J.M. Coburn, T. Keang, K.S. Mistretta
Worcester Polytechnic Institute,
Keywords: chondroitin sulfate, hydrogel, drug binding, cancer
Summary:There will be an estimated 600,000 deaths this year alone from cancer in the US. Chemotherapy, while critical to many cancer therapy regimes, has many negative side effects as it is generally non-specific and targets all proliferative cells. Local delivery has the potential to allow for higher drug concentrations at the tumor site, while minimizing systemic toxicity. Injectable photocrosslinked hydrogels may be used for local delivery. Chondroitin sulfate (CS) is a sulfated glycosaminoglycan that has many promising properties, including biocompatibility and anionic groups, allowing for binding with cationic chemotherapy drugs such as doxorubicin and sunitinib through electrostatic interactions. CS can be modified with photocrosslinkable methacryloyl groups for injectable hydrogel fabrication (CSMA). These hydrogels are tunable, allowing for the manipulation of physical and mechanical properties that may be used to tune drug release kinetics. Their ability to be bind and slowly release cationic drugs allows them to be an ideal system for local chemotherapeutic delivery. However, a fundamental understanding of how cationic drugs bind beyond simple electrostatic interactions and the impact on drug release is not fully understood. In this work, we will first report on the injection properties of these hydrogels with and without drug loading to show some of the formulations exhibit injection force requirements below 38 N, a cut-off found to be subjectively and objectively acceptable for injectable hydrogels. Next, we will discuss binding and release of doxorubicin and daunorubicin, two anthracycline drugs that are structurally similar with a single difference in a hydroxyl group present in doxorubicin replaced by a hydrogen in daunorubicin. We found that the drug binding on a mole per mass of CSMA hydrogel is similar. However, the release kinetics are vastly different attributed to the hydroxyl group. Using spectrophotometric based techniques, we explored drug binding to the CSMA and CS polymer in solution to develop an understanding of the drug binding mechanisms and polymer or drug structural changes. By developing this fundamental understanding of drug binding and release from CSMA hydrogels, in addition to our knowledge on manipulated CSMA hydrogel properties, we will begin to address our long-term goal to develop intra-tumoral drug delivery systems as adjuvant therapies for cancer treatment. References: Ornell, J. Mater. Chem. B, 2019,7,2151-2161;  Robinson, Adv. Healthcare Mater. 2020,9,1901521.