Nanostructured lipid carrier for co-delivery of siRNA and berberine in topical therapy of chronic skin wounds: development, physicochemical characterization and in vitro efficacy

• Grant number: 24/05678-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: January 01, 2025
• End date: January 31, 2026
• Field of knowledge: Health Sciences - Pharmacy - Pharmaceutical Technology
• Principal Investigator: Maria Vitória Lopes Badra Bentley
• Grantee: Milena Finazzi Morais
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 14/50928-2 - INCT 2014: Pharmaceutical Nanotechnology: a transdisciplinary approach, AP.TEM

Abstract

Skin wound healing is a highly complex process that requires the spatial and temporal synchronization of a variety of cells, cytokines and growth factors. When there is an immunological and biochemical imbalance, with abnormal innate and adaptive immune responses, varied redox and metabolic profiles, overexpression of proteases, dysregulated extracellular matrix deposition, cellular senescence, impaired cell proliferation and migration and bacterial infections, tissue repair is impaired leading to chronicity. Currently, chronic wounds present humanistic and economic burdens, in addition to contributing to high morbidity and mortality. Despite advances in understanding the factors that lead to delayed healing, currently available treatments are still limited and of reduced effectiveness. Therefore, the present study aims to develop a new therapeutic approach targeting multiple targets involved in deficient tissue repair. To achieve this, we will produce nanostructured lipid carriers (CLN) co-loaded with two therapeutic agents: berberine, an isoquinoline alkaloid, with potent anti-inflammatory and pro-healing action; and small interfering RNA (siRNA) targeting matrix metalloproteinase-9 (MMP-9), a collagenase highly expressed in chronic wounds and responsible for the degradation of important components of the extracellular matrix and cell proliferation. The CLN co-loaded with berberine and MMP-9 siRNA will be produced by the hot emulsification technique and characterized for their colloidal and physicochemical properties, such as hydrodynamic particle size, polydispersity index, zeta potential, berberine encapsulation efficiency, siRNA complexation efficiency to CLN and colloidal and chemical stability of formulations stored under different conditions. Studies in a Franz diffusion cell using a synthetic cellulose membrane and dermatomized pig ear will be carried out to assess the release profile and the content retained in the skin layers, respectively. Cellular studies will be carried out to investigate the formulation's cytocompatibility, cellular interaction and anti-inflammatory and pro-healing therapeutic efficacy. The experimental strategy suggested in this project will result in a technological and therapeutic feasibility study of multi-target nanoparticles for the therapy of chronic skin wounds.