Construction of Dynamic Hydrogel Inducing Effective and Selective 5-Fluorouracil Monotherapy against Cervical Cancer Cells

Abstract

The severe side effects of systemic chemotherapy for cervical cancer encourage the use of topical intravaginal drug delivery systems. 5-fluorouracil, 5-FU, is an anticancer drug accepted in clinical use in the cancer therapy of colorectal, gastric, and hepatocellular carcinoma. However, it shows low activity against cervical cancer cells (HeLa) and thus requires the usage of additional drugs to support the therapy, which is associated with side effects. We report on the polyglycidol/polyacrylamide-based hydrogel carrier providing effective monotherapy against cervical cancer cells, HeLa with 5-FU, along with a neutral effect on normal cells, HMEC-1. The use of hyperbranched polyglycidol modified with aryl groups, i.e., phenylurethane, 1,4-biphenylurethane, and benzoyl ester, respectively, to enhance the solubility of 5-FU in the aqueous medium ensured the drug’s efficacy and selectivity against Hela cells after 48 h at a low dose. Crucially, the cross-linking of drug-loaded aryl-enriched polyglycidol with an acrylamide copolymer bearing 2-acrylamidephenylboronic acid induced the anticervical cancer activity reducing the time required for complete cervical cancer cell death to 24 h. An in vitro study showed that boronic acid moieties are responsible for the promotion of anticervical cancer activity with 5-FU. Reported hydrogels’ structure based on reversibly cross-linked aryl-enriched HbPGLs provides the self-healing properties of the network crucial for the formation of the continuous layer of formulation ensuring the delivery of the drug to the afflicted area of the covered tissue. Among tested hydrogels, the system constructed from HbPGL which linear constitutional units were modified with benzoyl ester or and phenylurethane moieties at approximately 45 mol % showed the highest drug permeability through the STRAT-M model membrane. This study demonstrates the direction of the synthetic design of the hydrogel carrier of 5-FU assuring safe monotherapy of cervical cancer cells, avoiding side effects typical for combinatory therapies.