title: ScFv-decorated PEG-PLA-based nanoparticles for enhanced siRNA delivery to Her2⁺ breast cancer.
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.
authors.affiliation: Hefei 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.
authors.forename: Shuang
authors.initials: S
authors.lastname: Dou
authors.forename: Xian-Zhu
authors.initials: XZ
authors.lastname: Yang
authors.forename: Meng-Hua
authors.initials: MH
authors.lastname: Xiong
authors.forename: Chun-Yang
authors.initials: CY
authors.lastname: Sun
authors.forename: Yan-Dan
authors.initials: YD
authors.lastname: Yao
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Zhu
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000008:administration & dosage*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D011092:Polyethylene Glycols; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D057127:Single-Chain Antibodies; D000097869:Polo-Like Kinase 1; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer
keywords: Her2; breast cancer; siRNA delivery; single-chain antibody fragment; tumor targeting