Anisotropic microgels for spatiotemporal co-delivery of anticancer drugs

Codelivery of chemotherapeutic agents is often challenged by physicochemical incompatibility between co-administered drugs and the inability of conventional systems to achieve spatiotemporal control over drug release. Herein, anisotropic microgels were fabricated by an electrohydrodynamic co-jetting (EHDC) technique using PLGA as a sustained-release matrix and polyethyleneimine (PEI), along with a crosslinker, 1,2,3,4-butanetetracarboxylic dianhydride (BTDA), as a pH-responsive compartment, potentially enabling the compartmentalization of physicochemically incompatible drugs within a single platform. Two anticancer drug-loaded formulations, DGPI and DIPG, exhibited mean diameters of ∼11.3 µm and ∼6.15 µm, respectively, with high encapsulation efficiencies (∼90%) for both drugs. In DGPI, doxorubicin hydrochloride was loaded in the PLGA phase and paclitaxel in the PLGA-PEI-BTDA phase, whereas the drug distribution was reversed in DIPG. FTIR, DSC, and TGA analyses confirmed molecular-level drug-polymer interaction and system stability, while CLSM validated the bicompartmental morphology, indicating the predominant localization of dual drugs within their respective compartments. In vitro release studies at pH 5.0, 6.5, and 7.4 revealed that DGPI exhibited a sequential release profile, whereas DIPG achieved codelivery with preferential pH-triggered release under acidic conditions and near-complete drug retention at physiological pH (7.4), indicating systemic stability. Furthermore, evaluation using 3D tumour spheroids demonstrated maximum therapeutic efficacy for the DIPG formulation, with a residual cell viability of ∼35%, attributed to simultaneous multi-pathway cytotoxicity. Overall, this work establishes an anisotropic microgel-based platform capable of programmable, spatiotemporally controlled codelivery of dual drugs for enhanced therapeutic outcome.