Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China.
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH, Bethesda, MD, 20892, USA.
Adv Mater. 2018 Mar;30(10). doi: 10.1002/adma.201705737. Epub 2018 Jan 15.
Nanomedicine has shown unprecedented potential for cancer theranostics. Nucleic acid (e.g., DNA and RNA) nanomedicines are of particular interest for combination therapy with chemotherapeutics. However, current nanotechnologies to construct such nucleic acid nanomedicines, which rely on chemical conjugation or physical complexation of nucleic acids with chemotherapeutics, have restrained their clinical translation due to limitations such as low drug loading efficiency and poor biostability. Herein, in situ rolling circle transcription (RCT) is applied to synthesize short hairpin RNA (shRNA) on amphiphilic DNA-polylactide (PLA) micelles. Core-shell PLA@poly-shRNA structures that codeliver a high payload of doxorubicin (Dox) and multidrug resistance protein 1 (MDR1) targeted shRNA for MDR breast cancer (BC) therapy are developed. DNA-PLA conjugates are first synthesized, which then self-assemble into amphiphilic DNA-PLA micelles; next, using the conjugated DNA as a promoter, poly-shRNA is synthesized on DNA-PLA micelles via RCT, generating PLA@poly-shRNA microflowers; and finally, microflowers are electrostatically condensed into nanoparticles using biocompatible and multifunctional poly(ethylene glycol)-grafted polypeptides (PPT-g-PEG). These PLA@poly-shRNA@PPT-g-PEG nanoparticles are efficiently delivered into MDR breast cancer cells and accumulated in xenograft tumors, leading to MDR1 silencing, intracellular Dox accumulation, potentiated apoptosis, and enhanced tumor therapeutic efficacy. Overall, this nanomedicine platform is promising to codeliver anticancer nucleic acid therapeutics and chemotherapeutics.
纳米医学在癌症治疗学方面展现出前所未有的潜力。核酸（例如 DNA 和 RNA）纳米药物因其与化疗药物联合治疗的潜力而受到特别关注。然而，目前构建此类核酸纳米药物的纳米技术，依赖于核酸与化疗药物的化学偶联或物理复合，由于载药效率低和生物稳定性差等限制，限制了其临床转化。在此，通过原位滚环转录（RCT）将短发夹 RNA（shRNA）合成在两亲性 DNA-聚乳酸（PLA）胶束上。开发了载有多柔比星（Dox）和多药耐药蛋白 1（MDR1）靶向 shRNA 的高载药量的核-壳 PLA@聚-shRNA 结构，用于多药耐药乳腺癌（BC）治疗。首先合成 DNA-PLA 缀合物，然后自组装成两亲性 DNA-PLA 胶束；接下来，使用共轭 DNA 作为启动子，通过 RCT 在 DNA-PLA 胶束上合成多聚 shRNA，生成 PLA@poly-shRNA 微花；最后，使用生物相容性和多功能聚乙二醇接枝多肽（PPT-g-PEG）将微花静电凝聚成纳米颗粒。这些 PLA@poly-shRNA@PPT-g-PEG 纳米颗粒能够有效地递送至多药耐药乳腺癌细胞并在异种移植肿瘤中积累，导致 MDR1 沉默、细胞内 Dox 积累、增强凋亡和增强肿瘤治疗效果。总的来说，这种纳米医学平台有望共递抗癌核酸治疗药物和化疗药物。
