Mucus-penetrative nanoparticles with doxycycline: physicalchemical, biopharmaceutical, immunomodulatory and microbiological in vitro evaluation for pulmonary delivery

• Grant number: 21/12561-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2022
• End date: July 01, 2027
• Field of knowledge: Health Sciences - Pharmacy - Pharmaceutical Technology
• Principal Investigator: Laura de Oliveira Nascimento
• Grantee: Victória Soares Soeiro
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 23/10824-2 - Pharmaceutical development of powdered polymeric nanostructures to deliver doxycycline to the lungs, BE.EP.DR

Abstract

Respiratory tract infections are the main cause of mortality from infectious diseases in the world and in Brazil, even before the pandemic. Etiological agents include bacteria, which are resistant to various antibiotics and impair their eradication. In particular, chronic lung infections are often fatal to patients with cystic fibrosis, whose disease severity is related to biofilms in the lung, favored by thick mucus and an inflammatory environment. Among the antibiotics prescribed for lung infections is doxycycline (DOX), capable of inhibiting bacterial transcription by binding to a ribosomal subunit, in addition to interfering with Quorum sensing in biofilms, inhibiting their formation. Dox also inhibits human MMP-9 metalloprotease and increases expression of anti-inflammatory cytokines, decreasing local damage. Altogether, DOX is indicated in mild cases of pneumonia in some countries and studied as an adjunct in the treatment of cystic fibrosis. This project focuses on the development and study of mucopenetrating nanoparticles (MPN), covered by several stabilizers and optimized for the pulmonary route, aiming to reduce systemic exposure and increase local action. Encapsulated DOX will be protected from the physiological environment, being able to improve the distribution and residence time in the lung, and adsorb/fuse with bacterial membranes, circumventing the decrease in permeability and increase in the efflux of the drug in these agents. The objective is to obtain a stable, reproducible, non-toxic, effective NPM formulation with a high concentration of doxycycline in nanoparticles dispersed in an aqueous medium or lyophilized for subsequent resuspension and application by nebulizer. The NPMs will be characterized and selected according to their physicochemical, antibacterial (strains that infect the respiratory tract), cytotoxic, anti-inflammatory properties, in vitro pulmonary cell layer permeability, activity against bacterial biofilm and behavior in simulated pulmonary mucus . In addition to the formulation optimization, the study will contribute to expand the knowledge of the effects of NMP in the lung, which are recent and still scarce, as well as the technological knowledge of NPM lyophilization.