Development of biodegradable and mucoadhesive hydrogels for the controlled release of drugs in the bladder cancer treatment

Author(s)

Caroline Santos Alves de Lima

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Pesquisas Energéticas e Nucleares (IPEN/BT)
• Defense date: 2023-05-15

Examining board members

Ademar Benévolo Lugão; Wagner José Fávaro; Monica Beatriz Mathor; Amedea Barozzi Seabra

• Advisor: Ademar Benévolo Lugão

Abstract

Bladder cancer is the tenth most common type of cancer worldwide and represents 2.1% of cancer deaths. Treatment of bladder cancer is done primarily by a transurethral resection to remove the visible tumor, followed by intravesical chemotherapy, depending on the stage of the disease. However, the instillation of drugs into the human bladder presents some challenges, among which stand out the permeation of the active in the urothelium - a highly impermeable tissue - and the residence time of this drug, which is limited due to the presence of urine that ends up diluting it and washing it thoroughly. Thus, the main objective of this work was to develop strategies to increase adherence, permeation and residence time of intravesical therapy through the application of mucoadhesive hydrogels for the administration of chemotherapy drugs such as gemcitabine hydrochloride. Papain, a proteolytic enzyme capable of breaking peptide bonds of glycoproteins that compose the mucin, was added to the gels in order to favor the permeation of the chemotherapy agent. In this work, it was proposed the use of hydrogels such as gellan gum, CMC (carboxymethyl cellulose) and PVA (polyvinyl alcohol), already widely applied in the biomedical area, due to properties such as absence of toxicity, high biocompatibility and biodegradability. The studied hydrogels were evaluated concerning their mucoadhesiveness and rheological behavior. Possible interactions between the active and the matrices were also analyzed. Preliminary biological tests were carried out aiming to provide specific knowledge about the biocompatibility of the material, in order to investigate its safety for future clinical use. The formulations showed promising results, with mucoadhesion capacity, retention in the urothelium and interaction with the mucin present in the bladder mucosa. The release of the drug substance was sustained for up to 8 hours, extending in a significative way the available treatment nowadays that, in general, tend to be limited by the number of hours in which is possible to avoid patients\' micturition. Permeability of the formulations was also increased in the presence of papain. In addition, the formulations presented pseudoplastic rheological behavior and, therefore, suitable for intravesical application. Biocompatibility tests showed low or no cytotoxicity and non-irritability by the formulations, indicating they may be suitable for future preclinical studies. Thus, the proposed formulations constitute possible treatment alternative associated to better quality of life for patients. (AU)

• FAPESP's process: 19/01315-1 - Development of nanostructured systems to increase the efficacy of chemotherapy and immunotherapy for Bladder Cancer
• Grantee: Caroline Santos Alves de Lima
• Support Opportunities: Scholarships in Brazil - Doctorate