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Triple negative breast cancer therapy with CDK1 siRNA delivered by cationic lipid assisted PEG-PLA nanoparticles
Yang Liu1, Yan-Hua Zhu1, Cheng-Qiong Mao1
1CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, China.
Abstract:
There is no effective clinical therapy yet for triple-negative breast cancer (TNBC) without particular human epidermal growth factor receptor-2, estrogen and progesterone receptor expression. In this study, we report a molecularly targeted and synthetic lethality-based siRNA therapy for TNBC treatment, using cationic lipid assisted poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PLA) nanoparticles as the siRNA carrier. It is demonstrated that only in c-Myc overexpressed TNBC cells, while not in normal mammary epithelial cells, delivery of siRNA targeting cyclin-dependent kinase 1 (CDK1) with the nanoparticle carrier (NPsiCDK1) induces cell viability decreasing and cell apoptosis through RNAi-mediated CDK1 expression inhibition, indicating the synthetic lethality between c-Myc with CDK1 in TNBC cells. Moreover, systemic delivery of NPsiCDK1 is able to suppress tumor growth in mice bearing SUM149 and BT549 xenograft and cause no systemic toxicity or activate the innate immune response, suggesting the therapeutic promise with such nanoparticles carrying siCDK1 for c-Myc overexpressed triple negative breast cancer.
Insights
New nanoparticle therapy targets triple-negative breast cancer (TNBC) by inhibiting CDK1 in c-Myc overexpressing cells. This synthetic lethality approach shows promise for TNBC treatment with minimal toxicity.
Area of Science:
- Biomedical Engineering
- Oncology
- Nanotechnology
Background:
- Triple-negative breast cancer (TNBC) lacks effective targeted therapies due to the absence of specific receptor expression.
- Current treatment options for TNBC are limited, necessitating novel therapeutic strategies.
- The overexpression of c-Myc is a characteristic feature in a subset of TNBC cells.
Purpose of the Study:
- To develop and evaluate a molecularly targeted siRNA therapy for TNBC utilizing a synthetic lethality approach.
- To investigate the therapeutic potential of targeting cyclin-dependent kinase 1 (CDK1) in c-Myc overexpressing TNBC cells.
- To assess the efficacy and safety of cationic lipid-assisted PEG-PLA nanoparticles for delivering siRNA against CDK1 (siCDK1) in TNBC.
Main Methods:
- Development of poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PLA) nanoparticles for siRNA delivery.
- Systemic administration of nanoparticle-loaded siCDK1 (NPsiCDK1) in mouse models bearing TNBC xenografts (SUM149 and BT549).
- Evaluation of cell viability, apoptosis, CDK1 expression inhibition, tumor growth suppression, systemic toxicity, and innate immune response activation.
Main Results:
- NPsiCDK1 selectively induced cell viability decrease and apoptosis in c-Myc overexpressing TNBC cells, but not in normal mammary cells.
- RNA interference-mediated inhibition of CDK1 expression was confirmed, demonstrating synthetic lethality between c-Myc and CDK1 in TNBC.
- Systemic NPsiCDK1 delivery effectively suppressed tumor growth in vivo without causing systemic toxicity or activating innate immunity.
Conclusions:
- The study establishes a synthetic lethality strategy targeting the c-Myc/CDK1 pathway in TNBC.
- PEG-PLA nanoparticles serve as an effective and safe carrier for delivering siCDK1 for TNBC therapy.
- This nanoparticle-based siRNA therapy holds significant therapeutic promise for c-Myc overexpressing TNBC.
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