Sequential Release of Pooled siRNAs and Paclitaxel by Aptamer-Functionalized Shell-Core Nanoparticles to Overcome Paclitaxel Resistance of Prostate Cancer
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Published on: June 23, 2020
Qianqian Guo1, Yang Dong2, Yanhua Zhang2
1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
Abstract:
Paclitaxel (PTX) is a first-line chemotherapeutic agent to treat prostate cancer (PCa), but a large number of patients acquired drug resistance after short-term treatment. To develop combinational therapeutics to overcome PTX-resistant PCa, we established PTX-resistant LNCaP (LNCaP/PTX) cells and found that the LNCaP/PTX cells exhibited epithelial-mesenchymal transition (EMT) and enhanced metastasis during the selection process. We revealed that β-tubulin III, androgen receptor, and CXCR4 expressions were significantly increased in LNCaP/PTX cells and directly contributed to PTX resistance and EMT. Therefore, we developed prostate-specific membrane antigen aptamer (Apt)-functionalized shell-core nanoparticles (PTX/siRNAs NPs-Apt); the hydrophobic DSPE encapsulating PTX formed the dense inner core and the hydrophilic Apt-PEG2K with calcium phosphate (CaP) absorbing siRNAs formed the outer shell to sequentially release siRNAs and PTX, where CaP could trigger lysosomal escape to ensure that pooled siRNAs efficiently released into the cytoplasm to reverse EMT and resensitize PTX, while the PTX located in the core was subsequently released to exert the killing effect of chemotherapy to achieve the best synergistic effect. PTX/siRNAs NPs-Apt showed an enhanced tumor-targeting ability and achieved superior efficacy in the subcutaneous and orthotopic PCa tumor model with minimal side effects.
Insights
New nanoparticles combine paclitaxel (PTX) and siRNAs to overcome prostate cancer (PCa) drug resistance. This dual-action therapy reverses epithelial-mesenchymal transition (EMT) and enhances chemotherapy effectiveness with minimal side effects.
Area of Science:
- Oncology
- Nanomedicine
- Drug Delivery
Background:
- Paclitaxel (PTX) is a primary treatment for prostate cancer (PCa), but drug resistance frequently develops.
- PTX-resistant PCa cells (LNCaP/PTX) show increased epithelial-mesenchymal transition (EMT) and metastasis.
- Elevated β-tubulin III, androgen receptor, and CXCR4 expression contribute to PTX resistance and EMT.
Purpose of the Study:
- To develop novel combinational therapeutics to overcome PTX resistance in prostate cancer.
- To create a targeted nanoparticle system for sequential drug and siRNA delivery.
- To investigate the potential of reversing EMT and resensitizing PCa to PTX.
Main Methods:
- Established PTX-resistant LNCaP/PTX cells to study resistance mechanisms.
- Engineered prostate-specific membrane antigen aptamer (Apt)-functionalized shell-core nanoparticles (PTX/siRNAs NPs-Apt).
- Utilized DSPE for PTX encapsulation in the core and Apt-PEG2K with calcium phosphate (CaP) for siRNA loading in the shell.
Main Results:
- PTX/siRNAs NPs-Apt demonstrated enhanced tumor targeting.
- The nanoparticles sequentially released siRNAs to reverse EMT and PTX for chemotherapy.
- Superior efficacy was observed in subcutaneous and orthotopic PCa models with reduced side effects.
Conclusions:
- PTX/siRNAs NPs-Apt effectively overcome PTX resistance in prostate cancer.
- The nanoparticle system facilitates sequential release for synergistic therapeutic effects.
- This approach shows promise for treating advanced and resistant prostate cancer with improved safety.
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