Date Published: May 13, 2020
Publisher: Springer International Publishing
Author(s): Ahmed M. Mohammed, Shaaban K. Osman, Khaled I. Saleh, Ahmed M. Samy.
5-Fluorouracil is a member of cytotoxic drugs with poor selectivity to cancer cells. Currently, systemic administration of this anti-cancer drug (oral or injection) exposes normal tissues to the drug-induced toxicity. Nowadays, attention has been greatly directed towards in situ gel-forming systems that can be injected into the affected tissues in its sol form with a minimally invasive technique. More specifically, chitosan hydrogel systems were in focus due to their antibacterial effect as well as their biodegradable, biocompatible, and mucoadhesive properties. In the present work, 5-fluorouracil was loaded on various thermosensitive chitosan hydrogel systems cross linked with different linking agents like β-glycerophosphate, pluronic F127, and hydroxyapatite. Also, methotrexate was added to 5-fluorouracil in order to gain its previously reported synergistic effects. Firstly, a compatibility study was performed using UV-spectrophotometric, infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) techniques to exclude the possibility of any physical or chemical interactions between the selected drugs and excipients. The prepared hydrogel systems were characterized for their physicochemical properties including organoleptic, pH, syringeability and injectability, viscosity, and gelation temperature (Tgel) by various analysis techniques. Moreover, the in vitro release behavior of 5-fluorouracil and methotrexate was determined with a modified analytical method. The results indicated that chitosan hydrogel system cross-linked with a combination of β- glycerophosphate, and 10 % pluronicF127 (F4) showed the most suitable physicochemical properties and release profile. Accordingly, this formula can be considered as a missionary system for localized sustained delivery of cytotoxic drugs.
Current systemic administration of anti-cancer drugs exposes normal tissues to the drug-induced toxicity. This is because most cytotoxic drugs are non-selective and cannot distinguish between cancer and normal cells . In addition, rapid release of the loaded dose causes rapid elevation of the drug level with unintended side effects at the peak followed by shape declining and insufficient therapeutic effect at the low drug level . 5-fluorouracil (5-FU) is an anti-cancer drug having structural similarity to pyrimidine bases (Fig. 1), interfering with thymidylate synthase enzyme action and preventing DNA replication . It was reported that pretreatment with methotrexate (MTX) increases 5-FU uptake by cells, due to inhibition of purine synthesis by MTX as a result of increased levels of intracellular phosphoribosyl-pyrophosphate. Inhibition of purine synthesis will result in accumulation of N5,N10-methylene tetrahydrofolate which is an essential factor for tight binding of 5-fluorouracil active metabolite to thymidylate synthetase enzyme (TS) [4, 5].Fig. 1Chemical structure of 5-fluorouracil (a), methotrexate (b) and chitosan (c)
Different chitosan hydrogel systems were successfully prepared. Chitosan hydrogel prepared using combination of β-Gp and 10% Pl F127 as cross-linking agents (F4) was found to have the longest duration of action (over 4 weeks) with good physicochemical properties, including pH, viscosity, syringeability, and injectability. Since the monthly injection of drug will be more convenient than frequent application; this system can be considered as a promising vehicle for quantitative release of anti-cancer drugs in a sustained manner.