Glutathione and pH-responsive chitosan-based nanogel as an efficient nanoplatform for controlled delivery of doxorubicin

Farideh.mahmoodzade, PhD in Organic Chemistry

 Food and medicine expert of Aras Free Zone Organization

Cancer is a group of diseases with many possible causes in the worldwide and cancer patients are most often treated with radiation or chemotherapy. Chemotherapy is a most common types of treatment, but like other treatments, it often causes side effects [1,2]. Scientists work constantly to develop drugs, drug combinations, and ways of giving treatment with fewer side effects [3]. For example, the nano-sized drug carriers (NDC) has achieved most consideration, in the area of nanomedicine to overcome the problems which arising from side effects of chemotherapy via the enhanced penetration effect (EPR) [4,5] .Among the many types of NDC, three-dimensional polymeric networks named as nanogels (Ngs) have shown interesting potentials because of robustness and flexibility properties, nanoscale size and smart responsiveness to external stimuli [6–8]. The Ngs with smart responsiveness to endogenous or exogenous environmental changes (temperature, pH, and redox) can be candidate for targeted and controlled-delivery of drugs to cancerous cells [9,10]. The advantage of redox-responsive Ngs is due to the stability during their circulation in extracellular compartment and the degradation of Ngs is achieved by the high intracellular glutathione (GSH, a type of strong reducing agent inside cell) concentration inside cancer cells led to the fast drug release in the nucleus of cells [1,11,12]. Polymeric Ngs based on polysaccharides have developed as the most promising candidate owing to their biocompatibility, biodegradability, functionality, low toxicity, and low cost [6,8,13]. In this regard, chitosan-based Ngs can be prepared via controlled radical polymerization as well as reversible addition of fragmentation chain transfer (RAFT) polymerization technique due to the providing of polymers with narrow dispersity, and controlled molecular weight [14,15]. The goal of this study was the development of pH and redox-responsive Ngs based on N-phtaloyl chitosan-graft-poly (hydroxyl ethyl metacrylate)-graft-maleic acid-graft-N,N′ bis(acryloyl) cystamine (BAC) [(CTS-g-PHEMA-g-MAc-g-MBA)] for triggered DOX release in cancer tissue. In the first step, functionalized N-phthaloyl-chitosan with 4-cyano, 4-[(phenylcarbothioyl) sulfanyl] pentanoic acid (RAFT agent) was prepared to provide the macroinitiator. Then, HEMA polymerized via macroinitiator until the hydroxyl groups of HEMA could react with maleic anhydride (MAn) monomers to prepare the CTS-g-PHEMA-g-MAc. In the third step, by using the double bonds of MA, the N,N′ bis(acryloyl) cystamine (BAC) was grafted as a redox-sensitive monomer and the crosslinker agent to prepare a novel dual-responsive Ngs. The designed Ngs were applied for loading DOX and the improved drug’ anticancer activity was proved by the in vitro assessment such as cellular uptake, cell imaging, DAPI staining and cell cycle analyses against cancer cell.s

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