Codelivery of afuresertib and celecoxib by IL4RPep-1-targeting nanoparticles for effective treatment against melanoma

Abstract

Melanoma is one of the most aggressive and deadly forms of skin cancer, and effective treatments need to be developed. The combination of chemoimmunotherapy has emerged as a promising strategy for treating cancer. However, this strategy still has several limitations, including the inability of more than two drugs to reach tumor tissue simultaneously and the risk of serious adverse effects. The use of nanodrug delivery systems is an effective method to successfully combine these therapies, as they reduce side effects and improve bioavailability. In this study, we developed IL4RPep-1-targeting peptide nanoparticles (IPP NPs) for the codelivery of afuresertib and celecoxib for melanoma treatment by taking advantage of the high drug loading capacity and favorable pharmacokinetic profile of the poly(lactide-co-glycolide) nanoparticle platform. IPP NPs efficiently target three different types of melanoma cells in vitro and significantly accumulate at the tumor site in vivo. ​In both ectopic and pulmonary metastatic melanoma models, targeted codelivery of afuresertib and celecoxib not only promotes melanoma cell apoptosis but also reprograms M2-type macrophages into M1-type macrophages, reconstructing the tumor immune microenvironment and activating the immune response against cancer cells. In addition, this highly coordinated precise delivery of the drug to tumor cells significantly reduces adverse reactions associated with the combination of afuresertib and celecoxib. In summary, IPP NPs exhibit an accurate pH response and ideal targeted drug delivery capabilities for combination chemotherapy and immunotherapy, offering therapeutic potential for this combination in melanoma.