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Published on: April 28, 2021
pH-Sensitive Shell-Core Platform Block DNA Repair Pathway To Amplify Irreversible DNA Damage of Triple Negative
Yang Dong1, Hongze Liao2, Hao Fu1
1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine , Shanghai Jiao Tong University , Shanghai 200032 , China.
Abstract:
Triple negative breast cancer (TNBC) is insensitive to either chemotherapy or endocrine therapy because of the powerful DNA reparation and the negative expression of surface antigens, which urgently claims for an effective approach to improve the prognosis. Herein, DNA repair blocker BRCA1 small interfering RNA (siRNA) was introduced with cisplatin (Pt) into the elaborately designed pH-sensitive shell-core platform to enhance the chemotherapeutic treatment effect by silencing the DNA repair related gene. In this platform, BRCA1 siRNA and Pt prodrug (Pro-Pt) were separately encapsulated in the porous outer shell and hydrophobic inner core with extremely high encapsulation efficiency and stability effectively preventing them from degradation during circulation. Suitable size and urokinase plasminogen activator analogues (uPA) with high affinity for the uPA receptor (uPAR) realized an excellent dual passive and active tumor targeting ability. Moreover, the exposed PEG hydrophilic chain prevented the nanoparticles (NPs) from precipitating by serum protein or inactivating by nuclease in the blood cycle. Most importantly, the degradable CaP (calcium ions and phosphate ions) shell with smart pH sensitivity would dissipate from NPs in the lysosomes to burst the lysosome membranes so as to guarantee the lysosomal escape and the sequential release of the siRNA and Pro-Pt where the BRCA1 siRNA blocked the DNA repairing pathway followed by reducing Pro-Pt to Pt for irreversible DNA damage. Hence, the uPA-SP@CaP NPs provided a promising strategy for high-efficiency treatment of TNBC along with bringing new hope for more patients.
Insights
This study introduces a novel nanoparticle platform for treating triple-negative breast cancer (TNBC). The platform delivers BRCA1 siRNA and cisplatin to silence DNA repair and enhance chemotherapy, offering new hope for patients.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) lacks effective targeted therapies due to resistance mechanisms.
- Developing novel drug delivery systems is crucial for improving TNBC treatment outcomes.
Purpose of the Study:
- To develop a pH-sensitive nanoparticle platform for co-delivery of BRCA1 siRNA and cisplatin for TNBC treatment.
- To enhance therapeutic efficacy by silencing DNA repair genes and improving chemotherapy effects.
Main Methods:
- Encapsulation of BRCA1 siRNA and cisplatin prodrug into a pH-sensitive shell-core nanoparticle.
- Utilizing urokinase plasminogen activator analogues (uPA) for active tumor targeting.
- Investigating nanoparticle stability, tumor targeting, and drug release mechanisms.
Main Results:
- The nanoparticles demonstrated high encapsulation efficiency and stability.
- Dual passive and active targeting strategies achieved excellent tumor accumulation.
- pH-sensitive calcium phosphate shell facilitated lysosomal escape and sequential drug release.
- BRCA1 siRNA effectively silenced DNA repair, enhancing cisplatin's cytotoxic effect.
Conclusions:
- The developed uPA-SP@CaP nanoparticles represent a promising strategy for effective TNBC treatment.
- This approach offers a potential new therapeutic avenue for TNBC patients.
- The nanoparticle system enhances chemotherapy by targeting DNA repair pathways.
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