Protective Effect of Saccharides on Freeze-Dried Liposomes Encapsulating Drugs.

Diana Guimarães,Jennifer Noro,Artur Cavaco-Paulo,Carla Silva,Eugénia Nogueira

doi:10.3389/fbioe.2019.00424

Diana Guimarães, Jennifer Noro + Show 3 more

Open Access

https://doi.org/10.3389/fbioe.2019.00424

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Abstract

The production of freeze-dried liposomes encapsulating drugs is considered a key challenge since the drugs are prone to leakage. The aim of this work was to study the effect of different saccharides on preserving the stability and drug retention capacity of a previously developed liposomal formulation, when subjected to a freeze-drying process. The protective role of trehalose, lactose, glucose, mannitol and sucrose, known for their cryo/lyoprotective effect, was tested by addition of different concentrations to liposomes. Sucrose, in a concentration dependent manner (8:1 sugar:lipids mass ratio) proved to be a suitable cryo/lyoprotectant of these liposomes. Effectively, this saccharide prevents the fusion or/and aggregation of the liposomal formulation, protecting the integrity of the freeze-dried empty liposomes. The liposomal formulation containing sucrose was studied in terms of morphology, concentration, and anticancer drugs retention ability. The study involved two drugs encapsulated in the aqueous core, methotrexate (MTX) and doxorubicin (DOX), and one drug located in the lipid bilayer, tamoxifen (TAM). After the freeze-drying process, liposomes with sucrose encapsulating drugs revealed high physical stability, maintaining their narrow and monodisperse character, however high leakage of the drugs encapsulated in the aqueous core was observed. Otherwise, no significant drug leakage was detected on liposomes containing the TAM, which maintained its biological activity after the freeze-drying process. These findings reveal that sucrose is a good candidate for the cryo/lyoprotection of liposomes with drugs located in the lipid bilayer.

Highlights

Liposomes have received significant attention as drug delivery systems since they are composed of natural substances, making them non-toxic and biodegradable (Nogueira et al, 2015a)
We have previously described a liposomal formulation that prove to be an efficient system for the encapsulation and delivery of both hydrophobic and hydrophilic drugs (Nogueira et al, 2015c)
Encapsulation of drugs was done by their mixture during the liposomes preparation, MTX (7 mg/mL), as hydrophilic drug was included in aqueous phase (PBS buffer) and TAM (1 mg/mL) as hydrophobic drug was added in organic phase

Summary

Introduction

Liposomes have received significant attention as drug delivery systems since they are composed of natural substances, making them non-toxic and biodegradable (Nogueira et al, 2015a). Drugs encapsulated within liposomes are protected from early inactivation, immediate dilution or degradation, suggesting these devices as good carriers to targeting sites (Spuch and Navarro, 2011). Depending on their solubility, drugs can be encapsulated in the inner aqueous compartment (hydrophilic drugs), intercalated in the membrane bilayer structure or associated to the membrane surface (hydrophobic drugs) (Schwendener and Schott, 2017). A meticulous optimization and selection of the components of the formulation is crucial to achieve a long-term stability of liposome based drugs (Kannan et al, 2014)

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