cancer and multiple sclerosis patients,
alone or combined with TMZ, shows potential in managing GBM. López-Valero et al. found that combining
oral administration of extracts containing equal amounts of THC and
CBD (Sativex-like) with TMZ significantly reduced tumor growth in
subcutaneous and intracranial U87MG glioma xenografts. However, combining
Sativex-like extracts with BCNU offered no more significant benefit
than using each treatment alone. In another
scientific study, TMZ combined with THC:CBD mixtures (especially those
with a higher CBD ratio but not TMZ combined with CBD only) achieved
antitumor effects comparable to the THC:CBD (1:1 ratio) in U87MG glioma
cell-derived xenografts. TMZ with a THC:CBD (1:1 ratio) inhibited
the growth of orthotopic xenografts created with Glioma Initiating
Cells (GICs) derived from GBM patient and improved survival in animals
with these intracranial xenografts. Similarly,
Torres et al. exhibited that coapplication of TMZ with submaximal
doses of THC + CBD or a Sativex-like mixture (unlike CBD alone) significantly
inhibited the growth of U87MG and T98G xenografts. Lower doses of
THC + CBD enhanced TMZ’s antitumor effects and overcame glioma
xenografts’ resistance to TMZ.
3.3
Clinical Evidence for CBD in GBM
The current clinical evidence for CBD-containing interventions in
GBM is limited but generates rationale for further study. In a randomized
phase 1b study, adding a balanced THC:CBD oromucosal spray (nabiximols)
to dose-intense TMZ at first recurrence yielded an acceptable safety
profile and a signal for improved 12-month survival versus placebo,
motivating confirmatory trials. A pivotal,
biomarker-enriched, double-blind phase II trial (ARISTOCRAT) is underway
to test nabiximols plus TMZ in recurrent MGMT-methylated GBM, with
overall survival, progression-free survival, and HRQoL as key end
points; its design directly addresses the limitations of earlier small
studies. By contrast, a randomized trial
of a high-CBD, full-spectrum hemp product in newly diagnosed GBM prioritized
symptomatic end points and was terminated for low enrollment, underscoring
operational hurdles and the need for oncology-centric outcomes. Prospective observational data with adjunct
purified oral CBD suggest feasibility and reassuring tolerability
with hypothesis-generating survival times, but causal inference is
precluded by the nonrandomized design. A phase II study in high-grade glioma comparing fixed THC:CBD ratios
showed good tolerability and improvements in selected patient-reported
outcomes, with a 1:1 ratio favoredfindings that inform supportive-care
domains but are not themselves definitive for antitumor efficacy. Collectively, the evidence base is constrained
by small sample sizes, heterogeneous formulations (purified CBD vs
THC:CBD combinations), variable dosing/titration schemes, and inconsistent
primary end points, which complicate cross-study comparisons. Systematic
and narrative reviews converge on the conclusion that while preclinical
anticancer activity of cannabinoids is plausible, robust clinical
proof of efficacy in GBM remains unestablished. At the same time, mechanistic work identifies CBD-responsive
pathways (e.g., modulation of NF-κB activity) that could guide
biomarker-driven trials. Future studies
should be adequately powered, stratified by molecular features (e.g.,
MGMT status, IDH mutation), and integrate PK/PD, CNS penetration,
steroid exposure, and tumor-microenvironment readouts. Given challenges
posed by the blood–brain barrier (BBB) and intratumoral heterogeneity,
advanced delivery strategies (e.g., vesicular lipid systems and other
nanoformulations of CBD) merit early phase clinical translation following
encouraging preclinical data -provided that formulations, dosing algorithms,
and clinically meaningful end points are standardized to enable rigorous
efficacy testing within multimodal GBM care.
Kenyon et al. emphasized nominating pharmaceutical-grade synthetic
CBD as a potential therapy for breast cancer and glioma based on the
evaluation of pharmaceutical-grade synthetic CBD (oily drops at 5%
(w/v)) across 119 cancer patients (including 7 with GBM) using routinely
collected data over four years. Clinical responses were observed in
92% of solid-tumor cases, as evidenced by reductions in circulating
tumor cells and, in other patients, a decrease in tumor size. Additionally,
they have no adverse effects.
Table
summarizes
the key clinical trials and cohort studies investigating CBD alone
or THC:CBD combinations.
3.4
Nanotechnology to CBD Delivery in Glioma Context
Nanotechnology has been identified as a promising solution to maximize
the therapeutic potential of different substances and overcome the
challenges associated with their delivery in GBM. In this context,
CBD is particularly amenable to nanomedicine-based formulations. Currently, the number of studies using CBD in
GBM using nanotechnology is limited, including using nanocarriers,
nanoemulsions, nanoparticles (NPs), patches with NPs, nanocapsules,
and liposomes.
Zhou et al. designed “Nano-reshaper,”
a nanocarrier coencapsulating CBD (to alleviate lymphopenia) and the
T-cell–recruiting cytokine LIGHT. Nanoreshaper expanded systemic
T-cell pools and enhanced local T-cell recruitment, resulting in a
marked increase in intratumoral T-cell infiltration. In GBM mouse
models (males), combining Nanoreshaper with an immune checkpoint inhibitor
yielded 83.3% long-term, recurrence-free survivors.
Nanoemulsions, colloidal dispersions, can be used
as drug carriers,
mainly for molecules with a low solubility in water, composed of excipients
of a safe quality. Borges et al. pointed
to using multicharged nanoemulsions containing CBD in combination
with photoactive agents. Tumorigenic (U87MG) and nontumorigenic (T98G)
GBM cell lines demonstrated dose-dependent cytotoxic effects when
exposed to the multicharged nanoemulsion NE-PIC (containing CBD, Protoporphyrin,
and Indocyanine). As the CBD concentration in the nanoemulsion increased
(from 0.5 to 4 mM), viability in both cell lines dropped significantly
by more than 35% relative to untreated controls. Mobaleghol Eslam et al. developed a nanoemulsion containing
the two drugs (NED) to enhance THC and CBD delivery in a rat C6 glioblastoma
model. They benchmarked it against bulk drugs and a drug-free nanoemulsion
(NE). The optimized NED measured 29 ± 6 nm, improving the hemocompatibility
of the drugs. In vivo MRI and survival analyses revealed a ∼4-fold
smaller tumor volume on day 7 compared to the control, and markedly
prolonged survival: control, 9 days; bulk, 4 days; NE, 12.5 days;
NED, 51 days.
NPs with diameters
less than 100 nm can be effective DDS, particularly
for chemotherapy. Kuźmińska
et al. developed PLGA-based NPs to codeliver Etoricoxib (ETO) and
CBD, which significantly decreased cell (T98G, U-138 MG) viability
in a dose-dependent manner and triggered apoptosis. The T98G cell
line exhibited that ETO and CBD caused alterations in cell-cycle phase
distribution following 24 h of incubation. CBD significantly alters
cell-cycle distribution by increasing G1/G0 phase cells and decreasing
those in S and G2/M phases in both lines (particularly at a 25 μM
concentration; T98G cell line). Furthermore, intracellular accumulation
of substances in NP-treated cancer cells was notably higher than treated
with free substances, with CBD increasing 3.31-fold. In another study using NPs, Muresan et al. developed polymeric
microneedle (MN) patches loaded with CBD or olaparib NPs, designed
for insertion into brain resection cavities after tumor removal (isocitrate
dehydrogenase wildtype glioblastoma), allowing the substances to diffuse
up to 0.6 cm into brain tissue.
Freire et al. showed that environmentally friendly PBS NPs loaded
with CBD (CBD-PBS), but not empty PBS particles, produced a dose-dependent
loss of viability in glioma lines (U118MG, U87MG). The formulation
released ∼50% of CBD within hours, supporting controlled delivery
and improved bioavailability. Both free and PBS-encapsulated CBD similarly
decreased AKT Ser473 phosphorylation and increased LC3-II, confirming
that nanoencapsulation preserves CBD’s signaling effects. Sun et al. developed GZCX (particles approximately
200 nm), a dual receptor–mediated, BBB-permeable carrier coloading
Gboxin, a drug that was designed to inhibit the process of oxidative
phosphorylation in GBM cells, and CBD for GBM treatment. GZCX achieved
a 10-fold increase in brain Gboxin accumulation. In GBM-bearing mice,
GZCX increased apoptosis, reduced angiogenesis, decreased tumor burden
3.7-fold, and prolonged survival. They emphasized the combined CLTX–CBD–mediated
BBB penetration and GBM targeting, as well as receptor-mediated BBB
transport by CLTX.
