Abstract
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.
Highlights
Current systemic administration of anti-cancer drugs exposes normal tissues to the drug-induced toxicity
It was found that the components used in this study showed no absorbance at the specified selected wave lengths of 5-FU (266) and MTX (302)
The scanning of the 5-FU in the presence of MTX showed certain degree of cross overlapping at the selected absorbance values, which represents a great problem in measuring of 5-FU in the presence of MTX
Summary
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 [1]. 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]. To overcome the problem of poor selectivity, systemic administration of these anti-cancer drugs has been replaced by localized targeting and controlled drug delivery systems and it shows promising results in the fields of chemotherapy [6]
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