Protamine nanocapsules as carriers for oral peptide delivery

Lungile Nomcebo Thwala, Diego Pan Delgado, Kevin Leone, Ilaria Marigo, Federico Benetti, Miguel Chenlo, Clara V Alvarez, Sulay Tovar, Carlos Dieguez, Noemi Stefania Csaba, Maria Jose Alonso

Research output: Contribution to journalArticle

Abstract

Peptides represent a promising therapeutic class with the potential to alleviate many severe diseases. A key limitation of these active molecules relies on the difficulties for their efficient oral administration. The objective of this work has been the rational design of polymer nanocapsules (NCs) intended for the oral delivery of peptide drugs. For this purpose, we selected insulin glulisine as a model peptide. The polymer shell of the NCs was made of a single layer of protamine, a cationic polypeptide selected for its cell penetration properties, or a double protamine/polysialic acid (PSA) layer. Insulin glulisine-loaded protamine and protamine/PSA NCs, prepared by the solvent displacement method, exhibited a size that varied in the range of 200-400 nm and a neutral surface charge (from +8 mV to -6 mV), depending on the formulation. The stability of the encapsulated peptide was assessed using circular dichroism and an in vitro cell activity study. Colloidal stability studies were also performed in simulated intestinal media containing enzymes and the results indicated that protamine NCs were stable and able to protect insulin from the harsh intestinal environment, and that this capacity could be further enhanced with a double PSA-Protamine layer. These NCs were freeze-dried and stored at room temperature without alteration of the physicochemical properties. When the insulin-loaded protamine NCs were administered intra-intestinally to diabetic rats (12 h fasting) it resulted in a prolonged glucose reduction (60%) as compared to the control insulin solution. This work raises prospects that protamine NCs may have a potential as oral peptide delivery nanocarriers.

Original languageEnglish
Pages (from-to)157-168
Number of pages12
JournalJournal of Controlled Release
Volume291
DOIs
Publication statusPublished - Dec 10 2018

Fingerprint

Nanocapsules
Protamines
Peptides
Insulin
Polymers
Circular Dichroism
Oral Administration
Fasting
Glucose
Temperature

Cite this

Protamine nanocapsules as carriers for oral peptide delivery. / Thwala, Lungile Nomcebo; Delgado, Diego Pan; Leone, Kevin; Marigo, Ilaria; Benetti, Federico; Chenlo, Miguel; Alvarez, Clara V; Tovar, Sulay; Dieguez, Carlos; Csaba, Noemi Stefania; Alonso, Maria Jose.

In: Journal of Controlled Release, Vol. 291, 10.12.2018, p. 157-168.

Research output: Contribution to journalArticle

Thwala, LN, Delgado, DP, Leone, K, Marigo, I, Benetti, F, Chenlo, M, Alvarez, CV, Tovar, S, Dieguez, C, Csaba, NS & Alonso, MJ 2018, 'Protamine nanocapsules as carriers for oral peptide delivery', Journal of Controlled Release, vol. 291, pp. 157-168. https://doi.org/10.1016/j.jconrel.2018.10.022
Thwala, Lungile Nomcebo ; Delgado, Diego Pan ; Leone, Kevin ; Marigo, Ilaria ; Benetti, Federico ; Chenlo, Miguel ; Alvarez, Clara V ; Tovar, Sulay ; Dieguez, Carlos ; Csaba, Noemi Stefania ; Alonso, Maria Jose. / Protamine nanocapsules as carriers for oral peptide delivery. In: Journal of Controlled Release. 2018 ; Vol. 291. pp. 157-168.
@article{20bc1c9e75ed46d5b5d5c2d9ddcc8f02,
title = "Protamine nanocapsules as carriers for oral peptide delivery",
abstract = "Peptides represent a promising therapeutic class with the potential to alleviate many severe diseases. A key limitation of these active molecules relies on the difficulties for their efficient oral administration. The objective of this work has been the rational design of polymer nanocapsules (NCs) intended for the oral delivery of peptide drugs. For this purpose, we selected insulin glulisine as a model peptide. The polymer shell of the NCs was made of a single layer of protamine, a cationic polypeptide selected for its cell penetration properties, or a double protamine/polysialic acid (PSA) layer. Insulin glulisine-loaded protamine and protamine/PSA NCs, prepared by the solvent displacement method, exhibited a size that varied in the range of 200-400 nm and a neutral surface charge (from +8 mV to -6 mV), depending on the formulation. The stability of the encapsulated peptide was assessed using circular dichroism and an in vitro cell activity study. Colloidal stability studies were also performed in simulated intestinal media containing enzymes and the results indicated that protamine NCs were stable and able to protect insulin from the harsh intestinal environment, and that this capacity could be further enhanced with a double PSA-Protamine layer. These NCs were freeze-dried and stored at room temperature without alteration of the physicochemical properties. When the insulin-loaded protamine NCs were administered intra-intestinally to diabetic rats (12 h fasting) it resulted in a prolonged glucose reduction (60{\%}) as compared to the control insulin solution. This work raises prospects that protamine NCs may have a potential as oral peptide delivery nanocarriers.",
author = "Thwala, {Lungile Nomcebo} and Delgado, {Diego Pan} and Kevin Leone and Ilaria Marigo and Federico Benetti and Miguel Chenlo and Alvarez, {Clara V} and Sulay Tovar and Carlos Dieguez and Csaba, {Noemi Stefania} and Alonso, {Maria Jose}",
note = "Copyright {\circledC} 2018. Published by Elsevier B.V.",
year = "2018",
month = "12",
day = "10",
doi = "10.1016/j.jconrel.2018.10.022",
language = "English",
volume = "291",
pages = "157--168",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier B.V.",

