Synthesis, characterizations, and evaluation of crosslinked 5-fluorouracil-loaded thiolated chitosan-co-polymethacrylic acid hydrogel for colorectal cancer-targeted drug delivery

Abstract

5-Fluorouracil (5-FU) is a firstline chemotherapeutic agent used for treating colorectal cancer, but has short half-life, rapid metabolism which requires its continuous intravenous (IV) infusion, resulting in significant adverse events. synthesis as well as characterizations of 5-FU-loaded thiolated chitosan (TCS)-co-polymethacrylic acid (MAA)-based hydrogel for colon targeting to treat colorectal carcinoma. Free radical polymerization was employed for preparation of the 5-FU-loaded hydrogel. Potassium persulfate (KPS), methylene bis-acrylamide (MBA), and MAA were employed as initiator, crosslinker, and monomer, respectively. All the six 5-FU-TCS-co-poly (MAA) formulations (TCS1-TCS6) were subjected to in-vitro pH-dependent swelling and dissolution studies at pH 1.2 and 7.4 at 37 °C. TCS4 was selected for further in-vivo studies based upon swelling and release patterns evaluation. Reverse phase HPLC (RP-HPLC)-coupled with UV spectrophotometer was employed for estimation of 5-FU in plasma. In-vivo studies were performed to determine pharmacokinetics parameters (i.e., C_max, t_max and area-under-curve (AUC)) among control and treated groups. Release profile of TCS4 was optimal at pH 7.4. Indeed, 5-FU showed twofold higher release at pH 7.4 than at pH 1.2. C_max and t_max of TCS4 were found to be 300 ± 0.87 µg/mL and 4 ± 0.00 h, which are significantly higher than C_max and t_max oral solution (250 ± 0.65 µg/mL and 2 ± 0.00 h) used as a reference. TCS4-treated group depicted AUC_0-t of 2767 ± 0.54 ng/ml.hr which was remarkably higher as compared to controlled group. Toxicity studies were carried out on male albino rats and histological slides showed no signs of toxicity. TCS4 hydrogel could be effectively administered per os (orally) to improve the bioavailability of 5-FU.

Graphical abstract