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Prostate-Specific Membrane Antigen and Esterase Dual Responsive Camptothecin-Oligopeptide Self-Assembled
Bing Xu1, Mengmeng Yan1, Fei Zhou1
1School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People's Republic of China.
Background:
The clinical utility of camptothecin (CPT) is restricted by poor aqueous solubility, high lipophilicity, active lactone ring instability, and off-targeted toxicities. We report here a prostate-specific membrane antigen (PSMA) and esterase dual responsive self-assembled nanoparticles (CPT-WT-H NPs) for highly efficient CPT delivery and effective cancer therapy.
Methods And Results:
In this study, smart self-assembled nanoparticles CPT-WT-H NPs were elaborately designed and synthesized by combing hydrophobic CPT with hydrophilic PSMA-responsive penta-peptide via a cleavable ester bond. This dual responsive nanoparticle with negatively charged surface first respond to the extracellular PSMA and then to the intracellular esterase, achieving a programmable release of CPT at the tumor site and producing the byproducts of biocompatible glutamic acid and aspartic acid. Our data demonstrated that CPT-WT-H NPs exhibited greatly improved water solubility and stability. Results from MTT and flow cytometry showed CPT-WT-H NPs exhibited significantly higher cytotoxicity as well as apoptosis-inducing activity against PSMA-expressing LNCaP-FGC cells than the non-PSMA-expressing cancer cells, showing excellent cytotoxic selectivity. Moreover, the unique nanostructure provided the efficient transportation of CPT to tumor site, which resulted in the effective inhibition of tumor growth and low systemic toxicity in vivo.
Conclusion:
CPT-WT-H NPs exhibited excellent in vitro PSMA-response ability and in vivo antitumor activity and safety, holding the promise to become a new and potent anticancer drug. The current research presents a promising strategy for efficient drug delivery.
Insights
This study developed dual-responsive nanoparticles for camptothecin (CPT) delivery, enhancing its solubility and targeting prostate-specific membrane antigen (PSMA)-expressing tumors for effective cancer therapy with reduced toxicity.
Area of Science:
- Nanotechnology
- Drug Delivery Systems
- Cancer Therapeutics
Background:
- Camptothecin (CPT) has limited clinical use due to poor solubility, instability, and toxicity.
- Developing targeted delivery systems is crucial for improving CPT efficacy and safety.
Purpose of the Study:
- To design and synthesize dual-responsive nanoparticles (CPT-WT-H NPs) for enhanced camptothecin (CPT) delivery.
- To leverage prostate-specific membrane antigen (PSMA) and esterase responsiveness for targeted CPT release.
- To evaluate the in vitro and in vivo performance of CPT-WT-H NPs in cancer therapy.
Main Methods:
- Synthesized dual-responsive nanoparticles by conjugating CPT with a PSMA-responsive peptide via an ester bond.
- Investigated nanoparticle response to PSMA and intracellular esterase for controlled CPT release.
- Assessed cytotoxicity, apoptosis induction, and in vivo antitumor activity using cell lines and animal models.
Main Results:
- CPT-WT-H NPs demonstrated improved water solubility and stability compared to free CPT.
- The nanoparticles exhibited significant, selective cytotoxicity and apoptosis-inducing activity against PSMA-expressing cancer cells.
- In vivo studies showed effective tumor growth inhibition and low systemic toxicity.
Conclusions:
- CPT-WT-H NPs show promising in vitro and in vivo antitumor efficacy and safety.
- The dual-responsive nanoparticle system offers a potent strategy for efficient camptothecin drug delivery.
- This approach holds potential for developing novel anticancer therapeutics.
