pH-triggered chitosan nanogels via an ortho ester-based linkage for efficient chemotherapy

Publication date: Available online 4 May 2017
Source:Acta Biomaterialia
Author(s): Guanqing Yang, Xin Wang, Shengxiang Fu, Rupei Tang, Jun Wang
Herein, we report a new type of chitosan-based nanogels via an ortho ester-based linkage, used as drug carriers for efficient chemotherapy. First, we synthesize a novel diacrylamide containing ortho ester (OEAM) as an acid-labile cross-linker. Subsequently, methacrylated succinyl-chitosan (MASCS) was prepared and polymerized with OEAM at different molar ratio to give a series of pH-triggered MASCS nanogels. Doxorubicin (DOX) as a model anticancer drug was loaded into MASCS nanogels with a loading content of 16.5%. As expected, with the incorporation of orthoester linkages, these nanogels showed pH-triggered degradation and drug release at acidic pH values. In vitro cellular uptake shows that the DOX-loaded nanogels could be preferentially internalized by two-dimensional (2D) cells and three-dimensional (3D) multicellular spheroids (MCs), resulting higher inhibition on the proliferation of tumor cells. In vivo biodistribution and anti-tumor effect were determined in H22 tumor-bearing mice, and the results demonstrate that the acid-labile MASCS nanogels can significantly prolong the blood circulation time of DOX and improve the accumulation in tumor areas, leading to higher therapeutic efficacy.Statement of SignificanceWe design new pH-triggered chitosan nanogels via an ortho ester-based cross-linker for efficient drug-loading and chemotherapy. These drug-loaded nanogels exhibit excellent pH-triggered drug release behavior due to the degradation of ortho ester linkages at mildly acid environment. In vitro and in vivo results demonstrate that the nanogels could be efficiently internalized by 2D cells and 3D-MCs, improve drug concentration in solid tumor, and lead to higher therapeutic efficacy. To the best of our knowledge, this is the first report on using an ortho ester-based cross-linker to prepare pH-triggered chitosan nanogels as tumor carriers, which may provide a potential route for improved safety and to increase the therapeutic efficacy of anticancer therapy.

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