Biopolymeric Nanocapsules Exploiting the Synergistic Effects of Methotrexate and Curcumin Co-Delivery via Oral or Local Administration for Breast Cancer Therapy.

Alginate (ALG)-based nanocapsules for the co-delivery of methotrexate (MTX) and curcumin (CUR) have been insufficiently explored, particularly in terms of their potential use for various administration routes. This study prepared and evaluated biopolymeric ALG nanocapsules co-loaded with MTX and CUR to exploit their synergistic effects for breast cancer therapy via oral or intratumoral administration. Nanocapsules were fabricated using poloxamer P407 to enhance drug incorporation and stability, followed by Ca-mediated ionic crosslinking to form a robust matrix encapsulating MTX and CUR with different mechanisms in a single carrier. The selected formulation exhibited nanoscale particle size, narrow distribution, suitable surface charge, and high drug loading efficiency without significant drug-drug competition. Under simulated gastrointestinal conditions, the system demonstrated sustained release with minimal premature leakage in gastric-like environments, supporting oral delivery potential. pH-responsive release relevant to the tumor microenvironment was observed, with drug retention at mildly acidic extracellular pH and enhanced release under intracellular conditions, indicating feasibility for intratumoral administration. Kinetic modeling revealed distinct release mechanisms for MTX and CUR, confirming matrix-regulated and environment-sensitive transport behavior. The biocompatibility of nanocapsules was confirmed through the hemolytic assay and cytocompatibility in both cancerous and non-cancerous cell lines. Dual drug-loaded nanocapsules exhibited enhanced survival inhibition in the breast cancer cell line (MCF-7) compared to single-drug formulations. Strong drug synergism at a fixed 1:1 ratio was confirmed through combination index analysis based on the Chou-Talalay method. These findings highlight ALG-based nanocapsules as a promising platform for synergistic MTX-CUR co-delivery for oral and local breast cancer therapy.