Designing MOF-Thermogel Nanocomposites for Differential Multidrug Release in Combination Cancer Therapy

Combination chemotherapy is a leading strategy for advanced cancer treatment, bringing about improved therapeutic responses compared with single-drug chemotherapy. However, achieving the required sequence of drug delivery needed for optimal therapeutic benefits via a single-drug delivery system remains highly challenging, often involving systems of considerable complexities. Herein, we report the design of composites comprising nanoscale metal-organic frameworks (MOFs) and temperature-responsive hydrogels (thermogels) as versatile, modular, yet simple-to-formulate platforms for controlled, localized release of combination chemotherapeutics, which can be used for solid tumor treatment. First, the encapsulation behavior, drug-host interactions, and in vitro release kinetics of four chemotherapeutic drugs-gemcitabine (GEM), 5-fluorouracil (5-FU), doxorubicin (DOX), and paclitaxel (PTX)-from nanoscale MOF carriers and the bulk gel phase were elucidated. Based on these differences, we designed dual- and even triple-drug formulations that could achieve sustained drug release over 10-18 days, with different rates of drug release that mimic clinically relevant sequential dosage. In all cases, MOF-thermogel multidrug formulations were highly injectable when chilled, potentially allowing minimally invasive and site-specific administration of multidrug cocktails to targeted tumor sites. Our findings establish MOF-thermogel nanocomposites as a highly customizable platform for tailoring multidrug release kinetics, relative rates, sequence, and release duration to meet different therapeutic demands for solid tumor chemotherapy and related applications.