Liposomes coated with thiolated chitosan enhance oral peptide delivery to rats - PubMed (original) (raw)

Liposomes coated with thiolated chitosan enhance oral peptide delivery to rats

K Gradauer et al. J Control Release. 2013.

Abstract

The aim of the present study was the in vivo evaluation of thiomer-coated liposomes for an oral application of peptides. For this purpose, salmon calcitonin was chosen as a model drug and encapsulated within liposomes. Subsequently, the drug loaded liposomes were coated with either chitosan-thioglycolic acid (CS-TGA) or an S-protected version of the same polymer (CS-TGA-MNA), leading to an increase in the particle size of about 500 nm and an increase in the zeta potential from approximately -40 mV to a maximum value of about +44 mV, depending on the polymer. Coated liposomes were demonstrated to effectively penetrate the intestinal mucus layer where they came in close contact with the underlying epithelium. To investigate the permeation enhancing properties of the coated liposomes ex vivo, we monitored the transport of fluoresceinisothiocyanate-labeled salmon calcitonin (FITC-sCT) through rat small intestine. Liposomes coated with CS-TGA-MNA showed the highest effect, leading to a 3.8-fold increase in the uptake of FITC-sCT versus the buffer control. In vivo evaluation of the different formulations was carried out by the oral application of 40 μg of sCT per rat, either encapsulated within uncoated liposomes, CS-TGA-coated liposomes or CS-TGA-MNA-coated liposomes, or given as a solution serving as negative control. The blood calcium level was monitored over a time period of 24h. The highest reduction in the blood calcium level, to a minimum of 65% of the initial value after 6h, was achieved for CS-TGA-MNA-coated liposomes. Comparing the areas above curves (AAC) of the blood calcium levels, CS-TGA-MNA-coated liposomes led to an 8.2-fold increase compared to the free sCT solution if applied orally in the same concentration. According to these results, liposomes coated with S-protected thiomers have demonstrated to be highly valuable carriers for enhancing the oral bioavailability of salmon calcitonin.

Keywords: Chitosan; Liposome; Permeation enhancement; Salmon calcitonin; Thiomer.

© 2013. Published by Elsevier B.V. All rights reserved.

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Figures

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Graphical abstract

Fig. 1

Fig. 1

Reaction of CS–TGA with 6,6′-dinicotinamide leads to the S-protected thiomer CS–TGA–MNA. Both polymers were used for the coating of preformed liposomes.

Fig. 2

Fig. 2

Diffusion of rhodamine-labeled liposomes through porcine intestinal mucus. Mucus layers were incubated with uncoated liposomes (B), CS–TGA-coated liposomes (C), or CS–TGA–MNA coated liposomes (D) and compared with a control omitting any particles (A). Green (I) and red fluorescence (II) images were merged in order to distinguish between particles (red) and autofluorescence (yellow). The mucus layer thickness is displayed by the two dotted lines; the right side corresponds to the mucus surface, where particles have been applied.

Fig. 3

Fig. 3

Absorptive permeation studies of FITC-calcitonin across rat intestinal tissue. Effect of uncoated liposomes (△) and liposomes coated with the thiolated chitosans CS–TGA (■) and the S-protected version CS–TGA–MNA (♦) in comparison to the FITC-sCT control (×). Indicated values are the means ± SD of at least three experiments.

Fig. 4

Fig. 4

Decrease of the transepithelial electrical resistance (TEER) after adding uncoated liposomes (△) and liposomes coated with the thiolated chitosans CS–TGA (■) and its S-protected form CS–TGA–MNA (♦) in comparison to FITC-sCT control (×). Indicated values are the means ± SD of at least three experiments.

Fig. 5

Fig. 5

Effect of different application routes of sCT solution on the blood calcium level: The applied dose per rat was either 40 μg in case of an oral application (×), 2 μg in case of a s.c. application (□) or 1 μg for an i.v. injection (○). Indicated values are the means ± SD of three rats.

Fig. 6

Fig. 6

Decrease in the blood calcium level as a biological response to the oral application of sCT encapsulated within different liposomal formulations or given as a solution. sCT containing liposomes were coated with either CS–TGA (■) or CS–TGA–MNA (♦) and compared to uncoated, sCT loaded liposomes (△) and free sCT in solution (×). The applied dose per rat was 40 μg sCT in all cases. Indicated values are the means ± SD of three rats.

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