In another work,
researchers evaluated THC- and CBD-loaded poly-ε-caprolactone
microparticles (particles approximately 50 μm) as a long-term
delivery system in a murine glioma xenograft model. In vitro, microencapsulation
enabled the sustained release of cannabinoids over several days. In
vivo, in mice with glioma xenografts, local administration of THC,
CBD, or a 1:1 (w/w) THC:CBD mix every 5 days suppressed tumor growth
as effectively as daily local dosing of equivalent cannabinoid solutions.
Treated tumors exhibited increased apoptosis, reduced proliferation,
and decreased angiogenesis. Sharma et
al. encapsulated CBD in magnesium-gallate metal–organic framework
(MOF) microparticles (CBD/Mg-gallate-MOF), predominantly <2 μm.
They achieved ∼65% CBD release at pH 7.2; this suppressed the
viability of the rat glioma brain cancer (C6) cell line. CBD/Mg-GA
exhibits anticancer activity by significantly increasing ROS and suppressing
anti-inflammatory signaling, as evidenced by reduced TNF-α levels.
Mechanistically, it modulates NF-κB, thereby initiating apoptotic
cascades in glioma cells. In an in vitro BBB model, treatment reduced
transendothelial electrical resistance (TEER) by 53.1%, indicating
potential BBB penetration.
Aparicio-Blanco
et al. engineered PIT-made, monodisperse lipid
nanocapsules (LNCs) decorated with nonpsychotropic cannabinoids and
showed that the smallest constructs achieved the highest brain transcytosis.
CBD conjugation enhances brain targeting 6-fold compared to G-Technology,
the leading brain-active strategy already in clinical trials for CNS
disorders. In U373MG assays, CBD-incorporated
LNCs revealed strong size and surface effects: 20 nm LNCs lowered
IC50 3-fold versus 50 nm carriers; CBD decoration increased
glioma targeting 3.4-fold; and combining CBD loading with CBD surface
functionalization further reduced IC50.
Another study demonstrated the potential of coloading
ACT with
selected phytochemicals (e.g., CBD) into cationic DOTAP:POPC liposomes.
The nanoformulations were uniform and stable for 21 days, showing
narrow size distributions, PDI < 0.3, and a negative zeta potential;
vesicle diameters were <200 nm, supporting prospective clinical
use, including GBM therapy. Encapsulation efficiency exceeded 84%.
CBD-modulated liposomal molecular dynamics reduced molecular mobility
and strengthened interaction networks, thereby adjusting particle
size, whereas ACT alone retained the most excellent flexibility. Liposomes
showed higher IC50 values in MRC-5 fibroblasts than in
U-87 MG and U-138 MG glioma cells, indicating tumor-selective cytotoxicity;
the ACT + CBD system achieved IC50 = 7 μM (U-87 MG)
and 6 μM (U-138 MG) at 48 h, while the DOTAP:POPC control displayed
higher IC50 and lower cytotoxicity. In glioma cells, ACT
+ CBD liposomes increased pro-apoptotic Bax and decreased antiapoptotic
Bcl-xL in a dose- and time-dependent manner; the control had minimal
effect. Rybarczyk et al. reported in
a study using U-138 MG and T98G cell lines that CBD-, Celecoxib-,
and 2,5-dimethylcelecoxib-containing liposomes exert robust anti-GBM
effects by triggering apoptosis, oxidative stress, and modulating
key signaling cascades. While coloading CBD with Celecoxib or 2,5-Dimethylcelecoxib
did not yield clear synergistic or additive benefits, the CBD + Celecoxib
combination suppressed Wnt/β-catenin and NF-κB signaling
while activating the Nrf2 pathway.
Table
provides
a comprehensive summary of studies focused on the application of CBD
formulations in glioma treatment. The table compares various formulations,
models, and key outcomes, highlighting their effectiveness in improving
CBD delivery, overcoming the blood-brain barrier, and enhancing therapeutic
efficacy.
The CBD research in GBM, molecular mechanisms, role
in supportive
therapy, and nanotechnology-based delivery strategies are shown in Figure
.
Progress and Perspectives in CBD Studies on
GBM
Despite promising pharmacology, cannabinoids’
clinical use
is constrained by psychoactivity and marked lipophilicity. However,
nonpsychoactive CBD has been shown to alleviate cancer-related symptoms
and exert antitumor actions by inducing reactive oxygen species (ROS)-mediated
apoptosis, modulating autophagy, regulating immune checkpoints, inhibiting
angiogenesis, and reducing cell migration. Emerging evidence further
indicates that CBD can sensitize tumors to standard therapies, enhancing
the efficacy of chemotherapy and radiotherapy, and may act synergistically
with existing treatments in malignant brain tumors.
,
Given the therapeutic resistance of GBM and its persistently poor
survival outcomes, plant-derived agents, notably CBD, warrant evaluation
as adjuncts, or where appropriate, alternatives to current modalities.
Prospective research and rigorously designed clinical trials are necessary
to validate these observations, optimize delivery strategies (including
nanomedicine formulations), and define the therapeutic role of CBD
in glioma, with the aim of improving patient outcomes and survival.
3.1
Anticancer Molecular Pathways Modulated by
CBD in Glioma
At the molecular level, CBD’s impact
on GBM is profound. The transcription factor NF-κB promotes
cancer progression, while CBD can transform NF-κB into a tumor
suppressor. Volmar et al. discovered that CBD enhances DNA binding
of the NF-κB subunit v-rel avian reticuloendotheliosis viral
oncogene homologue A (RELA) while inhibiting its phosphorylation at
serine-311, a critical site for genetic transactivation. Additionally,
CBD sensitivity was prominent in human primary GBM stem-like cells
(hGSC) with low ROS levels. In contrast, high ROS levels in other
tumors inhibited CBD-induced hGSC death, making ROS a predictive marker
for CBD responsiveness. The transcriptional
regulator Id-1 is present in GBM cell lines and primary cultures,
and its expression is associated with heightened invasiveness. In
U251 cells, CBD concentration-dependently reduced Id-1, which correlated
with inhibition of cell invasion, with similar effects seen in primary
GBM cells. CBD altered the phosphorylation of key kinases, including
AKT, in U251 cells. CBD suppresses GBM invasion by organotypic brain
slice and decreases Id-1 expression and GBM progression in vivo. Similarly, CBD increased ROS levels in GSCs,
reducing cell survival, phosphorylated (p)-AKT, self-renewal, and
enhancing survival in GSC-bearing mice. CBD-inhibited self-renewal
was linked to p-p38 pathway activation and reduced pivotal stem cell
regulators p-STAT3, Sox2, and Id1. However, some GSCs adapted, causing
tumor regrowth. Combining CBD with system Xc (key in antioxidant response)
inhibition increased ROS, significantly reducing GSC survival, self-renewal,
and invasion. Kim et al. demonstrated
that in GBM cells (U87, U373), CBD enhanced autophagy-related protein
(LC3 II, Atg7, Beclin-1) and altered ferroptosis-related proteins
(GPX4, SLC7A11, TFRC). CBD also raised endoplasmic reticulum (ER)
stress, ROS levels, and iron accumulation while reducing Glutathione
(GSH) levels. In vitro studies showed
that CBD reduced U87-MG and T98G cell proliferation and invasiveness
by downregulating proteins linked to growth, invasion, and angiogenesis.
In U87-MG cells, CBD suppressed ERK and Akt prosurvival pathways in
a dose-dependent manner and decreased hypoxia-inducible factor (HIF-1α)
expression.
The role of TRPV channels
in mediating CBD’s effects has gained increasing attention.
The activation of transient receptor potential vanilloid type 2 (TRPV2)
has been demonstrated to reduce the growth of GBM cells and mitigate
their resistance to chemotherapy agents. Nabissi et al. showed that
CBD-induced TRPV2 activation affects glioma cell (U87MG cell line
and primary glioblastoma cells from a patient with grade IV GBM) sensitivity
to TMZ, BCNU, and DOXO. CBD enhances TRPV2 expression and activity,
modulates Ca2+ influx, increases drug uptake, and synergizes
with cytotoxic agents to apoptosis in glioma cells without affecting
normal astrocytes. In another study,
CBD upregulates acute myeloid leukemia (Aml-1) expression, crucial
in GBM growth and differentiation, through a TRPV2 and PI3K/AKT-dependent
mechanism. CBD-induced TRPV2 activation triggers autophagy, promoting
Aml-1a-dependent GSC differentiation and overcoming BCNU resistance
in GSCs. Huang et al. demonstrated that
CBD-induced calcium flux via transient receptor potential cation channel
subfamily V member 4 (TRPV4) activation was crucial for initiating
mitophagy. High TRPV4 levels were linked to more aggressive tumors
and poorer survival in patients with glioma. ER stress and the ATF4-DDIT3-TRIB3-AKT-MTOR
axis (downstream of TRPV4) contribute to CBD-induced mitophagy.
In another study, Lah et al. reported
that CBD and phytocannabinoids’
precursor in the biosynthesis, cannabigerol (CBG), affect GBM, showing
that both individually and combined induce caspase-dependent apoptosis.
They identified GPR55 and TRPV1 receptors as key targets for CBD and
CBG to remove GSCs. In patient-derived GSCs, the most effective cytotoxicity
was observed with a 3:1 molar ratio of CBG to CBD.
Marcu et al. demonstrated that CBD was more effective
than Δ9-THC
in inhibiting cell growth in SF126, U251, and U87 GBM cells, with
lower IC50 values (CBD: 1.2, 0.6, and 0.6 μmol/L,
respectively; Δ9-THC: 2.5, 3.3, and 3.3 μmol/L, respectively).
Combined treatment of CBD with Δ9-THC significantly modulated
the cell cycle, induced ROS and apoptosis, and specifically modulated
ERK and caspase activities. Δ9-THC and CBD synergistically inhibited
proliferation in U251 and SF126 cell lines, with unique effects on
signal transduction pathways not seen with either compound alone. Adding a mechanistic perspective, Kolbe et al.
investigated the effect of CBD and the GPR55 antagonist CID16020046
(CID) in effectively decreasing the reduction in Ki67 (a proliferation
marker) caused by lysophosphatidylinositol (LPI), thereby confirming
LPI’s binding to GPR55. They highlighted THC’s ability
to bind to GPR55 and suggested that CBD may act as a potential antagonist
at GPR55.
Massi et al. conducted
a study to assess the in vitro antiproliferative
effects of CBD on U87 and U373 human glioma cell lines. CBD treatment
led to a significant reduction in mitochondrial oxidative metabolism
and cell viability, in a concentration-dependent manner, with an IC50 of 25 μM (after 24 h). This effect was partially mitigated
by the CB2 receptor antagonist (SR144528; SR2) and alpha-tocopherol,
but not by the CB1 receptor antagonist (SR141716; SR1), capsazepine,
ceramide inhibitors, or pertussis toxin. CBD induced apoptosis, independent
of cannabinoid receptor antagonists. In vivo, CBD administration (0.5
mg/mouse) significantly suppressed the growth of U87 glioma cells
in nude mice. Turizo Smith et al. report
that CBD, evaluated alongside Cannabichromene, cannabigerol, and Piper nigrum derivatives, shows high-affinity binding
to glioblastoma-relevant targets GPR55 and PINK1. In in vitro assays,
CBD exerted cytotoxic effects in glioblastoma cell lines (U87MG, T98G,
CCF-STTG1), as well as in neuroblastoma (SH-SY5Y) and oligodendroglial
(MO3.13) cells, with evidence of interactions among these compounds.
The tumor-vs-normal differential expression of GPR55 and PINK1 further
underscores their value as therapeutic targets and biomarkers.
In studies with mice, the researchers
highlight the potential of
inhalation delivery of CBD for treating GBM. Khodadadi et al. exhibited
that inhaled CBD inhibited GBM tumor growth and also modified the
TME by reducing P-selectin, apelin, interleukin IL-8 and blocking
indoleamine 2,3-dioxygenase (IDO), a key immune checkpoint. Additionally,
CBD increased the expression of cluster of differentiation (CD) 103,
suggesting enhanced antigen presentation, strengthened CD8 immune
responses, and decreased the presence of innate Lymphoid Cells within
the tumor. Wang et al. underscored that
CBD treatment notably enhanced the volume of T-cell intracellular
antigen-related proteins (TIAR-1), which was closely associated with
an increase in eukaryotic translation initiation factor 2 alpha (eIF2α)
expression and phosphorylation of eIF2α (p-eIF2α)
in tissues treated with CBD compared to the placebo group (p < 0.05). Inhaled CBD markedly promoted the upregulation
of stress granules (SGs) in GBM.
CBD may modulate treatment responsiveness in cancer by altering
the PI3K/AKT/mTOR and ERK signaling pathways. Studies indicate that
combining CBD with standard chemotherapies can augment anticancer
activity via these pathway effects.
Translationally, these mechanisms map onto actionable biomarkers,
RAD51 suppression, TRPV2 activity, NF-κB/STAT3 and Wnt/β-catenin
signatures, that can guide patient selection and pharmacodynamic readouts
in early phase GBM trials.
3.2
CBD in Supportive Therapy for GBM
In clinical settings, CBD has shown promising outcomes when used
alongside standard GBM therapies. Likar et al. explored CBD as a supportive
treatment for GBM alongside standard care (surgery and radiochemotherapy).
In 2019, they demonstrated a case series of 9 brain tumor patients,
including 6 with GBM, with longer survival rates with CBD (twice daily,
dose: 100 mg, later usually increased to 200 mg). By 2021, the cohort expanded to 15 GBM patients, including
the original 6. Patients received 400–600 mg of CBD daily,
with two also taking 7.5 mg of THC. Among these patients, 46.7% (7
patients) survived for at least 24 months, and 26.7% (4 patients)
lived for at least 36 months. In 2023,
a follow-up of the same 15 GBM patients demonstrated a median survival
of 28 months and an average of 30.9 months, which is 3–5 times
longer than expected. Higher doses of CBD (400–600 mg/day)
were linked to significantly longer survival, while lower doses (200
mg/day) corresponded with survival time less than the median value.
One of the most compelling aspects of
CBD research in GBM is its ability to enhance the efficacy of standard
chemotherapies, particularly TMZ. TMZ resistance is often caused by
methylguanine DNA-methyltransferase (MGMT) overexpression and DNA
mismatch repair (MMR) deficiency. CBD and its derivative, 4′-Fluoro-cannabidiol
(4′-F-CBD), which has demonstrated enhanced activity in vivo
behavioral studies, have been shown to overcome these mechanisms in
GBM. Brookes et al. identified methylated DNA as a previously unrecognized
anticancer mechanism of CBD. Additionally, in vitro studies using
human GBM cell lines U373–V (−MGMT, +MMR) and U373-M
(+MGMT, +MMR) demonstrated synergy among imidazotetrazines (TMZ and
its analog: T25) and cannabinoids (CBD and 4′-F-CBD). CBD improved TMZ’s effectiveness in U251
and U87MG cell lines and patient-derived GBM163 cells by increasing
ROS levels, activating the ROS sensor AMP-activated protein kinase
(AMPK), and elevating the autophagy marker LC3A. CBD sensitized U87
and GBM163 intracranial tumors to TMZ and showed a considerable increase
in survival in tumor-bearing mice (the effect was absent in orthotopic
GBM models with intact MGMT expression). CBD suppressed RAD51 expression
in MGMT-methylated GBM models, suggesting a potential mechanism for
its ability to enhance tumor sensitivity to TMZ. Deng et al. investigated that CBD dose-dependently reduced
cell proliferation and viability across human GBM cell lines (T98G,
U251, U87MG), PDGF-GBM cells from a mouse model, and cultured mouse
neural progenitor cells (NPCs), exhibiting similar potency and lacking
cancer-cell selectivity, through an allosteric mechanism in all tested
cells. Combining CBD with DNA-damaging agents (TMZ, BCNU, cisplatin)
resulted in synergistic antiproliferative and cytotoxic effects within
a specific concentration range in the used cell lines. However, low
concentrations caused antagonistic effects in some human and mouse
GBM cells. Kosgodage et al. exhibited
that CBD with TMZ increased antioncogenic miR126 while decreasing
pro-oncogenic miR21 expression in GBM cells and GBM-derived extracellular
vesicles (EVs), in comparison with treatment with only TMZ. CBD treatment
reduced prohibitin (PHB), a protein involved in mitochondrial protection
and chemoresistance in GBM cells. Additionally,
combining CBD with TMZ synergistically inhibited tumor growth in patient-derived
GBM cultures and glioma cell lines (U251, U87 MG, LN18, and GL261).
In U87MG, U118MG, and T98G cell lines,
CBD with γ-irradiation
and KU60019 (ATM kinase inhibitor) increased apoptosis, G2/M cell
cycle arrest, inhibited proliferation, and induced pro-inflammatory
cytokine production, leading to apoptotic and inflammation-linked
cell death. CBD-activated JNK-AP1, which has active NF-κB pathways,
increased DR5/TRAIL-R2 gene and protein expression and enhanced GBM
cell sensitivity to TRAIL-induced apoptosis. CBD significantly reduced
PD-L1 surface levels in GBM cells, a key T-lymphocyte immune checkpoint.
TS543 human proneural glioma neurospheres showed significant sensitivity
to CBD-induced cell death, which was further enhanced when combined
with γ-irradiation and KU60019.
Scott et al. studied the effects of THC and CBD, alone and
combined
with radiotherapy, on human GBM cell lines (T98G, U87MG) and the mouse
glioma cell line (GL261). Cannabinoids were tested as pure (P) and
botanical drug substances (BDS). THC-BDS was more effective than THC-P,
while CBD-P outperformed CBD-BDS. Pretreating cells with CBD-P and
THC-P together preirradiation enhanced radiosensitivity compared to
pretreating the cannabinoids individually. The enhanced radiosensitivity
was linked with increased autophagy and apoptosis markers. In vivo,
the combination of CBD, THC, and irradiation notably restrained tumor
progression in an orthotopic syngeneic model. Using GBM cell lines (U87MG, U118MG, and T98G), scientists exhibited
that CBD-mediated signaling can amplify γ-irradiation-induced
cell death in GBM while having minimal impact on neural stem/progenitor
cells and astrocytes. MAPK p38 was a major driver of CBD-induced cell
death, whereas death levels after CBD + radiation treatment depended
on MAPK p38 and JNK, which regulate endogenous TRAIL expression. CBD
upregulated TNF/TNFR1 and TRAIL/TRAIL-R2 signaling (via ligand and
receptor modulation) and apoptosis. NF-κB p65-P(Ser536) was
not a primary CBD target level of this factor, which was high in CBD-treated
GBM cells, but its inhibition enhanced CBD-induced apoptosis.
Scientists noticed that CBD significantly
amplifies THC-induced
autophagy, indicating its role in supporting THC’s autophagy
activation pathway. CBD, in combination with THC, potentiates the
antitumor effects of THC, thus potentially resulting in a reduced
THC dose and a diminished incidence of psychoactive side effects in
cannabinoid-based therapeutic regimens. Additionally, Sativex, currently
used for palliative care in cancer and multiple sclerosis patients,
alone or combined with TMZ, shows potential in managing GBM. López-Valero et al. found that combining
oral administration of extracts containing equal amounts of THC and
CBD (Sativex-like) with TMZ significantly reduced tumor growth in
subcutaneous and intracranial U87MG glioma xenografts. However, combining
Sativex-like extracts with BCNU offered no more significant benefit
than using each treatment alone. In another
scientific study, TMZ combined with THC:CBD mixtures (especially those
with a higher CBD ratio but not TMZ combined with CBD only) achieved
antitumor effects comparable to the THC:CBD (1:1 ratio) in U87MG glioma
cell-derived xenografts. TMZ with a THC:CBD (1:1 ratio) inhibited
the growth of orthotopic xenografts created with Glioma Initiating
Cells (GICs) derived from GBM patient and improved survival in animals
with these intracranial xenografts. Similarly,
Torres et al. exhibited that coapplication of TMZ with submaximal
doses of THC + CBD or a Sativex-like mixture (unlike CBD alone) significantly
inhibited the growth of U87MG and T98G xenografts. Lower doses of
THC + CBD enhanced TMZ’s antitumor effects and overcame glioma
xenografts’ resistance to TMZ.
3.3
Clinical Evidence for CBD in GBM
The current clinical evidence for CBD-containing interventions in
GBM is limited but generates rationale for further study. In a randomized
phase 1b study, adding a balanced THC:CBD oromucosal spray (nabiximols)
to dose-intense TMZ at first recurrence yielded an acceptable safety
profile and a signal for improved 12-month survival versus placebo,
motivating confirmatory trials. A pivotal,
biomarker-enriched, double-blind phase II trial (ARISTOCRAT) is underway
to test nabiximols plus TMZ in recurrent MGMT-methylated GBM, with
overall survival, progression-free survival, and HRQoL as key end
points; its design directly addresses the limitations of earlier small
studies. By contrast, a randomized trial
of a high-CBD, full-spectrum hemp product in newly diagnosed GBM prioritized
symptomatic end points and was terminated for low enrollment, underscoring
operational hurdles and the need for oncology-centric outcomes. Prospective observational data with adjunct
purified oral CBD suggest feasibility and reassuring tolerability
with hypothesis-generating survival times, but causal inference is
precluded by the nonrandomized design. A phase II study in high-grade glioma comparing fixed THC:CBD ratios
showed good tolerability and improvements in selected patient-reported
outcomes, with a 1:1 ratio favoredfindings that inform supportive-care
domains but are not themselves definitive for antitumor efficacy. Collectively, the evidence base is constrained
by small sample sizes, heterogeneous formulations (purified CBD vs
THC:CBD combinations), variable dosing/titration schemes, and inconsistent
primary end points, which complicate cross-study comparisons. Systematic
and narrative reviews converge on the conclusion that while preclinical
anticancer activity of cannabinoids is plausible, robust clinical
proof of efficacy in GBM remains unestablished. At the same time, mechanistic work identifies CBD-responsive
pathways (e.g., modulation of NF-κB activity) that could guide
biomarker-driven trials. Future studies
should be adequately powered, stratified by molecular features (e.g.,
MGMT status, IDH mutation), and integrate PK/PD, CNS penetration,
steroid exposure, and tumor-microenvironment readouts. Given challenges
posed by the blood–brain barrier (BBB) and intratumoral heterogeneity,
advanced delivery strategies (e.g., vesicular lipid systems and other
nanoformulations of CBD) merit early phase clinical translation following
encouraging preclinical data -provided that formulations, dosing algorithms,
and clinically meaningful end points are standardized to enable rigorous
efficacy testing within multimodal GBM care.
Kenyon et al. emphasized nominating pharmaceutical-grade synthetic
CBD as a potential therapy for breast cancer and glioma based on the
evaluation of pharmaceutical-grade synthetic CBD (oily drops at 5%
(w/v)) across 119 cancer patients (including 7 with GBM) using routinely
collected data over four years. Clinical responses were observed in
92% of solid-tumor cases, as evidenced by reductions in circulating
tumor cells and, in other patients, a decrease in tumor size. Additionally,
they have no adverse effects.
Table
summarizes
the key clinical trials and cohort studies investigating CBD alone
or THC:CBD combinations.
3.4
Nanotechnology to CBD Delivery in Glioma Context
Nanotechnology has been identified as a promising solution to maximize
the therapeutic potential of different substances and overcome the
challenges associated with their delivery in GBM. In this context,
CBD is particularly amenable to nanomedicine-based formulations. Currently, the number of studies using CBD in
GBM using nanotechnology is limited, including using nanocarriers,
nanoemulsions, nanoparticles (NPs), patches with NPs, nanocapsules,
and liposomes.
Zhou et al. designed “Nano-reshaper,”
a nanocarrier coencapsulating CBD (to alleviate lymphopenia) and the
T-cell–recruiting cytokine LIGHT. Nanoreshaper expanded systemic
T-cell pools and enhanced local T-cell recruitment, resulting in a
marked increase in intratumoral T-cell infiltration. In GBM mouse
models (males), combining Nanoreshaper with an immune checkpoint inhibitor
yielded 83.3% long-term, recurrence-free survivors.
Nanoemulsions, colloidal dispersions, can be used
as drug carriers,
mainly for molecules with a low solubility in water, composed of excipients
of a safe quality. Borges et al. pointed
to using multicharged nanoemulsions containing CBD in combination
with photoactive agents. Tumorigenic (U87MG) and nontumorigenic (T98G)
GBM cell lines demonstrated dose-dependent cytotoxic effects when
exposed to the multicharged nanoemulsion NE-PIC (containing CBD, Protoporphyrin,
and Indocyanine). As the CBD concentration in the nanoemulsion increased
(from 0.5 to 4 mM), viability in both cell lines dropped significantly
by more than 35% relative to untreated controls. Mobaleghol Eslam et al. developed a nanoemulsion containing
the two drugs (NED) to enhance THC and CBD delivery in a rat C6 glioblastoma
model. They benchmarked it against bulk drugs and a drug-free nanoemulsion
(NE). The optimized NED measured 29 ± 6 nm, improving the hemocompatibility
of the drugs. In vivo MRI and survival analyses revealed a ∼4-fold
smaller tumor volume on day 7 compared to the control, and markedly
prolonged survival: control, 9 days; bulk, 4 days; NE, 12.5 days;
NED, 51 days.
NPs with diameters
less than 100 nm can be effective DDS, particularly
for chemotherapy. Kuźmińska
et al. developed PLGA-based NPs to codeliver Etoricoxib (ETO) and
CBD, which significantly decreased cell (T98G, U-138 MG) viability
in a dose-dependent manner and triggered apoptosis. The T98G cell
line exhibited that ETO and CBD caused alterations in cell-cycle phase
distribution following 24 h of incubation. CBD significantly alters
cell-cycle distribution by increasing G1/G0 phase cells and decreasing
those in S and G2/M phases in both lines (particularly at a 25 μM
concentration; T98G cell line). Furthermore, intracellular accumulation
of substances in NP-treated cancer cells was notably higher than treated
with free substances, with CBD increasing 3.31-fold. In another study using NPs, Muresan et al. developed polymeric
microneedle (MN) patches loaded with CBD or olaparib NPs, designed
for insertion into brain resection cavities after tumor removal (isocitrate
dehydrogenase wildtype glioblastoma), allowing the substances to diffuse
up to 0.6 cm into brain tissue.
Freire et al. showed that environmentally friendly PBS NPs loaded
with CBD (CBD-PBS), but not empty PBS particles, produced a dose-dependent
loss of viability in glioma lines (U118MG, U87MG). The formulation
released ∼50% of CBD within hours, supporting controlled delivery
and improved bioavailability. Both free and PBS-encapsulated CBD similarly
decreased AKT Ser473 phosphorylation and increased LC3-II, confirming
that nanoencapsulation preserves CBD’s signaling effects. Sun et al. developed GZCX (particles approximately
200 nm), a dual receptor–mediated, BBB-permeable carrier coloading
Gboxin, a drug that was designed to inhibit the process of oxidative
phosphorylation in GBM cells, and CBD for GBM treatment. GZCX achieved
a 10-fold increase in brain Gboxin accumulation. In GBM-bearing mice,
GZCX increased apoptosis, reduced angiogenesis, decreased tumor burden
3.7-fold, and prolonged survival. They emphasized the combined CLTX–CBD–mediated
BBB penetration and GBM targeting, as well as receptor-mediated BBB
transport by CLTX.
In another work,
researchers evaluated THC- and CBD-loaded poly-ε-caprolactone
microparticles (particles approximately 50 μm) as a long-term
delivery system in a murine glioma xenograft model. In vitro, microencapsulation
enabled the sustained release of cannabinoids over several days. In
vivo, in mice with glioma xenografts, local administration of THC,
CBD, or a 1:1 (w/w) THC:CBD mix every 5 days suppressed tumor growth
as effectively as daily local dosing of equivalent cannabinoid solutions.
Treated tumors exhibited increased apoptosis, reduced proliferation,
and decreased angiogenesis. Sharma et
al. encapsulated CBD in magnesium-gallate metal–organic framework
(MOF) microparticles (CBD/Mg-gallate-MOF), predominantly <2 μm.
They achieved ∼65% CBD release at pH 7.2; this suppressed the
viability of the rat glioma brain cancer (C6) cell line. CBD/Mg-GA
exhibits anticancer activity by significantly increasing ROS and suppressing
anti-inflammatory signaling, as evidenced by reduced TNF-α levels.
Mechanistically, it modulates NF-κB, thereby initiating apoptotic
cascades in glioma cells. In an in vitro BBB model, treatment reduced
transendothelial electrical resistance (TEER) by 53.1%, indicating
potential BBB penetration.
Aparicio-Blanco
et al. engineered PIT-made, monodisperse lipid
nanocapsules (LNCs) decorated with nonpsychotropic cannabinoids and
showed that the smallest constructs achieved the highest brain transcytosis.
CBD conjugation enhances brain targeting 6-fold compared to G-Technology,
the leading brain-active strategy already in clinical trials for CNS
disorders. In U373MG assays, CBD-incorporated
LNCs revealed strong size and surface effects: 20 nm LNCs lowered
IC50 3-fold versus 50 nm carriers; CBD decoration increased
glioma targeting 3.4-fold; and combining CBD loading with CBD surface
functionalization further reduced IC50.
Another study demonstrated the potential of coloading
ACT with
selected phytochemicals (e.g., CBD) into cationic DOTAP:POPC liposomes.
The nanoformulations were uniform and stable for 21 days, showing
narrow size distributions, PDI < 0.3, and a negative zeta potential;
vesicle diameters were <200 nm, supporting prospective clinical
use, including GBM therapy. Encapsulation efficiency exceeded 84%.
CBD-modulated liposomal molecular dynamics reduced molecular mobility
and strengthened interaction networks, thereby adjusting particle
size, whereas ACT alone retained the most excellent flexibility. Liposomes
showed higher IC50 values in MRC-5 fibroblasts than in
U-87 MG and U-138 MG glioma cells, indicating tumor-selective cytotoxicity;
the ACT + CBD system achieved IC50 = 7 μM (U-87 MG)
and 6 μM (U-138 MG) at 48 h, while the DOTAP:POPC control displayed
higher IC50 and lower cytotoxicity. In glioma cells, ACT
+ CBD liposomes increased pro-apoptotic Bax and decreased antiapoptotic
Bcl-xL in a dose- and time-dependent manner; the control had minimal
effect. Rybarczyk et al. reported in
a study using U-138 MG and T98G cell lines that CBD-, Celecoxib-,
and 2,5-dimethylcelecoxib-containing liposomes exert robust anti-GBM
effects by triggering apoptosis, oxidative stress, and modulating
key signaling cascades. While coloading CBD with Celecoxib or 2,5-Dimethylcelecoxib
did not yield clear synergistic or additive benefits, the CBD + Celecoxib
combination suppressed Wnt/β-catenin and NF-κB signaling
while activating the Nrf2 pathway.
Table
provides
a comprehensive summary of studies focused on the application of CBD
formulations in glioma treatment. The table compares various formulations,
models, and key outcomes, highlighting their effectiveness in improving
CBD delivery, overcoming the blood-brain barrier, and enhancing therapeutic
efficacy.
The CBD research in GBM, molecular mechanisms, role
in supportive
therapy, and nanotechnology-based delivery strategies are shown in Figure
.
Perspectives on Vesicular Lipid Systems in GBM
4
Perspectives on Vesicular Lipid Systems in GBM
Vesicular lipid carriers have a documented advantage in traversing
or bypassing the BBB owing to their biophysical compatibility with
endothelial lipid membranes, their capacity to exploit receptor-mediated
transcytosis, and their efficiency via the intranasal “nose-to-brain”
route.
−
Recent reviews indicate that intranasally administered liposomes
increase brain deposition and retention while partially circumventing
the BBB, yielding higher CNS drug levels and potentially lower systemic
exposure compared with conventional routes.
,
In GBM models, intranasal liposomes have demonstrated direct distribution
to brain and tumor tissue, with delivery further modulated by interventions
affecting meningeal lymphatic function, providing strong evidence
for the effectiveness of vesicular carriers in this pathway. High-impact evidence indicates that transferrin-targeted
(and other ligand-modified) liposomes exploit receptor-mediated transcytosis
in postcapillary venules, providing a demonstrable pathway for vesicular
carriers to traverse the BBB. A critical
translational proof comes from glutathione-PEGylated liposomal doxorubicin
(2B3-101), which achieved approximately 5-fold higher brain penetration
and prolonged survival in high-grade glioma models relative to conventional
liposomes (Caelyx/Doxil).
−
The same technology was subsequently
tested clinically (phase 1/2a) in patients with primary and metastatic
brain tumors, providing clinical feasibility evidence for BBB-targeted
vesicular carriers.
,
Niosomes, as a closely related
vesicular class based on nonionic surfactants, have likewise shown
enhanced brain uptake after intranasal administration (e.g., bromocriptine)
together with favorable stability profiles, broadening the vesicular
toolkit for CNS-directed agents such as CBD.
,
In contrast to many nonvesicular platforms (polymeric or inorganic),
vesicular lipid systems uniquely satisfy three criteria of direct
relevance to GBM translation: demonstrated BBB transport via RMT,
validated BBB bypass via the intranasal route, and clinical-class
evidence (2B3-101), collectively yielding a favorable risk–benefit
profile for further development.
−
These foundations support the design of early phase CBD trials employing
vesicular carriers with intranasal delivery and/or receptor targeting,
embedding CNS PK/PD readouts and GBM molecular stratification (e.g.,
MGMT/IDH), alongside head-to-head comparisons with competing platforms
within harmonized protocols.
−
,
Perspectives on Vesicular Lipid Systems in GBM
Vesicular lipid carriers have a documented advantage in traversing
or bypassing the BBB owing to their biophysical compatibility with
endothelial lipid membranes, their capacity to exploit receptor-mediated
transcytosis, and their efficiency via the intranasal “nose-to-brain”
route.
−
Recent reviews indicate that intranasally administered liposomes
increase brain deposition and retention while partially circumventing
the BBB, yielding higher CNS drug levels and potentially lower systemic
exposure compared with conventional routes.
,
In GBM models, intranasal liposomes have demonstrated direct distribution
to brain and tumor tissue, with delivery further modulated by interventions
affecting meningeal lymphatic function, providing strong evidence
for the effectiveness of vesicular carriers in this pathway. High-impact evidence indicates that transferrin-targeted
(and other ligand-modified) liposomes exploit receptor-mediated transcytosis
in postcapillary venules, providing a demonstrable pathway for vesicular
carriers to traverse the BBB. A critical
translational proof comes from glutathione-PEGylated liposomal doxorubicin
(2B3-101), which achieved approximately 5-fold higher brain penetration
and prolonged survival in high-grade glioma models relative to conventional
liposomes (Caelyx/Doxil).
−
The same technology was subsequently
tested clinically (phase 1/2a) in patients with primary and metastatic
brain tumors, providing clinical feasibility evidence for BBB-targeted
vesicular carriers.
,
Niosomes, as a closely related
vesicular class based on nonionic surfactants, have likewise shown
enhanced brain uptake after intranasal administration (e.g., bromocriptine)
together with favorable stability profiles, broadening the vesicular
toolkit for CNS-directed agents such as CBD.
,
In contrast to many nonvesicular platforms (polymeric or inorganic),
vesicular lipid systems uniquely satisfy three criteria of direct
relevance to GBM translation: demonstrated BBB transport via RMT,
validated BBB bypass via the intranasal route, and clinical-class
evidence (2B3-101), collectively yielding a favorable risk–benefit
profile for further development.
−
These foundations support the design of early phase CBD trials employing
vesicular carriers with intranasal delivery and/or receptor targeting,
embedding CNS PK/PD readouts and GBM molecular stratification (e.g.,
MGMT/IDH), alongside head-to-head comparisons with competing platforms
within harmonized protocols.
−
,
CBD-Loaded Vesicular Lipid Systems
5
CBD-Loaded Vesicular Lipid Systems
Formulation studies demonstrate that the high lipophilicity of
CBD (log P ≈ 6–7) promotes its preferential
partitioning into the lipid bilayers of vesicular carriers.
,
This physicochemical affinity underlies the high encapsulation efficiency
and structural stability of these systems, rendering vesicular lipid
carriers particularly advantageous for CBD delivery (Figure
).
Verrico et al. showed that CBD reduced proinflammatory
cytokines
IL-6 and TNF-α while increasing the anti-inflammatory IL-10
in vitro and mouse models. Liposomal formulation (∼100 nm liposomes
encapsulating 10–20 mg/mL CBD) improved bioavailability in
mice and humans and remained stable for three months (4 °C and
pH 5–9). Blair and Miller demonstrated
that THC-free liposomal hemp extract (containing 20% CBD and other
cannabinoids) may help treat or reverse cancer-related cachexia and
improve survival in a mouse model. Mice inoculated with colon 26 tumor
cells and treated with 0.2 mg or 1 mg of THC-free liposomal hemp extract
(additional doses to nonresponding or relapsing mice) showed improved
weight gain and survival, with 4 of 7 mice receiving 1 mg and 2 of
7 receiving 0.2 mg surviving, compared to 1 of 9 control mice. Zapata et al. synthesized core–shell
nanoliposomes (size <100 nm) containing CBD, which were noncytotoxic
to nonmalignant human keratinocytes (HaCaT) cells up to 1000 mg·L–1, while higher concentrations exhibited antitumor
activity against colon carcinoma (SW480) cells, suggesting potential
as a chemotherapeutic agent. Jurgelane
et al. prepared CBD-containing liposomes using commercial lipids DSPC,
DPPC, and DSPE-PEG, with the following encapsulation efficiency: DPPC
CBD (63%), DSPC CBD (74%), DSPC DPPC CBD (81%), DSPC DSPE-PEG CBD
(87%). CBD release was highest initially in DPPC CBD liposomes, while
DSPC DSPE-PEG CBD showed sustained release (79% over 504 h). The highest
GMSC viability was observed at 96 h for all CBD liposomes, while liposomes
without CBD showed no reduction in viability.
Interestingly, in vitro experiments on bovine teeth suggested
that
olivetol-loaded γ-cyclodextrin metal–organic frameworks
(γ-CD-MOFs) and DPPC liposomes are potential systems for delivering
CBD in dental hypersensitivity treatment. Their findings revealed
that olivetol, a precursor for CBD production, performed comparably
to CBD, confirming its suitability as a CBD analog. The therapy reached
the enamel and dentin layers.
,
CBD has an impact
on seizures and quality of life (QoL) in refractory
frontal lobe epilepsy. Ebadi et al., conducted under a triple-blinding
protocol, involved 27 patients (12 receiving a purified liposomal
CBD preparation alongside standard medications, while 15 in the placebo
group received only antiseizure drugs). After 4 weeks, 66.67% of CBD
patients (versus 20.00% placebo) showed seizure improvement. Unlike
standard ADEs, CBD significantly reduced seizure frequency by the
study’s end time point [mean difference 45.58, 95% CI (8.987–82.18), p = 0.009]. At 8 weeks, QoLI-31(quality of life questionnaire
score) scores improved significantly from baseline [mean diff. −5.031,
95% CI (−9.729 to −0.333), p = 0.032],
with a notable QoL improvement in the CBD group compared to placebo
[RR 2.160, 95% CI (1.148 to 4.741), p = 0.018], though
no significant difference was seen at 4 weeks (p =
0.653). QoL improvement was positively correlated with reduced seizure
frequency [r = 0.638, 95% CI (0.296 to 0.835), p = 0.001], but in the CBD group alone, QoL changes were
not associated with seizure severity or frequency (p > 0.05).
Fu et al. explored
the coencapsulation of CBD with 20(S)-Protopanaxadiol
(PPD), a ginseng-derived compound, to develop a low-toxicity antitumor
agent. While neither CBD nor PPD alone showed strong antitumor effects,
their coencapsulation in liposomes significantly inhibited tumor growth
in 4T1 murine breast tumors, achieving an 82.2% inhibition rate (45
mg/kg i.v.), outperforming injection of 8 mg/kg of Paclitaxel (64.4%).
CBD-PPD liposomes administered orally (45 mg/kg) resulted in a significantly
lower TIR (56.8%) than those administered intravenously. The CBD-PPD
liposomes (mean size 138.8 nm) caused no side effects, and the mice
remained healthy and active.
In
topical applications, Franzè et al. investigated the
potential of using deformable liposomes to deliver a combination of
CBD and lidocaine (LD) into deeper skin. Two formulations were used:
G-liposomes (CBD in the lipid bilayer and LD in the core via a pH
gradient) and Drug-in-Micelles-in-Liposomes system (DiMiL), where
LD was pre-encapsulated in micelles. DiMiL and G-liposomes outperformed
control formulations with free drugs in enhancing skin penetration.
The DiMiL enhanced skin permeation and dermal retention of substances
compared to G-liposomes (CBD: 11.52 ± 2.4 vs 4.51 ± 0.8
μg/cm2; LD: 19.6 ± 2.9 vs 3.2 ± 0.1 μg/cm2). Moreover, removing Tween 80 from the liposome membrane,
especially when a fluidizing agent like CBD is present, improves drug
release and retention in the dermis. Additionally,
Franzè et al. demonstrated that proliposomes, dry powders formed
by coating phospholipids onto a porous, soluble carrier, serve as
a promising intermediate for creating deformable liposome-based topical
formulations, enhancing stability without affecting performance. The
delivery of CBD through the human epidermis was significantly increased
with DiMiL systems (developed by hydrating proliposomes with a micellar
dispersion) compared to conventional deformable liposomes of identical
lipid composition or an oil-based solution.
Rao et al. introduced lipid nanocarrier bionic oleosomes (BOLE;
natural lipid-based capsules with a triacylglycerol core encased by
a dense monolayer of phospholipids and hydrophobic proteins) as an
alternative to liposomes for encapsulating CBD. Using high-pressure
homogenization, they created CBD-BOLE, demonstrating a 3.13 times
greater loading efficiency and a 7.8 times higher CBD-phospholipid
ratio than CBD-loaded liposomes. Moreover, CBD’s free radical
scavenging capacity was enhanced while the cytotoxicity diminished. For cost-effective production of nanocarriers,
Tiboni et al. indicated using 3D-printed polypropylene-based microfluidic
devices produced via fused deposition modeling (FDM) printing. Microfluidic
chips effectively produced liposomes and polymeric NPs loaded with
CBD (as the model drug under experimental conditions) with adjustable
properties and efficient drug loading.
In addition to liposomes, the vesicular systems category encompasses
niosomes, transfersomes, ethosomes, and archaeosomes, all of which
have documented applications in CBD delivery, as well as pharmacosomes,
phytosomes, vesosomes, and colloidosomes, which have not yet been
explored in CBD-related research.
Ethosomes have exhibited significant
promise in CBD transdermal
delivery. Lodzki et al. highlight the promising potential of ethosomal
carriers for transdermal CBD delivery, showcasing their ability to
enhance skin permeation and create a localized CBD depot for targeted
anti-inflammatory effects. In ICR mice, transdermal application of
ethosomes to the abdomen maintained steady-state levels of CBD from
24 to 72 h. Moreover, ethosomal CBD by transdermal application effectively
prevented inflammation and edema caused by carrageenan injection.
Moqejwa et al. successfully created nanosized
transferosomes loaded
with CBD and formulated them into a rectal colloid to increase CBD
absorption. The transferosomes, which exhibited a particle size distribution
ranging from 102.2 to 130.1 nm, demonstrated encapsulation efficiency
of 55.7–80.0% with different compositions of edge activators.
Lyophilization ensured the preservation of their physicochemical properties
for up to six months. Ex vivo studies indicated that,
in comparison with pristine CBD, transferosomes significantly enhanced
CBD diffusivity and permeation through excised colorectal membranes,
while in vitro tests confirmed the trend and stable release kinetics
of CBD.
Gugleva et al. highlighted
the potential of niosomes for CBD delivery.
They demonstrated that amphiphilic copolymer-modified niosomal formulations
effectively deliver CBD, maintaining its low micromolar cytotoxicity
in tumor cells while enhancing its anti-inflammatory and pro-apoptotic
properties. A formulation based on Tween 60:Span 60:Chol (3.5:3.5:3
molar ratio) with 2.5 mol % of a 3-arm star-shaped copolymer showed
high CBD encapsulation efficiency (94%), a suitable particle size
for parenteral use (235 nm), and controlled release. Encapsulated
CBD formulations significantly enhance death receptor signaling (TRAILR2,
FADD, Fas/CD95) and HIF-1α in T-24 urothelial
cancer cells. Formulations with CBD reduce adhesion molecule ICAM-1,
and CBD form of solution or in modified niosomes inhibits MMP-9 expression,
likely lowering cancer invasiveness and metastasis. In mycosis fungoides
CTCL-derived MJ cells, CBD and its niosomal form lower PON2 levels,
reducing tolerance to free radicals in the inflammatory microenvironment.
Additionally, they decrease cIAP-1 and survivin, potentially enhancing
the chemosensitivity of the CTCL cells.
The possibilities of archaeosomes for CBD delivery were demonstrated
by Sedlmayr et al. in 2023, who evaluated archaeosomes (ether lipid-based)
against lecithin-derived liposomes for delivering CBD orally. Archaeosomes
showed a loading capacity six times higher than conventional liposomes
and remained stable for more than six months after lyophilization.
Under simulated GI tract conditions, CBD recovery was significantly
higher in archaeosomes (57 ± 3%) than in conventional liposomes
(34 ± 1%), while particle uptake in Caco-2 cells increased up
to 6-fold. The researchers also suggested that archaeosomes are less
dependent on the influence of food effects than conventional liposomes
and commercial CBD oil products.
CBD-Loaded Vesicular Lipid Systems
Formulation studies demonstrate that the high lipophilicity of
CBD (log P ≈ 6–7) promotes its preferential
partitioning into the lipid bilayers of vesicular carriers.
,
This physicochemical affinity underlies the high encapsulation efficiency
and structural stability of these systems, rendering vesicular lipid
carriers particularly advantageous for CBD delivery (Figure
).
Verrico et al. showed that CBD reduced proinflammatory
cytokines
IL-6 and TNF-α while increasing the anti-inflammatory IL-10
in vitro and mouse models. Liposomal formulation (∼100 nm liposomes
encapsulating 10–20 mg/mL CBD) improved bioavailability in
mice and humans and remained stable for three months (4 °C and
pH 5–9). Blair and Miller demonstrated
that THC-free liposomal hemp extract (containing 20% CBD and other
cannabinoids) may help treat or reverse cancer-related cachexia and
improve survival in a mouse model. Mice inoculated with colon 26 tumor
cells and treated with 0.2 mg or 1 mg of THC-free liposomal hemp extract
(additional doses to nonresponding or relapsing mice) showed improved
weight gain and survival, with 4 of 7 mice receiving 1 mg and 2 of
7 receiving 0.2 mg surviving, compared to 1 of 9 control mice. Zapata et al. synthesized core–shell
nanoliposomes (size <100 nm) containing CBD, which were noncytotoxic
to nonmalignant human keratinocytes (HaCaT) cells up to 1000 mg·L–1, while higher concentrations exhibited antitumor
activity against colon carcinoma (SW480) cells, suggesting potential
as a chemotherapeutic agent. Jurgelane
et al. prepared CBD-containing liposomes using commercial lipids DSPC,
DPPC, and DSPE-PEG, with the following encapsulation efficiency: DPPC
CBD (63%), DSPC CBD (74%), DSPC DPPC CBD (81%), DSPC DSPE-PEG CBD
(87%). CBD release was highest initially in DPPC CBD liposomes, while
DSPC DSPE-PEG CBD showed sustained release (79% over 504 h). The highest
GMSC viability was observed at 96 h for all CBD liposomes, while liposomes
without CBD showed no reduction in viability.
Interestingly, in vitro experiments on bovine teeth suggested
that
olivetol-loaded γ-cyclodextrin metal–organic frameworks
(γ-CD-MOFs) and DPPC liposomes are potential systems for delivering
CBD in dental hypersensitivity treatment. Their findings revealed
that olivetol, a precursor for CBD production, performed comparably
to CBD, confirming its suitability as a CBD analog. The therapy reached
the enamel and dentin layers.
,
CBD has an impact
on seizures and quality of life (QoL) in refractory
frontal lobe epilepsy. Ebadi et al., conducted under a triple-blinding
protocol, involved 27 patients (12 receiving a purified liposomal
CBD preparation alongside standard medications, while 15 in the placebo
group received only antiseizure drugs). After 4 weeks, 66.67% of CBD
patients (versus 20.00% placebo) showed seizure improvement. Unlike
standard ADEs, CBD significantly reduced seizure frequency by the
study’s end time point [mean difference 45.58, 95% CI (8.987–82.18), p = 0.009]. At 8 weeks, QoLI-31(quality of life questionnaire
score) scores improved significantly from baseline [mean diff. −5.031,
95% CI (−9.729 to −0.333), p = 0.032],
with a notable QoL improvement in the CBD group compared to placebo
[RR 2.160, 95% CI (1.148 to 4.741), p = 0.018], though
no significant difference was seen at 4 weeks (p =
0.653). QoL improvement was positively correlated with reduced seizure
frequency [r = 0.638, 95% CI (0.296 to 0.835), p = 0.001], but in the CBD group alone, QoL changes were
not associated with seizure severity or frequency (p > 0.05).
