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

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.

Automated summary

An intestine enzyme-responsive hydrogel was developed to encapsulate hydrophobic imatinib with long-term controlled release and enhanced intestinal permeability. The hydrogel showed improved therapeutic efficiency compared to imatinib mesylate, providing an effective approach to improve the bioavailability of hydrophobic anticancer drugs with oral administration.