Intestine Enzyme-responsive Polysaccharide-based Hydrogel to Open Epithelial Tight Junctions for Oral Delivery of Imatinib against Colon Cancer

Cong-Yu Wang; Min Sun; Zhen Fan; Jian-Zhong Du

doi:10.1007/s10118-022-2726-0

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Intestine Enzyme-responsive Polysaccharide-based Hydrogel to Open Epithelial Tight Junctions for Oral Delivery of Imatinib against Colon Cancer

RESEARCH ARTICLE | Updated：2022-09-23

- Intestine Enzyme-responsive Polysaccharide-based Hydrogel to Open Epithelial Tight Junctions for Oral Delivery of Imatinib against Colon Cancer
- Chinese Journal of Polymer Science Vol. 40, Issue 10, Pages: 1154-1164(2022)
- Affiliations：
  
  a.Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, Shanghai 201804, China
  b.Department of Gynaecology and Obstetrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
- Author bio：
  
  fanzhen2018@tongji.edu.cn (Z.F.)
  jzdu@tongji.edu.cn (J.Z.D.)
- Funds：
- DOI：10.1007/s10118-022-2726-0
  CLC：
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Cong-Yu Wang, Min Sun, Zhen Fan, et al. Intestine Enzyme-responsive Polysaccharide-based Hydrogel to Open Epithelial Tight Junctions for Oral Delivery of Imatinib against Colon Cancer. [J]. Chinese Journal of Polymer Science 40(10):1154-1164(2022)
DOI：

Cong-Yu Wang, Min Sun, Zhen Fan, et al. Intestine Enzyme-responsive Polysaccharide-based Hydrogel to Open Epithelial Tight Junctions for Oral Delivery of Imatinib against Colon Cancer. [J]. Chinese Journal of Polymer Science 40(10):1154-1164(2022) DOI： 10.1007/s10118-022-2726-0.

摘要

We developed an intestine enzyme-responsive hydrogel to co-deliver anticancer drug (hydrophobic imatinib) and permeation enhancer (sodium deoxycholate) with long-term controlled release and enhanced intestinal permeability through oral administration (6-fold enhancement of in vivo anticancer effects compared to free imatinib mesylate). This intestine enzyme-responsive hydrogel has great potentials for cancer treatment.

Abstract

Imatinib has been widely used as a selective kinase inhibitor for treating a variety of cancers, and this molecule is very hydrophobic so it is usually modified with mesylate salt in clinic to increase bioavailability. However, pH-dependent aqueous solubility and relatively high dosage of imatinib mesylate greatly reduce the clinical outcomes. To solve this problem, we developed an intestine enzyme-responsive hydrogel to efficiently encapsulate hydrophobic imatinib with long-term controlled release and enhanced intestinal permeability through oral administration. Methacrylic anhydride-modified carboxymethyl chitosan (MA-CMCS) was synthesized ,via, amidation reaction and then MA-CMCS was crosslinked with photoinitator under UV-irradation to form a three-dimensional hydrophilic polymer network. The intestine enzyme responsiveness was endowed with imatinib-loaded hydrogel through hydrolyzation of glucosidic bond, which could achieve enzyme-triggered long-term drug release of up to 2 days. Furthermore, sodium deoxycholate was embedded into the hydrogel to synchronously open epithelial tight junctions with improved intestinal permeability. ,In vitro, studies revealed similar lethality against colon cancer cell for both imatinib mesylate and imatinib-loaded hydrogels. Moreover, significantly enhanced ,in vivo, tumor inhibition (6-fold higher compared to imatinib mesylate) was achieved after oral administration with imatinib-loaded hydrogels. Overall, this enzyme-responsive hydrogel could achieve long-term synchronous release of kinase inhibitor (imatinib) and tight junction permeation enhancer (sodium deoxycholate) at intestine with enhanced therapeutic efficiency, which could provide an effective approach to improve the bioavailability of hydrophobic anticancer chemodrugs with oral administration.

关键词

Keywords

Carboxymethyl chitosanImatinibHydrogelsOral deliveryTight junctions

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