Efficient and targeted drug/siRNA co-delivery mediated by reversibly crosslinked polymersomes toward anti-inflammatory treatment of ulcerative colitis (UC)
- 27 Downloads
Co-delivery of anti-inflammatory siRNA and hydrophilic drug provides a promising approach for the treatment of ulcerative colitis (UC). However, lack of a suitable and efficient co-delivery carrier poses critical challenge against their utilization. We herein developed macrophage-targeting, reversibly crosslinked polymersomes (TKPR-RCP) based on the TKPR-modified, poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) triblock copolymer, which could efficiently encapsulate TNF-α siRNA and dexamethasone sodium phosphate (DSP) in their hydrophilic core. The cationic PEI segments provided additional electrostatic interactions with cargo molecules to promote the encapsulation, and disulfide crosslinking of the polymersome membrane endowed the TKPR-RCP with high colloidal stability. Because the cationic PEI was embedded in the hydrophilic core, the polymersomes displayed neutral surface charge and thus possessed high serum stability. The TKPR-RCP co-encapsulating TNF-α siRNA and DSP could be efficiently internalized by macrophages (∼ 98%) and undergo redox-responsive membrane de-crosslinking to accelerate cargo release in the cytoplasm, thus inducing efficient gene silencing and anti-inflammatory effect. Intravenous injection of the co-delivery TKPR-RCP mediated potent and cooperative anti-inflammatory effect in inflamed colons of UC mice, and significantly prevented animals from colonic injury. This study therefore provides a promising approach for the co-delivery of hydrophilic drug/siRNA toward the treatment of inflammatory bowel diseases.
Keywordsulcerative colitis (UC anti-inflammatory therapy polymersomes reversible crosslinking siRNA/drug co-delivery macrophage targeting
Unable to display preview. Download preview PDF.
This study was supported by the National Natural Science Foundation of China (Nos. 51573123, 51722305, and 51633005), the Ministry of Science and Technology of China (No. 2016YFA0201200), 111 project, and Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
- Yin, L. C.; Song, Z. Y.; Qu, Q. H.; Kim, K. H.; Zheng, N.; Yao, C.; Chaudhury, I.; Tang, H. Y.; Gabrielson, N. P.; Uckun, F. M. et al. Supramolecular selfassembled nanoparticles mediate oral delivery of therapeutic TNF-α siRNA against systemic inflammation. Angew. Chem., Int. Ed. 2013, 52, 5757–5761.CrossRefGoogle Scholar
- Zhang, S. F.; Ermann, J.; Succi, M. D.; Zhou, A.; Hamilton, M. J.; Cao, B.; Korzenik, J. R.; Glickman, J. N.; Vemula, P. K.; Glimcher, L. H. et al. An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease. Sci. Transl. Med. 2015, 7, 300ra128.Google Scholar
- Molodecky, N. A.; Soon, I. S.; Rabi, D. M.; Ghali, W. A.; Ferris, M.; Chernoff, G.; Benchimol, E. I.; Panaccione, R.; Ghosh, S.; Barkema, H. W. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012, 142, 46–54.e42.CrossRefGoogle Scholar
- Meng, H.; Mai, W. X.; Zhang, H. Y.; Xue, M.; Xia, T.; Lin, S. J.; Wang, X.; Zhao, Y.; Ji, Z. X.; Zink, J. I. et al. Codelivery of an optimal drug/siRNA combination using mesoporous silica nanoparticles to overcome drug resistance in breast cancer in vitro and in vivo. ACS Nano 2013, 7, 994–1005.CrossRefGoogle Scholar
- Wong, C. K.; Laos, A. J.; Soeriyadi, A. H.; Wiedenmann, J.; Curmi, P. M. G.; Gooding, J. J.; Marquis, C. P.; Stenzel, M. H.; Thordarson, P. Polymersomes prepared from thermoresponsive fluorescent protein-polymer bioconjugates: Capture of and report on drug and protein payloads. Angew. Chem., Int. Ed. 2015, 127, 5407–5412.CrossRefGoogle Scholar
- Zou, Y.; Fang, Y.; Meng, H.; Meng, F. H.; Deng, C.; Zhang, J.; Zhong, Z. Y. Self-crosslinkable and intracellularly decrosslinkable biodegradable micellar nanoparticles: A robust, simple and multifunctional nanoplatform for high-efficiency targeted cancer chemotherapy. J. Control. Release 2016, 244, 326–335.CrossRefGoogle Scholar
- Crielaard, B. J.; Rijcken, C. J.; Quan, L. D.; Van der Wal, S.; Altintas, I.; Van der Pot, M.; Kruijtzer, J. A. W.; Liskamp, R. M. J.; Schiffelers, R. M.; van Nostrum, C. F. et al. Glucocorticoid-loaded core-cross-linked polymeric micelles with tailorable release kinetics for targeted therapy of rheumatoid arthritis. Angew. Chem., Int. Ed. 2012, 124, 7366–7370.CrossRefGoogle Scholar
- He, H.; Zheng, N.; Song, Z. Y.; Kim, K. H.; Yao, C.; Zhang, R. J.; Zhang, C. L.; Huang, Y. H.; Uckun, F. M.; Cheng, J. J. et al. Suppression of hepatic inflammation via systemic siRNA delivery by membrane-disruptive and endosomolytic helical polypeptide hybrid nanoparticles. ACS Nano 2016, 10, 1859–1870.CrossRefGoogle Scholar