Using low-molecular-weight ligands for targeting in integrated chemodynamic/starvation therapy and chemotherapy for prostate cancer

Targeted therapy enhances tumor elimination while reducing adverse effects by integrating multiple tumoricidal mechanisms. Low molecular weight (LMW) ligands, offering faster pharmacokinetics and improved tumor permeability, present a viable alternative to antibodies. This study presents a novel nanomedicine for prostate cancer therapy, leveraging mesoporous silica nanoparticles (MSN) as the nanocarrier to encapsulate manganese dioxide (MnO2) and doxorubicin (DOX). The resultant nanoparticles are further coated with a polydopamine (PDA) layer and covalently conjugated with glucose oxidase (GOx), forming the MSN@Mn@PDA-GOx/DOX hybrid system (hereafter termed SMPG/DOX NPs). LMW ligands (small-molecule inhibitor DCL and nanobody VHH) targeting prostate-specific membrane antigen (PSMA) were conjugated to create DCL-SMPG/DOX and VHH-SMPG/DOX. Mn2+-mediated Fenton-like reactions converted H2O2 into toxic hydroxyl radicals (·OH) under acidic conditions, enabling chemodynamic therapy (CDT). GOx-generated H2O2 and gluconic acid disrupted nutrient supply, inducing tumor starvation therapy (ST). The increased H2O2 and acidity amplified the Fenton-like reaction, creating a "ROS storm" that synergistically enhanced chemotherapy. LMW targeting improved tumor specificity, efficacy, and reduced side effects. In vitro, DCL-SMPG/DOX showed superior tumor cell internalization and cytotoxicity compared to VHH-SMPG/DOX. In vitro, the cellular internalization rates of VHH-SMPG/DOX and DCL-SMPG/DOX were 34.1% and 44.5%, respectively, significantly higher than that of free DOX uptake (10.3%). Moreover, DCL-SMPG/DOX-induced stronger cytotoxicity compared to VHH-SMPG/DOX. In vivo studies further demonstrated the strong anti-tumor activity of the DCL-SMPG/DOX nanomedicine, underscoring its potential as a prostate cancer treatment. Further research is needed to elucidate its anti-tumor mechanisms.