Nanomedicine with Stepwise Targeting of GGT/CAIX Relay to Potentiate Transcytosis and Antitumor Efficacy

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Poor tumor penetration and hypoxic microenvironments limit nanodrug efficacy. In this study, we engineered a nanodrug delivery system via relay transcytosis mediated by stepwise targeting of GGT/CAIX to promote tumor penetration and antitumor efficacy. The multifunctional polymer carrier, P1, was constructed via the Michael addition reaction. DLS confirmed the micelle responsiveness. The in vitro drug release properties, cellular uptake properties, and tumor penetration ability of the GEM-loaded micelles were investigated. The in vitro antitumor effects of GEM-loaded micelles were studied separately against normoxic/hypoxic cancer cells using the MTT assay and against 3D MTSs using the alamarBlue assay. The in vivo antitumor efficacy of GEM-loaded micelles was evaluated in a subcutaneous PANC-1 xenograft model. As a result, the GEM-loaded P1 micelles demonstrated deep tumor penetration and potent anticancer efficacy through relay transcytosis mediated by the stepwise targeting of GGT/CAIX. Our work provides new insights into constructing nanodrug delivery systems with enhanced tumor delivery capabilities.