Study of low-Frequency Ultrasound in topical sonodynamic therapy associated with mesoporous silica nanoparticles

• Grant number: 21/12573-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: June 01, 2023
• End date: November 30, 2026
• Field of knowledge: Health Sciences - Pharmacy - Pharmaceutical Technology
• Principal Investigator: Renata Fonseca Vianna Lopez
• Grantee: Tais de Cassia Ribeiro
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Sonodynamic therapy (SDT) is a new therapeutic strategy that has been studied for the treatment of tumors. The SDT involves the interaction of ultrasound, a sonosensitizing agent and molecular oxygen in the tumor, which interact and result in cell death. The mechanisms of the antitumor action of SDT have not been well understood yet. However, the frequency of ultrasound, its intensity, duration and application regimen, modifications generated by it at the site of application, the influence of the delivery system of the sonosensitizing agent, are only some of the variables present in SDT that need further investigation. Mesoporous silica nanoparticles (NSM) present pores of adjustable diameters and volumes besides silanol groups available on the surface or pores that confer them the capacity to incorporate amounts of drugs and modulate their release. Encapsulated with a sonosensitizing agent, NSMs showed benefits in the TSD of tumors when irradiated with high-frequency ultrasound, after intratumoral administration. The behavior of NSMs against irradiation with low-frequency ultrasound (LFU), whether in cavitation, reactive species production or skin penetration, has never been studied. With the hypothesis that the pore distribution in NSMs affects the cavitational activity and the release of encapsulated drugs in response to irradiation with LFU, the aim of this work is to develop NSMs targeting topical TSD and evaluate the influence of LFU on their skin penetration and TSD of melanoma. It is assumed that LFU enables the penetration of NSMs into the skin/tumor and activates sonodynamic responses that result in tumor cell death, including immunogenic cell death. NSMs will be developed and characterized for incorporation of the sonosensitizing agent ZnPc (NSM@ZnPc). Cytotoxicity and reactive oxygen species production studies will be performed in vitro in melanoma cells under various conditions of application of ultrasound, ZnPc and NSM@ZnPc. The mechanisms of cell death mediated by TSD will also be investigated. Finally, in vivo studies in induced melanoma in mice will be performed to verify the potential antitumor activity of TSD associated with topical administration of ZnPc and NSM@ZnPc stimulated by LFU.