Curcumin-loaded nanoliposomes linked to homing peptides for integrin targeting and neuropilin-1-mediated internalization.

CONTEXT: Curcumin, a naturally occurring polyphenol, has been extensively studied for its broad-spectrum anticancer effects. The potential benefits are, however, limited due to its poor water solubility and rapid degradation which result in low bioavailability on administration. OBJECTIVES: This study encapsulates curcumin in nanoliposomes including an integrin-homing peptide combined with a C end R neuropilin-1 targeting motif for targeted delivery and receptor-mediated internalization, respectively. MATERIALS AND METHODS: The linear GHHNGR (Glycine-Histidine-Histidine-Asparagine-Glycine-Arginine) was synthesized through F-moc chemistry on 2-chlorotrityl chloride resin and conjugated to oleic acid. The lipoyl-peptide units were then co-assembled with lecithin and 0-75 mole % Tween-80 into liposomes. Curcumin was passively entrapped using a film hydration technique and its degradation profile was examined within seven consecutive days. The cytotoxic effects of the curcumin-loaded liposomes were studied on MCF-7 and MDA-MB-468, during 24 h exposure in MTT assay. RESULTS: The maximum curcumin entrapment (15.5% W/W) and minimum degradation (< 23%) were obtained in a pH switch loading method from 5.7 to 8, in nanoliposomes (< 50 nm) containing oleyl-peptide, lecithin and Tween-80 (1:1:0.75 mole ratio). The oleyl-peptide did not prove any haemolytic activity (< 1.5%) up to 10-fold of its experimental concentration. The curcumin-loaded liposomes displayed significant reduction in the viabilities of MCF-7 (IC50 3.8 µM) and MDA-MB-468 (IC50 5.4 µM). DISCUSSION AND CONCLUSION: This study indicated potential advantages of the peptide-conjugated liposomes in drug transport to the cancer cells. This feature might be an outcome of probable interactions between the targeted nanoliposomes with the integrin and neuropilin-1 receptors.

Mechanistic model and analysis of doxorubicin release from liposomal formulations.

Reliable and predictive models of drug release kinetics in vitro and in vivo are still lacking for liposomal formulations. Developing robust, predictive release models requires systematic, quantitative characterization of these complex drug delivery systems with respect to the physicochemical properties governing the driving force for release. These models must also incorporate changes in release due to the dissolution media and methods employed to monitor release. This paper demonstrates the successful development and application of a mathematical mechanistic model capable of predicting doxorubicin (DXR) release kinetics from liposomal formulations resembling the FDA-approved nanoformulation DOXIL® using dynamic dialysis. The model accounts for DXR equilibria (e.g. self-association, precipitation, ionization), the change in intravesicular pH due to ammonia release, and dialysis membrane transport of DXR. The model was tested using a Box-Behnken experimental design in which release conditions including extravesicular pH, ammonia concentration in the release medium, and the dilution of the formulation (i.e. suspension concentration) were varied. Mechanistic model predictions agreed with observed DXR release up to 19h. The predictions were similar to a computer fit of the release data using an empirical model often employed for analyzing data generated from this type of experimental design. Unlike the empirical model, the mechanistic model was also able to provide reasonable predictions of release outside the tested design space. These results illustrate the usefulness of mechanistic modeling to predict drug release from liposomal formulations in vitro and its potential for future development of in vitro - in vivo correlations for complex nanoformulations.

Determination of key parameters for a mechanism-based model to predict Doxorubicin release from actively loaded liposomes.

Despite extensive study of liposomal drug formulations, reliable predictive models of release kinetics in vitro and in vivo are still lacking. Progress in the development of robust, predictive release models has been hindered by a lack of systematic, quantitative characterization of these complex drug delivery systems with respect to the myriad of factors that may influence drug release kinetics and the wide range of dissolution media/methods employed to monitor release. In this paper, the key processes and parameters needed to develop a complete mechanism-based model for doxorubicin release from actively loaded liposomal formulations resembling Doxil(®) are determined. Quantitative models must account for the driving force(s) [i.e., activity gradient(s) of the permeable species between the intraliposomal and external media] and the permeability-area product(s) for lipid bilayer transport. These factors are intertwined as membrane permeability-area products require knowledge of the drug species and concentrations that account for the release. The necessary information includes values for the drug pKa, identity of the permeable species and species permeability coefficients, a model to describe drug self-association and the relevant equilibrium constant(s), the bilayer/water partition coefficient of the predominant drug species under relevant pH conditions, and the solubility product (Ksp ) for intraliposomal precipitates that exist in such formulations.

Physico-mechanical analysis of free ethyl cellulose films comprised with novel plasticizers of vitamin resources.

This research was conducted to investigate the physico-mechanical characteristics of the EC-based coating membranes plasticized with two informal ingredients of vitamin resources, cholecalciferol and alpha-tocopherol, with respect to the commercial plasticizer DBS. Proceeding the experiment, free thin polymer sheetings of the sample formulations, incorporating incremental weight percents of the individual plasticizers were prepared employing a revised casting method of delayed solvent evaporation whereby similar flat specimens of standard dimensions were subjected to tensile loadings and extensions. The data were analyzed through the known equations of membrane theory in spherical subjects considering the complete symmetry of assumingly spherical pellets and/or granules. The relative tensile parameters of the experimental and commercial plasticizers in the resilient region were also estimated to fairly decide on a moderate explanation of a strong, hard, and tough structure among the specimens. The results implied the great compatibility of the oily soluble vitamins in EC networks projecting higher factors of safety and greater ultimate strength, toughness, and young coefficient of the formulations compared to the specimens plasticized with the commercial DBS within a concentration range of 40-50% (w/w) of the polymer solids. alpha-Tocopherol represented supremacy over colecalciferol to result in relatively a 2-fold (and practically a 4-fold with respect to DBS) greater increase in the modulus of resilience. The vitamin compounds and in essential alpha-tocopherol, in consequence, can properly be applied at concentrations of 40-50% (w/w) as efficient plasticizers to provide a greater protection of the structure against sudden fractures of dynamic and continuously increasing environmental and biological stresses.