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Development of targeted therapy therapeutics to sensitize triple-negative breast cancer chemosensitivity utilizing
Long Zhang1,2, Chaofeng Mu3, Tinghong Zhang4,5
1School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China.
Background:
To date, triple-negative breast cancer (TNBC) treatment options are limited because of the loss of target receptors and, as a result, are only managed with chemotherapy. What is worse is that TNBC is frequently developing resistance to chemotherapy. By using small interfering RNA (siRNA)-based therapeutics, our recent work demonstrated X-box-binding protein 1 (XBP1) was linked to human epidermal growth factor receptor 2 positive (HER2+) breast cancer development and chemoresistance. Given the instability, off-target effects, net negative charge, and hydrophobicity of siRNA in vivo utilization and clinical transformation, its use in treatment is hampered. Thus, the development of a siRNA-based drug delivery system (DDS) with ultra-stability and specificity is necessary to address the predicament of siRNA delivery.
Results:
Here, we assembled RNase resistant RNA nanoparticles (NPs) based on the 3WJ structure from Phi29 DNA packaging motor. To improved targeted therapy and sensitize TNBC to chemotherapy, the RNA NPs were equipped with an epidermal growth factor receptor (EGFR) targeting aptamer and XBP1 siRNA. We found our RNA NPs could deplete XBP1 expression and suppress tumor growth after intravenous administration. Meanwhile, RNA NPs treatment could promote sensitization to chemotherapy and impede angiogenesis in vivo.
Conclusions:
The results further demonstrate that our RNA NPs could serve as an effective and promising platform not only for siRNA delivery but also for chemotherapy-resistant TNBC therapy.
Insights
Researchers developed novel RNA nanoparticles (NPs) to deliver X-box-binding protein 1 (XBP1) small interfering RNA (siRNA) for treating chemotherapy-resistant triple-negative breast cancer (TNBC). These NPs target epidermal growth factor receptors (EGFR), suppress tumor growth, and enhance chemotherapy sensitivity.
Area of Science:
- Biotechnology
- Nanomedicine
- Oncology
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies and often develops chemoresistance.
- X-box-binding protein 1 (XBP1) is implicated in TNBC development and chemoresistance.
- Current small interfering RNA (siRNA) therapeutics face challenges in stability, specificity, and clinical application.
Purpose of the Study:
- To develop a stable and specific siRNA-based drug delivery system (DDS) for TNBC treatment.
- To create RNA nanoparticles (NPs) capable of targeting and delivering XBP1 siRNA to TNBC cells.
- To evaluate the efficacy of these RNA NPs in sensitizing TNBC to chemotherapy and suppressing tumor growth.
Main Methods:
- Assembly of RNase-resistant RNA nanoparticles (NPs) utilizing the 3WJ structure from Phi29 DNA packaging motor.
- Functionalization of RNA NPs with an epidermal growth factor receptor (EGFR) targeting aptamer and XBP1 siRNA.
- Intravenous administration of RNA NPs in vivo for therapeutic evaluation.
Main Results:
- The developed RNA NPs effectively depleted XBP1 expression in vivo.
- Treatment with RNA NPs suppressed tumor growth after intravenous administration.
- RNA NP treatment enhanced chemotherapy sensitization and impeded tumor angiogenesis.
Conclusions:
- The engineered RNA NPs represent a promising platform for siRNA delivery in cancer therapy.
- This novel DDS is effective for treating chemotherapy-resistant TNBC by targeting XBP1 and enhancing treatment efficacy.
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