Augmented anti-cancer effect of hypoxia-inducible factor 2α (HIF2α)- targeting PT2385 delivered in α-synuclein-AuNP microcapsules for clear cell renal carcinoma mouse model

Abstract

Development of anti-cancer drug carrier system capable of delivering chemotherapeutic and immunotherapeutic agents to cancerous lesions is essential to overcome severe side effects and reduced therapeutic efficacy of the drugs. The microcapsules of gold nanoparticles (AuNPs) fabricated with a self-assembly protein of alpha-synuclein (alpha S) have been employed to carry the hypoxia-inducible factor 2 alpha (HIF2 alpha)-targeting PT2385 in a mouse model xenografted with clear cell renal cell carcinoma (ccRCC). Hydrophobic cargo like rhodamine 6G entrapped within the microcapsules was demonstrated to be selectively released under cancer-related stimuli including acidic pH, local hyperthermia, and proteases such as matrix metalloproteinases. The alpha S-AuNP mi-crocapsules containing the hydrophobic drug of PT2385 suppressed the expression of HIF2 alpha and its downstream genes in ccRCC A498 cells in vitro to the level comparable to that obtained with direct PT2385 treatment, indicating that the PT2385 remained active inside the capsules. In the A498 xenograft mouse model, intraper-itoneal administration of the alpha S-AuNP-PT2385 microcapsules significantly reduced the tumor volume and Ki-67 scores from those monitored in the PT2385-treated group. Therefore, the alpha S-AuNP microcapsule is suggested to be a promising cancer-targeting drug delivery system which exhibits several merits such as improved loading efficiency for hydrophobic drugs, their protection from metabolism, and selective cargo release in tumor mi-croenvironments in addition to its physicotherapeutic potential due to the photothermal effect of AuNPs.