Development and characterization of folate-modified PLGA nanoparticles containing paclitaxel for optimization of ovarian cancer treatment

Author(s)

Marcela Tavares Luiz

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2018-04-05

Examining board members

Juliana Maldonado Marchetti; Marlus Chorilli; Maria Teresa Junqueira Garcia; Marilisa Guimarães Lara

• Advisor: Juliana Maldonado Marchetti; Priscyla Daniely Marcato Gaspari

Abstract

Paclitaxel (PCX) is a first-line medicinal treatment for ovarian cancer. However, the low PCX water solubility makes necessary the addition of toxic adjuvants to the commercial formulation (Taxol®). Thus, the development of nanostructured delivery systems has been studied to promote a reduction on side effects and an increase on safety and PCX therapeutic efficacy. One of strategies used to increase nanocarriers selectivity to tumor cells is the modification of their surfaces with folate due to folate receptor overexpression on tumor cells membrane. The aim of this work was the development and characterization of folate-modified PLGA nanoparticles (NP-PCXAF) and unmodified nanoparticles (NP-PCX) to PCX delivery, as well as the evaluation of in vitro efficacy of developed systems using human ovarian cancer cell lines. The nanocarriers were produced through nanoprecipitation technique and evaluated through physico-chemical parameters like particle size, polydispersity index, zeta potential, encapsulation efficiency, colloidal stability and infrared spectroscopy. Besides that, antitumoral efficacy and cellular uptake were evaluated using resazurin cytotoxicity assay, confocal microscopy and flow cytometry. The results obtained for folate-modified nanoparticles and unmodified nanoparticles showed low particle size distribution (less than 150 nm) and polydispersity index (less than 0.2) with high PCX encapsulation efficiency (about 100%) which is suitable for intravenous administration and for promoting active and passive targeting to tumor microenvironment. The in vitro cellular cytotoxicity assays of OVCAR-3 and SKOV-3 cell lines demonstrated the high ability of both formulations to release PCX and consequently to cause cellular damage. Furthermore, in lower concentrations NP-PCX-AF formulation showed higher cytotoxicity capacity than NP-PCX with higher cell viability reduction, about 22% for SKOV-3 cell line and 11% for OVCAR-3, using concentration of 1000 nM at 72 hours. Finally, flow cytometry and confocal microscopy assays indicated a high capacity of both nanocarriers to be internalized through endocytosis process. Therefore, subsequent in vivo studies are necessary to confirm the NP-PCX-AF potential for ovarian cancer treatment (AU)

• FAPESP's process: 16/03170-2 - Development and characterization of PLGA nanoparticles containing paclitaxel targeted with f olate for optimization of ovarian cancer therapy
• Grantee: Marcela Tavares Luiz
• Support Opportunities: Scholarships in Brazil - Master