Tandem Effect Of Decursin And Enzalutamide Co-Delivered By Elastin Nanogel In Prostate Cancer Xenografts

Prostate cancer frequently develops resistance to androgen receptor-targeted therapies such as enzalutamide, underscoring the need for rational combination strategies that exploit complementary mechanisms while improving delivery and tolerability. Here, we investigated the tandem therapeutic potential of decursin—a natural coumarin with documented anti-proliferative, anti-androgenic, and pathway-modulating effects in prostate cancer—co-delivered with enzalutamide via a biocompatible elastin-based nanogel. In silico predictions using ProTox and STITCH confirmed favorable toxicity profiles and minimal adverse interaction risks for the combination, supporting its preclinical advancement. In vivo toxicity assessments in zebrafish embryos and Sprague-Dawley rats revealed negligible systemic toxicity at therapeutic doses, with only mild, reversible, dose-dependent liver function perturbations at higher exposures. The core efficacy evaluation utilized DU145 human prostate cancer cells, a well-established model of aggressive, androgen-independent disease in athymic nude mouse xenografts. The elastin nanogel-co-loaded formulation elicited a considerable reduction in tumor volume and burden compared to free drugs or monotherapy controls, demonstrating clear tandem synergy and superior anti-tumor activity. These findings highlight the elastin nanogel as an effective platform for overcoming enzalutamide resistance through synergistic pathway targeting, offering a promising translational strategy for castration-resistant prostate cancer with an excellent safety margin.