Modulation of the Tumor Microenvironment by Nanostructured Lipid Carrier-Mediated Chemo-Photodynamic Therapy in Experimental Non-Muscle Invasive Bladder Cancer

• Grant number: 26/07506-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2026
• End date: May 31, 2027
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Wagner José Fávaro
• Grantee: Winícius Rozario da Silva
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Non-muscle invasive bladder cancer (NMIBC) represents one of the most prevalent urological malignancies worldwide and is characterized by high recurrence rates and a substantial risk of tumor progression. Although transurethral resection of the bladder tumor (TURBT) combined with intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) constitutes the standard therapeutic approach for patients with intermediate- and high-risk disease, a considerable proportion of individuals develop therapeutic failure, intolerance, or early recurrence. This scenario highlights the urgent need for more effective and biologically targeted therapeutic strategies. In this context, approaches based on pharmaceutical nanotechnology and combination therapies have emerged as promising alternatives to enhance antitumor efficacy and improve the bioavailability of therapeutic agents within the bladder tumor microenvironment. The present project aims to evaluate the antitumor efficacy and biological impact of nanostructured lipid carriers (NLCs) containing doxorubicin (DOXO) and chloroaluminum phthalocyanine (ClAlPc), employing chemotherapy- and photodynamic therapy (PDT)-based approaches, either individually or in combination, for the treatment of non-muscle-invasive bladder cancer in an experimental model. For this purpose, an animal model of bladder carcinogenesis induced by N-ethyl-N-nitrosourea (ENU) in Fischer 344 rats will be used, in which different experimental groups will be compared, including animals treated with free DOXO, NLCDOXO, NLCClAlPc associated with light irradiation, and the combined formulation NLCDOXO/ClAlPc. In addition to morphological and histopathological evaluation of urothelial lesions, the study will investigate molecular alterations associated with tumor progression and the tumor microenvironment through immunohistochemical analysis of biomarkers related to hypoxia, angiogenesis, cell cycle regulation, and epithelial-mesenchymal transition (EMT). The evaluated markers include HIF-1¿, VEGF, endostatin, and p53, as well as the transcription factors SNAIL and TWIST, which are associated with tumor plasticity and acquisition of an invasive phenotype. This integrative approach will allow a comprehensive investigation of the biological mechanisms involved in therapeutic response, as well as the impact of nanostructured therapeutic strategies on the modulation of the tumor microenvironment. The findings of this study are expected to expand current knowledge regarding the therapeutic effects of nanostructured systems combined with photodynamic therapy and chemotherapy in bladder cancer, providing relevant experimental evidence for the development of novel intravesical therapeutic strategies for NMIBC. Thus, this project presents significant translational potential and may contribute to the identification of innovative therapeutic approaches capable of improving tumor control while reducing recurrence and disease progression rates. (AU)