Tumor acidity-sensitive linkage-bridged block copolymer for therapeutic siRNA delivery

• Published in: Biomaterials 2016-05, Vol.88, p.48-59
• Main Authors: Xu, Cong-Fei, Zhang, Hou-Bing, Sun, Chun-Yang, Liu, Yang, Shen, Song, Yang, Xian-Zhu, Zhu, Yan-Hua, Wang, Jun
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Breast - metabolism; Breast - pathology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cancer nanotechnology; Cell Cycle Proteins - genetics; Cell Line, Tumor; Delayed-Action Preparations - chemistry; Dentistry; Female; Humans; Hydrogen-Ion Concentration; Lactic Acid - chemistry; Mice; Nanoparticles - chemistry; PEG detachment; Polo-Like Kinase 1; Polyethylene Glycols - chemistry; Polyglycolic Acid - chemistry; Polylactic Acid-Polyglycolic Acid Copolymer; Protein Serine-Threonine Kinases - genetics; Proto-Oncogene Proteins - genetics; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; RNA, Small Interfering - pharmacokinetics; RNA, Small Interfering - therapeutic use; RNAi Therapeutics; siRNA; Tumor pH-responsive
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2016.02.031

Abstract The design of ideal nanoparticle delivery systems should be capable of meeting the requirements of several stages of drug delivery, including prolonged circulation, enhanced accumulation and penetration in the tumor, facilitated cellular internalization and rapid release of the active drug in the tumor cells. However, among the current design strategies, meeting the requirements of one stage often conflicts with the other. Herein, a tumor pH-labile linkage-bridged block copolymer of poly(ethylene glycol) with poly(lacide- co -glycolide) (PEG- Dlink m -PLGA) was used for siRNA delivery to fulfill all aforementioned requirements of these delivery stages. The obtained siRNA-encapsulating PEG- Dlink m -PLGA nanoparticle gained efficiently prolonged circulation in the blood and preferential accumulation in tumor sites via the PEGylation. Furthermore, the PEG surface layer was detached in response to the tumor acidic microenvironment to facilitate cellular uptake, and the siRNA was rapidly released within tumor cells due to the hydrophobic PLGA layer. Hence, PEG- Dlink m -PLGA nanoparticles met the requirements of several stages of drug delivery, and resulted in the enhanced therapeutic effect of the nanoparticular delivery systems.