Fabrication and evaluation of smart pH/thermo dual-responsive injectable intratumoral in situ depot hydrogels for controlled 5-FU delivery

Abstract

Abstract Background 5-FU has multiple applications in various cancers but has limitations owing to its shorter half-life and rapid metabolism. In this study, injectable intratumoral gels were developed to enhance 5-FU concentrations in tumor vicinity. Sterile tunable poly (N-isopropylacrylamide)-based pH/thermo dual-sensitive self-assembled and in situ crosslinkable injectable depot gels with low viscous grade of chitosan (LVCS) were developed via cold and free radical polymerization method for localized and sustained delivery. Results Rheological analysis confirmed the gelation temperature, sol–gel transitions and viscoelastic behavior of in situ gels. Swelling–deswelling–reswelling cycles established the effect of temperature on structural changes. Swelling tests and in vitro drug release conducted in various dissolution media at variable temperatures confirmed pH/thermal dual response of formulations. Methyl thiazolyl tetrazolium assay confirmed that the hydrogels have good cytocompatibility with above 85% cells viability in Vero cells. In vitro cytotoxicity assay against MCF-7 cells displayed that 5-fluorouracil has good anticancer activity in loaded gel form as compared to free 5-FU. The cytotoxic studies showed that IPLVCS-2 and IPLVCS-6 have the highest inhibition (IC50 = 47 ± 1 µg/ml, 34 ± 17 µg/ml) as compared to free 5-FU (IC50 = 52 ± 3 µg/ml). Conclusion Current findings conclude that taking the advantage of physiologic environment acidic pH and high temperature of cancer cells, poly(NIPAAm)-g-LVCS formulations can effectively be used as intratumoral controlled depot of 5-FU. Graphical Abstract