Author(s):
Nunes, Rute ; Araújo, Francisco ; Barreiros, Luísa ; Bártolo, Inês ; Segundo, Marcela A. ; Taveira, Nuno ; Sarmento, Bruno ; Neves, José Das
Date: 2018
Persistent ID: http://hdl.handle.net/10451/58979
Origin: Repositório da Universidade de Lisboa
Project/scholarship:
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FQUI%2F50006%2F2013/PT;
info:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F96519%2F2013/PT;
info:eu-repo/grantAgreement/FCT/FARH/SFRH%2FBPD%2F89668%2F2012/PT;
info:eu-repo/grantAgreement/FCT/OE/SFRH%2FBPD%2F76225%2F2011/PT;
info:eu-repo/grantAgreement/FCT/OE/SFRH%2FBPD%2F92934%2F2013/PT;
Subject(s): efavirenz; mucus-penetrating nanoparticles; nanomedicine; poloxamer; pre-exposure prophylaxis; rectal drug delivery
Description
Antiretroviral drug nanocarriers hold great promise for developing anti-human immunodeficiency virus (HIV) rectal microbicides. However, challenges remain, namely, concerning which properties are more suited for enhancing colorectal distribution and retention of microbicide compounds. In this work, we developed and assessed the in vitro and in vivo performance of poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) as carriers for the model drug efavirenz (EFV). We particularly focused on the effect of noncovalent poly(ethylene glycol) coating of PLGA NPs (PEG–PLGA NPs) conferring a mucus-diffusive behavior on the pharmacokinetics (PK) of EFV following rectal administration to mice. Drug-loaded PLGA NPs and PEG–PLGA NPs (200–225 nm) were obtained by nanoprecipitation. Both types of systems were able to retain native antiretroviral activity of EFV in vitro, while featuring lower cytotoxicity against different epithelial cell lines and HIV target cells. Also, PLGA NPs and PEG–PLGA NPs were readily taken up by colorectal cell lines and mildly reduced EFV permeation while increasing membrane retention in Caco-2 and Caco-2/HT29-MTX cell monolayer models. When administered intrarectally to CD-1 mice in phosphate-buffered saline (pH 7.4), EFV-loaded PEG–PLGA NPs consistently provided higher drug levels in colorectal tissues and lavages, as compared to free EFV or drug-loaded PLGA NPs. Mean values for the area-under-the-curve between 15 min and 12 h following administration were particularly higher for PEG–PLGA NPs in distal and middle colorectal tissues, with relative bioavailability values of 3.7 and 29, respectively, as compared to free EFV (2.2 and 6.0 over PLGA NPs, respectively). Systemic exposure to EFV was reduced for all treatments. NPs were further shown safe after once-daily administration for 14 days, as assessed by histological analysis of colorectal tissues and chemokine/cytokine assay of rectal lavages. Overall, PEG–PLGA NPs demonstrated to be safe carriers for rectal microbicide drug delivery and able to provide enhanced local PK that could be valuable in preventing rectal HIV transmission.
This work was supported by Programa Gilead GÉNESE, Gilead Portugal (ref PGG/002/2016). This article is a result of the project NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274), and also Partnership Agreement PT2020 UID/QUI/50006/2013-POCI/01/0145/FEDER/007265. R.N., L.B., I.B., and J.d.N. gratefully acknowledge FCT for financial support (SFRH/BD/96519/2013, SFRH/BPD/89668/2012, SFRH/BPD/76225/2011, and SFRH/BPD/92934/2013 scholarships, respectively). The authors also acknowledge the support of the following i3S Scientific Platforms: Biointerfaces and Nanotechnology (BN), Translational Cytometry (TraCy), Histology and Electron Microscopy (HEMES) and b.IMAGE-Bioimaging Centre for Biomaterials and Regenerative Therapies.
