2024 AIChE Annual Meeting
Controlled Release Profiles of Resiquimod from a Novel Melanoma Vaccine Using in Vitro Subcutaneous Models
Metastatic melanoma, the deadliest form of skin cancer, is limited in the number of viable treatment methods. Early-stage melanoma can often be removed surgically, provided the tumor remains localized in the body or metastasizes in regions that permit surgical removal. Upon metastasis to parts of the body such as distant lymph nodes, other areas of the skin, or other organs, melanomas become harder to detect and less viable for surgical removal, thus creating the need for alternative treatments. The majority of melanoma cases are attributed to genetic mutations in the BRAF oncogene resulting in the malignant growth of melanocytes. Given the immunogenic nature of melanoma tumors, immunotherapy proves a promising treatment method. This project works to develop a safe and feasible vaccine as a late-stage treatment method for BRAF-mutant metastatic melanoma using a novel polycaprolactone multiblock copolymer containing orthoester linkages (CAP-OA1) as a drug delivery vessel. The polymer’s liquid state provides suitable drug encapsulation that allows for administration via subcutaneous injection while the biocompatibility associated with polycaprolactone allows for safe degradation in the body. The vaccine consists of CAP-OA1 loaded with tumor-associated antigens and resiquimod, an imidazoquinolinamine derivative and Toll-like Receptor 7/8 agonist that has anti-tumor and immunostimulatory effects. Upon subcutaneous injection, the liquid polymer serves as a depot for the continuous release of the antigen and resiquimod. This study provides valuable insight into the transport mechanisms and release kinetic profiles of resiquimod-loaded CAP-OA1 through in vitro release studies that aim to mimic the release kinetics of the components in vivo. Release studies were performed using two different models of subcutaneous delivery: a bulk fluid model and a hydrogel model. The most common setup for these studies consists of the release of a drug from its polymeric encapsulation directly into an aqueous collecting solution that resembles the pH of the human body. This is referred to as the bulk fluid model. This method offers ease of setup but lacks the representation of drug release into a native tissue environment which may affect degradation mechanisms of the encapsulation and diffusion of the drug through native tissue. Agarose hydrogels have been shown to mimic the mechanical properties of native tissue, offering a more biomimetic drug-release environment. Resiquimod concentrations were quantified using UV-vis spectrophotometry. The models resulted in similar resiquimod release profiles, with the majority of resiquimod being released after nine days. This implies that the immune response to the vaccine will begin no sooner than nine days post-injection. Higher initial rates of release were observed in the bulk fluid model, indicating that bulk fluid release studies may be less accurate in predicting release rates for up to seven days after injection. Higher variability was observed in the bulk fluid model, pointing to the nonuniform nature of polymer degradation in a bulk fluid compared to in a hydrogel structure. These findings demonstrate the increased performance of hydrogel models over bulk fluid models; it is recommended that hydrogel structures be implemented in future release studies.