A nanoprodrug derived from branched poly (ethylene glycol) recognizes prostate-specific membrane antigen to precisely suppress prostate cancer progression

Prostate-specific membrane antigen (PSMA) is overexpressed in 80–90 % of prostate cancers (PCa) and is widely used as a diagnostic and therapeutic biomarker. Docetaxel (DTX), an FDA-approved anti-microtubule drug, is commonly employed to manage metastatic castration-resistant PCa; however, DTX therapy is often associated with severe side effects. One promising strategy to mitigate these side effects is the development of nanomedicine by loading small molecules into biocompatible vectors. Poly (ethylene glycol) (PEG) has been extensively used in clinical settings for this purpose, with PEGylated drugs demonstrating significant success. Compared to linear PEG, branched PEG (multi-arm PEG) provides enhanced stability for nanomedicines. In this study, we developed a novel nanoprodrug 4armPEG-Docetaxel DCL (4armPEG-DD) by conjugating a 4-arm PEG with DTX via a reduction-sensitive disulfide bond and further modifying it with 2-[3-[5-amino-1-carboxypentyl]-ureido]-pentanedioic acid (DCL), a PSMA-targeting ligand. Both in vitro and in vivo results demonstrated that the designed nanoprodrug specifically recognized PSMA-positive PCa cells and effectively released DTX in response to the intracellular reducing environment, leading to potent cytotoxic effects on PSMA-positive prostate tumors. Importantly, 4armPEG-DD exhibited improved in vivo safety compared to small-molecule DTX. Thus, we propose that 4armPEG-DD represents a promising candidate for the clinical treatment of PSMA-positive PCa. A nanoprodrug (4armPEG-DD) is derived from branched poly (ethylene glycol) modified with DCL (PSMA ligand) and conjugated with docetaxel, specifically recognizing and suppressing PSMA positive prostate cancer in vitro and in vivo. [Display omitted] •A novel nanoprodrug 4armPEG-DD is developed by conjugating a 4-arm PEG with Docetaxel via a reduction-sensitive disulfide bond and further modifying it with 2-[3-[5-amino-1-carboxypentyl]-ureido]-pentanedioic acid (DCL), a PSMA-targeting ligand.•4armPEG-DD exhibits amphiphilicity and self-assembles into near-spherical nanostructures in an aqueous environment, with a particle size of approximately 110 nm and a surface potential of approximately 0 mV, which confers long circulation in vivo and excellent passive targeting to tumor tissue.•4armPEG-DD specifically recognizes and suppresses PSMA positive prostate cancer progression in vitro and in vivo•4armPEG-DD has less toxicity towards PSMA-positive PCa tumors compared to the traditional