Hydrogels as Delivery Platforms for Immunotherapeutic Agents in Cancer Therapy

Since the FDA approval of Rituximab as the first monoclonal antibody for cancer immunotherapy in 1997, there has been an increasing effort to develop drug delivery systems that can reduce the side effects and increase the efficacy of these agents in cancer patients (58). Some of the most common side effects of immunotherapy include decreased appetite, diarrhea, dermatitis, extreme fatigue, flu-like symptoms, and infusion-related reactions or injection site pain (59,60). Therefore, the need for formulations with more patient compliance and personalization is increasing day by day. So far, several promising systems have been developed and many more are under study in clinical trials. The main focus of this thesis is on the development of tumor microenvironment-sensitive nano and macro hydrogel systems (mainly based on hyaluronic acid). These hydrogel systems are capable of encapsulating protein-based therapeutics such asimmunotherapeutics that are widely used in cancer treatment and can provide a diverse range of possibilities for further modifications for tailored drug delivery systems. In Chapter 2, the definition, properties, and present cellular and non-cellular components of TME are explained. In addition, how nanoparticle formulations can benefit from these specific properties for enhanced drug delivery is discussed and various examples of stimuli-sensitive and targeted nanoparticles have been reviewed. In Chapter 3, a redox-sensitive hyaluronic acid-based hydrogel platform for the delivery of immunotherapeutic agents in TME has been developed and studied. These hydrogels were formulated by utilizing thiolated hyaluronic acid with different degrees of substitution (DS). The effects of cross-linking density on their morphology, redox response, and rheological properties were fully inspected. The hydrogels were also utilized for studying the release profile of physically encapsulated IgG (as a model drug for immunotherapy). Finally, the cytocompatibility of the hydrogels was studied in vitro. In Chapter 4 stimuli-sensitive nanospheres were formulated based on thiolated hyaluronic acid with different cross-linking densities (NS30 and NS50). These nanoparticles were formulated by different formulation techniques and their size, morphology, and stimuli- response were studied. The cellular uptake of the nanohydrogels as a drug delivery system for cancer therapy was also investigated. In Chapter 5, a core-shell structured nanocapsule (NC) based on thiolated hyaluronic acid in the core and vinyl sulfonated poly(N-(2-hydroxypropyl) methacrylamide mono/dilactate)- polyethylene glycol-poly(N-(2-hydroxypropyl) methacrylamide mono/dilactate) triblock copolymer in the shell part as a potential targeting nanoparticle was developed. Protein corona formation upon exposure to bovine serum albumin (BSA) around these nanocapsules and the thiolated hyaluronic acid nanospheres (NS30 and NS50) was studied and compared. Due to a significantly less protein corona formation in nanocapsules, they were selected as the optimal nanosystem for further bioconjugation steps. The selected chemical reaction for the bioconjugation was the thiol-ene reaction based on the present chemical reactive groups on the polymeric shell of the nanocapsules. The nanocapsules were modified on their surface by a prostate-specific membrane antigen (PSMA) targeting antibody and their cellular uptake in prostate cancer cell lines was studied. Finally, Chapter 6 presents a critical review and conclusion of the studies of all previous chapters. In addition, as a future perspective, a novel method for measuring the molecular weight of pharmaceutical polymers by the use of rheometry as an alternative to gel permeation chromatography (GPC) is introduced.