Injectable Microgel-Hydrogel Composite for SynergisticTherapy of Rectal Cancer Model Based on SequentialDelivery of Chemotherapy Agents

Objective: In situ formed injectable hydrogels based on Schiff'sbase reaction with pH-responsiveness and self-healing abilityhave great potential for anti-cancer drug delivery. The combinationof multiple chemotherapeutics offers an effective approachto reduce disadvantages of single drug therapy, such as highdose and easy generation of multi drug resistance (MDR). Wereport herein the development of drug delivery system based ona novel Injectable Microgel-Hydrogel Composite for sequentiallylocal co-delivery of Curcumin (Cur) and ۵-Fluorouracil(۵-FU). The prepared composite could be a promising drug deliverysystem with sustained-release action for up to ۲۵ daysfor ۵-FU and enhanced drug bioavailability. Furthermore, theactivity of drugs released from composite matrix was evaluatedby employing a human adenocarcinoma cell line. The combinationtherapy of antimetabolite and cytotoxic drugs using thisdelivery system offers a promising approach for improved cancertherapeutic efficacy. The synergistic inhibitory effects onthe cell cycle progression and cell proliferation in rectal cancercells were also confirmed. Taken together, this study demonstratesa promising dual-drug enhanced microgel-embeddedinjectable hydrogel for local dual drug delivery with sequentialrelease behaviors by simple injection and thus provides a novelstrategy for combination therapy of rectal cancer.Materials and Method: Pluronic F۱۲۷, gelatin, ۵-Fluorouracil,Curcumin, EDC, NIPAm, acrylic acid, ammonium persulfate,N, N′-methylenebisacrylamide and MTT were purchasedfrom Sigma-Aldrich. The combination of ۵-FU loaded microgeland Gel-ADH solution was mixed with the pluronic micellesolution to obtain composite.Results: ۵-FU release could be sustained for more than a monthfrom these composite hydrogels, significantly longer than thatachievable using the microgels alone. The synergistic inhibitoryeffects were observed on the cell cycle progression and proliferationrate of in rectal cells using the dual drug loaded system.Conclusion: In conclusion, this composite system is a synergismtherapeutic delivery system that can achieve prolonged,sustained-release action for combination of chemotherapyagent, ۵-FU and a selective COX-۲ inhibitor, curcumin, againstthe human colon cancer cell line.