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 language | English |
|---|---|
| Pages (from-to) | 157-168 |
| Number of pages | 12 |
| Journal | Journal of Controlled Release |
| Volume | 291 |
| DOIs | |
| Publication status | Published - Dec 10 2018 |
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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 journal › Article
}
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 -