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ScFv-decorated PEG-PLA-based nanoparticles for enhanced siRNA delivery to Her2⁺ breast cancer
Shuang Dou1, Xian-Zhu Yang, Meng-Hua Xiong
1Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China.
Abstract:
Patients with Her2-overexpressing (Her2(+)) breast cancers generally have a poorer prognosis due to the high aggressiveness and chemoresistance of the disease. Small interfering RNA (siRNA) targeting the gene encoding polo-like kinase 1 (Plk1; siPlk1) has emerged as an efficient therapeutic agent for Her2(+) breast cancers. Poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PLA)-based nanoparticles for siRNA delivery were previously developed and optimized. In this study, for targeted delivery of siPlk1 to Her2(+) breast cancer, anti-Her2 single-chain variable fragment antibody (ScFv(Her2))-decorated PEG-PLA-based nanoparticles with si Plk1 encapsulation (ScFv(Her2)-NP(si) Plk1) are developed. With the rationally designed conjugation site, ScFv(Her2)-NP(siRNA) can specifically bind to the Her2 antigen overexpressed on the surface of Her2(+) breast cancer cells. Therefore, ScFv(Her2)-NP(si) Plk1 exhibits improved cellular uptake, promoted Plk1 silencing efficiency, and induced enhanced tumor cell apoptosis in Her2(+) breast cancer cells, when compared with nontargeted NP(si) Plk1. More importantly, ScFv(Her2)-NP(siRNA) markedly enhances the accumulation of siRNA in Her2(+) breast tumor tissue, and remarkably improves the efficacy of tumor suppression. Dose-dependent anti-tumor efficacy further demonstrates that ScFvHer2 -decorated PEG-PLA-based nanoparticles with siPlk1 encapsulation can significantly enhance the inhibition of Her2(+) breast tumor growth and reduce the dose of injected siRNA. These results suggest that ScFvHer2 -decorated PEG-PLA-based nanoparticles show great potential for targeted RNA interference therapy of Her2(+) breast tumor.
Insights
Targeted nanoparticles delivering small interfering RNA (siRNA) against Plk1 (siPlk1) effectively treat Her2-overexpressing breast cancer. These ScFv(Her2)-decorated nanoparticles enhance siPlk1 delivery, improve tumor suppression, and reduce required siRNA dosage.
Area of Science:
- Biotechnology
- Nanomedicine
- Oncology
Background:
- Her2-overexpressing breast cancers are aggressive and chemoresistant, leading to poorer prognoses.
- Small interfering RNA (siRNA) targeting polo-like kinase 1 (Plk1; siPlk1) shows therapeutic potential for Her2(+) breast cancers.
- Poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PLA) nanoparticles are effective for siRNA delivery.
Purpose of the Study:
- To develop targeted nanoparticles for delivering siPlk1 to Her2(+) breast cancer cells.
- To evaluate the efficacy of anti-Her2 single-chain variable fragment antibody (ScFv(Her2))-decorated PEG-PLA nanoparticles carrying siPlk1 (ScFv(Her2)-NP(si)Plk1) for targeted RNA interference therapy.
Main Methods:
- Conjugation of ScFv(Her2) to PEG-PLA nanoparticles encapsulating siPlk1.
- Assessment of nanoparticle binding specificity to Her2 antigen on cancer cells.
- Evaluation of cellular uptake, Plk1 gene silencing, apoptosis induction, and tumor suppression in Her2(+) breast cancer models.
Main Results:
- ScFv(Her2)-NP(si)Plk1 specifically binds to Her2(+) breast cancer cells.
- Targeted nanoparticles show enhanced cellular uptake, Plk1 silencing, and apoptosis induction compared to non-targeted nanoparticles.
- Significant accumulation of siRNA in tumor tissue and improved tumor suppression efficacy were observed.
- Dose-dependent anti-tumor activity demonstrated enhanced inhibition of tumor growth and reduced siRNA dosage.
Conclusions:
- ScFv(Her2)-decorated PEG-PLA nanoparticles effectively deliver siPlk1 to Her2(+) breast tumors.
- This targeted approach shows significant potential for RNA interference therapy in Her2(+) breast cancer.
- The strategy enhances therapeutic efficacy and allows for reduced siRNA dosage.