}

TY - JOUR

T1 - Protamine nanocapsules as carriers for oral peptide delivery

AU - Thwala, Lungile Nomcebo

AU - Delgado, Diego Pan

AU - Leone, Kevin

AU - Marigo, Ilaria

AU - Benetti, Federico

AU - Chenlo, Miguel

AU - Alvarez, Clara V

AU - Tovar, Sulay

AU - Dieguez, Carlos

AU - Csaba, Noemi Stefania

AU - Alonso, Maria Jose

N1 - Copyright © 2018. Published by Elsevier B.V.

PY - 2018/12/10

Y1 - 2018/12/10

N2 - Peptides represent a promising therapeutic class with the potential to alleviate many severe diseases. A key limitation of these active molecules relies on the difficulties for their efficient oral administration. The objective of this work has been the rational design of polymer nanocapsules (NCs) intended for the oral delivery of peptide drugs. For this purpose, we selected insulin glulisine as a model peptide. The polymer shell of the NCs was made of a single layer of protamine, a cationic polypeptide selected for its cell penetration properties, or a double protamine/polysialic acid (PSA) layer. Insulin glulisine-loaded protamine and protamine/PSA NCs, prepared by the solvent displacement method, exhibited a size that varied in the range of 200-400 nm and a neutral surface charge (from +8 mV to -6 mV), depending on the formulation. The stability of the encapsulated peptide was assessed using circular dichroism and an in vitro cell activity study. Colloidal stability studies were also performed in simulated intestinal media containing enzymes and the results indicated that protamine NCs were stable and able to protect insulin from the harsh intestinal environment, and that this capacity could be further enhanced with a double PSA-Protamine layer. These NCs were freeze-dried and stored at room temperature without alteration of the physicochemical properties. When the insulin-loaded protamine NCs were administered intra-intestinally to diabetic rats (12 h fasting) it resulted in a prolonged glucose reduction (60%) as compared to the control insulin solution. This work raises prospects that protamine NCs may have a potential as oral peptide delivery nanocarriers.

AB - Peptides represent a promising therapeutic class with the potential to alleviate many severe diseases. A key limitation of these active molecules relies on the difficulties for their efficient oral administration. The objective of this work has been the rational design of polymer nanocapsules (NCs) intended for the oral delivery of peptide drugs. For this purpose, we selected insulin glulisine as a model peptide. The polymer shell of the NCs was made of a single layer of protamine, a cationic polypeptide selected for its cell penetration properties, or a double protamine/polysialic acid (PSA) layer. Insulin glulisine-loaded protamine and protamine/PSA NCs, prepared by the solvent displacement method, exhibited a size that varied in the range of 200-400 nm and a neutral surface charge (from +8 mV to -6 mV), depending on the formulation. The stability of the encapsulated peptide was assessed using circular dichroism and an in vitro cell activity study. Colloidal stability studies were also performed in simulated intestinal media containing enzymes and the results indicated that protamine NCs were stable and able to protect insulin from the harsh intestinal environment, and that this capacity could be further enhanced with a double PSA-Protamine layer. These NCs were freeze-dried and stored at room temperature without alteration of the physicochemical properties. When the insulin-loaded protamine NCs were administered intra-intestinally to diabetic rats (12 h fasting) it resulted in a prolonged glucose reduction (60%) as compared to the control insulin solution. This work raises prospects that protamine NCs may have a potential as oral peptide delivery nanocarriers.

U2 - 10.1016/j.jconrel.2018.10.022

DO - 10.1016/j.jconrel.2018.10.022

M3 - Article

C2 - 30343137

VL - 291

SP - 157

EP - 168

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -