CLL1 polymeric nanoparticles loaded with PI3K/BRD4 dual inhibitor MDP5 and azacitidine as a novel treatment for TP53 mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) in older adults, particularly with mutation in the tumor suppressor gene TP53, has high rates of resistance to standard chemotherapy regimens, often resulting in patients death within months of diagnosis. To address this unmet need, we investigated the therapeutic potential of targeted nanoparticles (NPs) loaded with MDP5 (our novel BRD4/PI3K dual inhibitor) and azacitidine (AZA), a standard-of-care hypomethylating agent. A combination of MDP5 and AZA demonstrated synergistic inhibitory effects in both TP53 wild-type and TP53-mutant AML cell lines, and downregulated expression levels of MYC, BCL-2, and CDK6. To improve delivery, we developed a novel AZA-conjugated polymer, mPEG-p(Asp-BLA)-p(Asp-AZA)-g-p(Asp-DA), which self-assembles into NPs. C-type lectin-like molecule-1 (CLL1) is highly expressed on leukemic blasts and leukemia stem cells (LSCs) but not universally across all AML subtypes. To leverage this selective targeting, we modified NPs with a peptide that recognizes CLL-1. The CLL-1 targeted NPs loaded with MDP5 and AZA demonstrated superior AML control and targeting of LSCs in TP53-mutant mice models, while sparing normal hematopoiesis in healthy NSG mice. These promising results highlight a potential efficacy of our novel CLL-1 targeted NP combination approach to treat AML, particularly those harboring TP53 mutation.