PSMA-targeted delivery of docetaxel in prostate cancer using small-sized PDA-based micellar nanovectors

In this study, we present the first comparative analysis of active and passive drug delivery systems for docetaxel (DTX) in prostate cancer using supramolecular self-assembled micellar nanovectors. Specifically, we developed two novel micelles based on polydiacetylenic amphiphiles (PDA) for passive and active targeting. The active targeting micelles were designed with a prostate-specific membrane antigen (PSMA) ligand, ACUPA, to facilitate recognition by PSMA-positive cancer cells. These PDA-based micelles feature a well-defined structure with a hydrophobic PDA core and a surface functionalized with PEG, and for active targeting, ACUPA. Our micelles demonstrated excellent encapsulation capacity, significantly improving DTX solubility in water, a crucial factor for clinical drug use. In vitro studies confirmed the safety and cytotoxic profiles of both systems, with ACUPAfunctionalized micelles showing notable internalization into PSMA-positive LNCaP cells, mediated through the PSMA-ACUPA interaction. In vivo imaging revealed preferential accumulation of ACUPA-functionalized nanomicelles in LNCaP xenograft tumors, suggesting enhanced retention via specific ACUPA-PSMA interactions and active uptake by LNCaP cells. Notably, Balb/c-Foxn1nu/nu early in vivo studies showed a marked reduction in tumor volume and tumor expression levels of proliferation, cell cycle progression, cell survival and anti-apoptotic markers with DTX-loaded micelles functionalized with ACUPA compared to those without ACUPA. Overall, our studies collect initial evidence regarding the feasibility of supramolecular self-assembly of ACUPA-PDA-based nanomicelles for PSMA-targeted drug chemotherapy delivery developments.