Redox-responsive polymeric nanocarriers for targeted delivery of bruceantin to pancreatic cancer.
LHRH-targeted nanocarriers show promise in delivering bruceantin to pancreatic cancer cells, reducing tumor growth in preclinical models.
Where it sits
this study against the rest of the leuprorelin corpusSummary and findings
This study investigates a redox-responsive polymeric nanocarrier system for delivering bruceantin to pancreatic cancer cells. The system uses LHRH peptides to target cancer cells overexpressing LHRH receptors. The targeted formulation showed superior cytotoxicity and reduced tumor growth in a murine model.
Abstract
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)-<i>block</i>-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. <i>In vitro</i> assays highlight the superior cytotoxicity of the LHRH-targeted BCT formulation (IC<sub>50</sub>, 224.1 μg mL<sup>-1</sup>) compared to the non-targeted formulation (IC<sub>50</sub>, 279.5 μg mL<sup>-1</sup>). 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.
Background
Pancreatic cancer remains a challenging malignancy with limited effective treatments. Bruceantin, a natural product, has shown potential anticancer properties but is hindered by poor bioavailability and toxicity. This study explores a novel delivery system to enhance bruceantin's therapeutic potential by targeting pancreatic cancer cells using LHRH-functionalized nanocarriers.
Methods
The study employed a redox-responsive polymeric nanocarrier system using PEG-SS-PCL copolymer functionalized with LHRH peptides. The system was tested for drug encapsulation efficiency, particle size, and zeta potential. In vitro cytotoxicity assays and in vivo biodistribution studies were conducted using an orthotopic pancreatic cancer murine model.
Results
The LHRH-targeted nanocarrier demonstrated a particle size of 45.7 nm and a zeta potential of +3.5 mV, with a drug encapsulation efficiency of 74.8%. In vitro assays showed enhanced cytotoxicity of the targeted formulation with an IC50 of 224.1 μg mL^-1 compared to 279.5 μg mL^-1 for the non-targeted formulation. In vivo, the targeted nanoparticles accumulated in tumors, reducing tumor growth by approximately 72.4% without adverse effects.
Interpretation
The study suggests that LHRH-functionalized nanocarriers can effectively deliver bruceantin to pancreatic cancer cells, enhancing its cytotoxicity and reducing tumor growth in a murine model. While the results are promising, the clinical significance remains uncertain due to the lack of human data. Further research is needed to assess the potential for clinical translation.
Key findings
- Particle size: 45.7 nm, zeta potential: +3.5 mV.
- Drug encapsulation efficiency: 74.8%.
- IC50 of LHRH-targeted BCT: 224.1 μg mL^-1.
- IC50 of non-targeted BCT: 279.5 μg mL^-1.
- Tumor growth reduced by ~72.4% in murine model.
Limitations
- In vitro and murine model only, no human data.
- Potential translation issues to clinical settings.
- Short-term study, long-term effects unknown.
- Surrogate endpoints, not direct clinical outcomes.