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.