Exploring a flexible and cytotoxic drug carrier of cisplatin and 5-fluorouracil for a multitarget therapeutic approach in colorectal cancer

The therapeutic potential of many anticancer drugs is frequently hindered by challenges such as non-specific distribution, suboptimal dosing, and premature degradation, which collectively compromise treatment efficacy. To overcome these limitations, advanced drug delivery systems capable of targeted, controlled, and synchronised release are essential. This study presents the development and complete characterisation of the flexible supramolecular metal-organic framework (SMOF) Cu7Naph as a multifunctional carrier for the co-delivery of the chemotherapeutic agents cisplatin (cisPt) and 5-fluorouracil (5-FU), aiming to enhance therapeutic efficacy against cancer. The water-stable Cu7Naph is assembled from heptanuclear copper-adenine units and naphthalene-2,6-dicarboxylate counterions, held together by π-π stacking and hydrogen bonding interactions, which confer high structural flexibility and porosity. Single-crystal X-ray diffraction analyses demonstrate that Cu7Naph undergoes significant structural expansion or contraction depending on hydration stages and guest molecule inclusion, enabling simultaneous incorporation of cisPt and 5-FU within the same porous matrix. This co-loading results in synergistic effects, increasing 5-FU loading capacity to 14.1 wt% in the presence of cisPt and synchronising their release kinetics, thereby reducing kinetic disparity (<i>K</i>_5-FU/<i>K</i>_cisPt = 2.5 <i>versus</i> 4.2 when loaded separately). The first stage of the drug release follows pseudo-first-order kinetics under physiologically relevant conditions (35 °C). Cytotoxicity assays using HCT116 colorectal cancer cells cultured in the presence of Cu7Naph reveal that Cu7Naph exhibits intrinsic antiproliferative activity, which is enhanced upon 5-FU loading but attenuated with cisPt inclusion, suggesting a possible interaction between cisPt and the carrier's cytotoxic mechanism. Transcriptomic analysis <i>via</i> RNA sequencing identifies downregulation of <i>AKR1A1</i> and <i>PUF60</i> genes as contributors to the observed biological effects. Collectively, these findings highlight the potential of structurally adaptable SMOFs as versatile platforms for the synchronised co-delivery of multiple drugs with distinct release profiles and therapeutic mechanisms, offering a promising strategy for improved drug combination cancer therapies.