Clotrimazole-loaded N -(2-hydroxy)-propyl-3-trimethylammonium, O -palmitoyl chitosan nanoparticles for topical treatment of vulvovaginal candidiasis

Author(s)

Facchinatto, William Marcondes ^[1] ; Galante, Joana ^{[2, 3, 4]} ; Mesquita, Leticia ^{[2, 3, 4]} ; Silva, Daniella Souza ^[5] ; dos Santos, Danilo Martins ^[6] ; Moraes, Tiago Bueno ^[7] ; Campana-Filho, Sergio Paulo ^[1] ; Colnago, Luiz Alberto ^[6] ; Sarmento, Bruno ^{[3, 4]} ; das Neves, Jose ^{[3, 4]}

Affiliation

^[1] Univ Sao Paulo, IQSC Sao Carlos Inst Chem, Ave Trabalhador Sao Carlense 400, CP 780, BR-13566590 Sao Carlos, SP - Brazil

^[2] Univ Porto, ICBAS Inst Biomed Sci Abel Salazar, Rua Jorge Viterbo Ferreira 228, P-4050313 Porto - Portugal

^[3] Univ Porto, I3S Inst Res & Innovat Hlth, Rua Alfredo Allen, 208, P-4200135 Porto - Portugal

^[4] Univ Porto, INEB Inst Biomed Engn, Rua Alfredo Allen, 208, P-4200135 Porto - Portugal

^[5] State Univ Western Parana UNIOESTE, Dept Chem, 645 Jardim Salle, BR-85903000 Toledo, Parana - Brazil

^[6] Embrapa Instrumentat, Brazilian Corp Agr Res, Rua XV Novembro 1452, BR-13560970 Sao Carlos, SP - Brazil

^[7] Fed Univ Minas Gerais UFMG, Inst Exact Sci, Dept Chem, Ave Antonio Carlos, 6627, BR-31270901 Belo Horizonte, MG - Brazil

• Document type: Journal article
• Source: Acta Biomaterialia; v. 125, p. 312-321, APR 15 2021.
• Web of Science Citations: 6

Abstract

Vulvovaginal candidiasis (VVC) represents a considerable health burden for women. Despite the availability of a significant array of antifungal drugs and topical products, the management of the infection is not always effective, and new approaches are needed. Here, we explored cationic N-(2-hydroxy)-propyl-3-trimethylammonium, O-palmitoyl chitosan nanoparticles (NPs) as carriers of clotrimazole (CLT) for the topical treatment of VVC. CLT-NPs with approximately 280 nm in diameter were obtained by self assembly in water and subsequent stabilization by ionic crosslinking with tripolyphosphate. The nanosystem featured pH-independent sustained drug release up to 24 h, which affected both in vitro anti-Candida activity and cytotoxicity. The CLT-loaded nanostructured platform yielded favorable selectivity index values for a panel of standard strains and clinical isolates of Candida spp. and female genital tract cell lines (HEC-1-A, Ca Ski and HeLa), as compared to the free drug. CLT-NPs also improved in vitro drug permeability across HEC-1-A and Ca Ski cell monolayers, thus suggesting that the nanocarrier may provide higher mucosal tissue levels of the active compound. Overall, data support that CLT-NPs may be a valuable asset for the topical treatment of VVC. Statement of significance Topical azoles such as clotrimazole (CLT) are first line antifungal drugs for the management of vulvovaginal candidiasis (VVC), but their action may be limited by issues such as toxicity and poor capacity to penetrate the genital mucosa. Herein, we report on the ability of a new cationic N-(2-hydroxy)-propyl-3-trimethylammonium, O-dipalmitoyl chitosan derivative (DPCat35) to yield tripolyphosphate-reinforced micelle-like nanostructures that are suitable carriers for CLT. In particular, these nanosystems were able to improve the in vitro selectivity index of the drug and to provide enhanced epithelial drug permeability when tested in cell monolayer models. These data support that CLT-loaded DPCat35 nanoparticles feature favorable properties for the development of new nanomedicines for the topical management of VVC. (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. (AU)

• FAPESP's process: 16/20970-2 - Study of chitosan and hydrophilic derivatives by time domain NMR
• Grantee: William Marcondes Facchinatto
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/20973-4 - Coaxial electrospun nanofibers based on chitosan for controlled release of antibiotics and periodontic lesion treatment
• Grantee: Danilo Martins dos Santos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/13656-8 - Development and application of nuclear magnetic resonance in products and agricultural processes
• Grantee: Luiz Alberto Colnago
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/11135-0 - Clotrimazole-loaded N-(2-hydroxy)-propyl-3-trimethylammonium, O-Palmitoyl chitosan micelles: preparation, characterization and in vitro evaluation against Candida species
• Grantee: William Marcondes Facchinatto
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate