Design of a Cholic Acid-based Triarmed Star Polymer Network for Targeted and Sustained Drug Delivery for Melanoma Treatment

Abstract

The growing challenge of therapy resistance in cancer remains a major obstacle in clinical oncology, limiting the long term success of conventional chemotherapeutics such as doxorubicin (Dox). Although Dox exhibits strong antitumor efficacy, its therapeutic potential is often compromised by biological barriers and systemic toxicity. To overcome these limitations, we developed a novel polyurethane (PU) based drug delivery platform utilizing a prepolymer (PP) and its cholic acid modified derivatives with varying graft densities for sustained and targeted cancer therapy. These systems exhibit structural flexibility and biodegradability, enabling adaptation to dynamic physiological environments, including irregular tumor microarchitectures. Among them, the highly grafted PU is found to be superior mechanical resilience, biocompatibility, and greater drug loading efficiency, making it ideal for injectable applications. In vitro cytotoxicity and intracellular trafficking studies in cancer cells, along with biocompatibility evaluations in normal fibroblasts, confirm the therapeutic efficacy and safety of the formulations. Furthermore, in vivo studies in melanoma bearing mice reveal that the Dox-loaded injectable hydrogel, administered subcutaneously near the tumor site, achieves enhanced tumor suppression with markedly reduced systemic toxicity. This formulation maintains therapeutic drug levels for up to 72 hours, owing to its network structure and durability, thereby, minimizing frequent dosing. Overall, this study presents a multifunctional and biocompatible drug delivery strategy based on various formulations, offering a promising approach for precise, prolonged, and effective melanoma therapy-bridging material innovation with clinical potential.