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Noncovalent PEG Coating of Nanoparticle Drug Carriers Improves the Local Pharmacokinetics of Rectal Anti-HIV Microbicides.
ACS Appl Mater Interfaces. 2018 Oct 17; 10(41):34942-34953.AA

Abstract

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.

Authors+Show Affiliations

CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde , Gandra 4585-116 , Portugal. ICBAS-Instituto de Ciências Biomédicas Abel Salazar Universidade do Porto, Porto 4050-313 , Portugal.No affiliation info availableLAQV, REQUIMTE, Departamento de Ciências Quı́micas, Faculdade de Farmácia , Universidade do Porto , Porto 4050-313 , Portugal.HIV Evolution, Epidemiology and Prevention, Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia , Universidade de Lisboa , Lisboa 1649-003 , Portugal.LAQV, REQUIMTE, Departamento de Ciências Quı́micas, Faculdade de Farmácia , Universidade do Porto , Porto 4050-313 , Portugal.HIV Evolution, Epidemiology and Prevention, Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia , Universidade de Lisboa , Lisboa 1649-003 , Portugal. Centro de Investigação Interdisciplinar Egas Moniz (CiiEM) , Instituto Universitário Egas Moniz , Monte de Caparica 2829-511 , Portugal.CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde , Gandra 4585-116 , Portugal.CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde , Gandra 4585-116 , Portugal.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30234288

Citation

Nunes, Rute, et al. "Noncovalent PEG Coating of Nanoparticle Drug Carriers Improves the Local Pharmacokinetics of Rectal Anti-HIV Microbicides." ACS Applied Materials & Interfaces, vol. 10, no. 41, 2018, pp. 34942-34953.
Nunes R, Araújo F, Barreiros L, et al. Noncovalent PEG Coating of Nanoparticle Drug Carriers Improves the Local Pharmacokinetics of Rectal Anti-HIV Microbicides. ACS Appl Mater Interfaces. 2018;10(41):34942-34953.
Nunes, R., Araújo, F., Barreiros, L., Bártolo, I., Segundo, M. A., Taveira, N., Sarmento, B., & das Neves, J. (2018). Noncovalent PEG Coating of Nanoparticle Drug Carriers Improves the Local Pharmacokinetics of Rectal Anti-HIV Microbicides. ACS Applied Materials & Interfaces, 10(41), 34942-34953. https://doi.org/10.1021/acsami.8b12214
Nunes R, et al. Noncovalent PEG Coating of Nanoparticle Drug Carriers Improves the Local Pharmacokinetics of Rectal Anti-HIV Microbicides. ACS Appl Mater Interfaces. 2018 Oct 17;10(41):34942-34953. PubMed PMID: 30234288.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Noncovalent PEG Coating of Nanoparticle Drug Carriers Improves the Local Pharmacokinetics of Rectal Anti-HIV Microbicides. AU - Nunes,Rute, AU - Araújo,Francisca, AU - Barreiros,Luisa, AU - Bártolo,Inês, AU - Segundo,Marcela A, AU - Taveira,Nuno, AU - Sarmento,Bruno, AU - das Neves,José, Y1 - 2018/10/04/ PY - 2018/9/21/pubmed PY - 2019/7/31/medline PY - 2018/9/21/entrez KW - efavirenz KW - mucus-penetrating nanoparticles KW - nanomedicine KW - poloxamer KW - pre-exposure prophylaxis KW - rectal drug delivery SP - 34942 EP - 34953 JF - ACS applied materials & interfaces JO - ACS Appl Mater Interfaces VL - 10 IS - 41 N2 - 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. SN - 1944-8252 UR - https://www.unboundmedicine.com/medline/citation/30234288/Noncovalent_PEG_Coating_of_Nanoparticle_Drug_Carriers_Improves_the_Local_Pharmacokinetics_of_Rectal_Anti_HIV_Microbicides_ L2 - https://dx.doi.org/10.1021/acsami.8b12214 DB - PRIME DP - Unbound Medicine ER -