pH-Responsive gradient hydrophobic multidrug co-delivery microcapsules based on sodium alginate for enhanced tumor accumulation.

Multi-drug-loaded microcapsules therapies are effective against tumor heterogeneity and drug resistance through synergistic effects. However, the varying physical and chemical properties of anti-cancer drugs make it challenging to ensure the microcapsules stability, high encapsulation efficiency (EE), and controlled release behavior within the carrier. This study created a series of gradient hydrophobic drug co-loaded oxidized sodium alginate (OSA) based microcapsules with polyether amine (PEA) and octylamine (OA) decorated, showing the affinity towards amphiphilic drugs and highly hydrophobic drugs simultaneously. And the loading capacity of amphiphilic drugs and highly hydrophobic drugs was tunable by varying the content of decorated PEA and OA, respectively. The pH-responsive Schiff base bonds were able to be specifically cleaved in tumor's acidic microenvironment, enabling controlled drug release. The prepared microcapsules (100-200 nm) co-loading paclitaxel (PTX), curcumin (Cur), and doxorubicin (DOX) maintained stable morphology in PBS over 30 days. In vitro tests demonstrated the pH 5.0-triggered drug release via Schiff-base cleavage, with similar release rates for all drugs. The multi-drug-loaded microcapsules achieved a cell inhibition rate of 67.59 % in MCF-7 cells after 48 h, significantly outperforming both single-drug-loaded microcapsules and their physical mixture. A similar enhanced therapeutic effect was also observed in MDA-MB-231 cells. The multi-drug system showed higher cellular uptake rates, reaching 2.52 % (DOX), 4.43 % (PTX), and 1.84 % (Cur), compared to the mixture of single-drug microcapsules. This study proposed a microcapsule design with the potential to overcome tumor heterogeneity and multidrug resistance, showing validity towards efficiently killing different types of cancer cells.