Fu et al. explored
the coencapsulation of CBD with 20(S)-Protopanaxadiol
(PPD), a ginseng-derived compound, to develop a low-toxicity antitumor
agent. While neither CBD nor PPD alone showed strong antitumor effects,
their coencapsulation in liposomes significantly inhibited tumor growth
in 4T1 murine breast tumors, achieving an 82.2% inhibition rate (45
mg/kg i.v.), outperforming injection of 8 mg/kg of Paclitaxel (64.4%).
CBD-PPD liposomes administered orally (45 mg/kg) resulted in a significantly
lower TIR (56.8%) than those administered intravenously. The CBD-PPD
liposomes (mean size 138.8 nm) caused no side effects, and the mice
remained healthy and active.
In
topical applications, Franzè et al. investigated the
potential of using deformable liposomes to deliver a combination of
CBD and lidocaine (LD) into deeper skin. Two formulations were used:
G-liposomes (CBD in the lipid bilayer and LD in the core via a pH
gradient) and Drug-in-Micelles-in-Liposomes system (DiMiL), where
LD was pre-encapsulated in micelles. DiMiL and G-liposomes outperformed
control formulations with free drugs in enhancing skin penetration.
The DiMiL enhanced skin permeation and dermal retention of substances
compared to G-liposomes (CBD: 11.52 ± 2.4 vs 4.51 ± 0.8
μg/cm2; LD: 19.6 ± 2.9 vs 3.2 ± 0.1 μg/cm2). Moreover, removing Tween 80 from the liposome membrane,
especially when a fluidizing agent like CBD is present, improves drug
release and retention in the dermis. Additionally,
Franzè et al. demonstrated that proliposomes, dry powders formed
by coating phospholipids onto a porous, soluble carrier, serve as
a promising intermediate for creating deformable liposome-based topical
formulations, enhancing stability without affecting performance. The
delivery of CBD through the human epidermis was significantly increased
with DiMiL systems (developed by hydrating proliposomes with a micellar
dispersion) compared to conventional deformable liposomes of identical
lipid composition or an oil-based solution.
Rao et al. introduced lipid nanocarrier bionic oleosomes (BOLE;
natural lipid-based capsules with a triacylglycerol core encased by
a dense monolayer of phospholipids and hydrophobic proteins) as an
alternative to liposomes for encapsulating CBD. Using high-pressure
homogenization, they created CBD-BOLE, demonstrating a 3.13 times
greater loading efficiency and a 7.8 times higher CBD-phospholipid
ratio than CBD-loaded liposomes. Moreover, CBD’s free radical
scavenging capacity was enhanced while the cytotoxicity diminished. For cost-effective production of nanocarriers,
Tiboni et al. indicated using 3D-printed polypropylene-based microfluidic
devices produced via fused deposition modeling (FDM) printing. Microfluidic
chips effectively produced liposomes and polymeric NPs loaded with
CBD (as the model drug under experimental conditions) with adjustable
properties and efficient drug loading.
In addition to liposomes, the vesicular systems category encompasses
niosomes, transfersomes, ethosomes, and archaeosomes, all of which
have documented applications in CBD delivery, as well as pharmacosomes,
phytosomes, vesosomes, and colloidosomes, which have not yet been
explored in CBD-related research.
Ethosomes have exhibited significant
promise in CBD transdermal
delivery. Lodzki et al. highlight the promising potential of ethosomal
carriers for transdermal CBD delivery, showcasing their ability to
enhance skin permeation and create a localized CBD depot for targeted
anti-inflammatory effects. In ICR mice, transdermal application of
ethosomes to the abdomen maintained steady-state levels of CBD from
24 to 72 h. Moreover, ethosomal CBD by transdermal application effectively
prevented inflammation and edema caused by carrageenan injection.
Moqejwa et al. successfully created nanosized
transferosomes loaded
with CBD and formulated them into a rectal colloid to increase CBD
absorption. The transferosomes, which exhibited a particle size distribution
ranging from 102.2 to 130.1 nm, demonstrated encapsulation efficiency
of 55.7–80.0% with different compositions of edge activators.
Lyophilization ensured the preservation of their physicochemical properties
for up to six months. Ex vivo studies indicated that,
in comparison with pristine CBD, transferosomes significantly enhanced
CBD diffusivity and permeation through excised colorectal membranes,
while in vitro tests confirmed the trend and stable release kinetics
of CBD.
Gugleva et al. highlighted
the potential of niosomes for CBD delivery.
They demonstrated that amphiphilic copolymer-modified niosomal formulations
effectively deliver CBD, maintaining its low micromolar cytotoxicity
in tumor cells while enhancing its anti-inflammatory and pro-apoptotic
properties. A formulation based on Tween 60:Span 60:Chol (3.5:3.5:3
molar ratio) with 2.5 mol % of a 3-arm star-shaped copolymer showed
high CBD encapsulation efficiency (94%), a suitable particle size
for parenteral use (235 nm), and controlled release. Encapsulated
CBD formulations significantly enhance death receptor signaling (TRAILR2,
FADD, Fas/CD95) and HIF-1α in T-24 urothelial
cancer cells. Formulations with CBD reduce adhesion molecule ICAM-1,
and CBD form of solution or in modified niosomes inhibits MMP-9 expression,
likely lowering cancer invasiveness and metastasis. In mycosis fungoides
CTCL-derived MJ cells, CBD and its niosomal form lower PON2 levels,
reducing tolerance to free radicals in the inflammatory microenvironment.
Additionally, they decrease cIAP-1 and survivin, potentially enhancing
the chemosensitivity of the CTCL cells.
The possibilities of archaeosomes for CBD delivery were demonstrated
by Sedlmayr et al. in 2023, who evaluated archaeosomes (ether lipid-based)
against lecithin-derived liposomes for delivering CBD orally. Archaeosomes
showed a loading capacity six times higher than conventional liposomes
and remained stable for more than six months after lyophilization.
Under simulated GI tract conditions, CBD recovery was significantly
higher in archaeosomes (57 ± 3%) than in conventional liposomes
(34 ± 1%), while particle uptake in Caco-2 cells increased up
to 6-fold. The researchers also suggested that archaeosomes are less
dependent on the influence of food effects than conventional liposomes
and commercial CBD oil products.
Conclusion and Future Direction
6
Conclusion and Future Direction
CBD
is a well-tolerated, nonpsychoactive phytocannabinoid that
exhibits antitumor activity against GBM and glioma stem-like cells.
This is achieved through mechanisms such as inducing oxidative stress,
activating caspases, modulating ERK and TRPV2/TRPV4 signaling, and
suppressing NF-κB and Id1. Convergent preclinical data and early
clinical indications, particularly when used in conjunction with TMZ,
support the need for rigorous clinical evaluation. Future work should
prioritize well-controlled, biomarker-integrated clinical trials to
refine CBD-based combination regimens within personalized treatment
frameworks. In parallel, the systematic development of nanocarriersparticularly
vesicular DDSis required to enhance the therapeutic index
of CBD by improving encapsulation, bioavailability, BBB transit, and
tumor-targeted exposure.
Conclusion and Future Direction
CBD
is a well-tolerated, nonpsychoactive phytocannabinoid that
exhibits antitumor activity against GBM and glioma stem-like cells.
This is achieved through mechanisms such as inducing oxidative stress,
activating caspases, modulating ERK and TRPV2/TRPV4 signaling, and
suppressing NF-κB and Id1. Convergent preclinical data and early
clinical indications, particularly when used in conjunction with TMZ,
support the need for rigorous clinical evaluation. Future work should
prioritize well-controlled, biomarker-integrated clinical trials to
refine CBD-based combination regimens within personalized treatment
frameworks. In parallel, the systematic development of nanocarriersparticularly
vesicular DDSis required to enhance the therapeutic index
of CBD by improving encapsulation, bioavailability, BBB transit, and
tumor-targeted exposure.
출처: PubMed Central (JATS). 라이선스는 원 publisher 정책을 따릅니다 — 인용 시 원문을 표기해 주세요.
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