Dual-Targeting Nanoplatform Integrating Metabolic Glycan Labeling and Bioorthogonal Chemistry for Precise Delivery of Oxaliplatin to PSMA-Positive Prostate Cancer

Abstract

Platinum-based chemotherapy drugs are widely used in the treatment of various cancers due to their broad antitumor spectrum, but their clinical application is severely limited by significant systemic toxicity resulting from nonspecific cytotoxicity. Prostate-specific membrane antigen (PSMA), which is highly overexpressed in most prostate cancer (PCa) cells, presents a promising target for tumor-selective drug delivery. In this study, we designed and synthesized a novel dual-targeting nanoplatform that combines metabolic glycan labeling and bioorthogonal chemistry for the precise delivery of oxaliplatin (OXP) to PSMA-positive prostate cancer cells. The nanoplatform (DDM-NPs) is functionalized with DUPA, a high-affinity PSMA ligand, and encapsulates Ac4ManNAz for metabolic cell surface engineering. Subsequently, a bioorthogonal reaction between the azido-labeled cells and the bicyclo[6.1.0]non-4-yne (BCN)-conjugated prodrug (BCN-OXP) enhanced cellular uptake and cytotoxicity in PSMA-high-expressed cell lines (22Rv1) compared to PSMA-low-expressed cells (PC-3) in vitro and in vivo. Our work establishes a promising strategy to enhance the therapeutic index of platinum drugs through active targeting and bioorthogonal reactions, offering a potential avenue for more effective and safer prostate cancer therapy.