Redox-responsive polymeric nanocarriers for targeted delivery of bruceantin to pancreatic cancer

Bruceantin (BCT), a natural product with promising anticancer properties, has limited clinical utility due to its hydrophobicity, low systemic bioavailability, and dose-limiting toxicity. Here, we report a redox-responsive polymeric nanoplatform based on a disulfide-linked diblock copolymer, poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-SS-PCL), functionalized with luteinizing hormone-releasing hormone (LHRH) peptides for the targeted delivery of BCT to pancreatic cancer cells overexpressing LHRH receptors. The nanoplatform exhibits favorable physicochemical characteristics, including optimal particle size (45.7 nm), zeta potential (+3.5 mV), and high drug encapsulation efficiency (74.8%). Notably, it demonstrates redox-responsive drug release under glutathione-rich conditions that mimic the tumor microenvironment. In vitro assays highlight the superior cytotoxicity of the LHRH-targeted BCT formulation (IC₅₀, 224.1 μg mL^-1) compared to the non-targeted formulation (IC₅₀, 279.5 μg mL^-1). Biodistribution studies in an orthotopic pancreatic cancer murine model revealed substantial accumulation of LHRH-targeted nanoparticles primarily in tumors following systemic administration, with minimal hepatic deposition. Furthermore, BCT-loaded nanoplatforms reduced tumor growth by ∼72.4% relative to controls, with no detectable adverse effects. Collectively, this work highlights the potential of LHRH-functionalized nanoplatforms as a promising strategy for the targeted treatment of pancreatic cancer with BCT, offering enhanced therapeutic efficacy with minimal systemic toxicity and paving the way for future clinical translation of this natural product.