A tumor vasculature targeted liposome delivery system for combretastatin A4: Design, characterization, and in vitro evaluation |
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Authors: | Ramakrishna Nallamothu George C Wood Christopher B Pattillo Robert C Scott Mohammad F Kiani Bob M Moore Laura A Thoma |
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Institution: | 1Parenteral Medications Laboratories, Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, TN, 26 S Dunlap St, Room 214, 38163 Memphis, TN ;2Department of Mechanical Engineering, Temple University, Philadelphia, PA ;3Department of Radiation Oncology, Temple University, Philadelphia, PA ;4Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN |
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Abstract: | The objective of this study was to develop an efficient tumor vasculature targeted liposome delivery system for combretastatin
A4, a novel antivascular agent. Liposomes composed of hydrogenated soybean phosphatidylcholine (HSPC), cholesterol, distearoyl
phosphoethanolamine-polyethylene-glycol-2000 conjugate (DSPE-PEG), and DSPE-PEG-maleimide were prepared by the lipid film
hydration and extrusion process. Cyclic RGD (Arg-Gly-Asp) peptides with affinity for αvβ3-integrins expressed on tumor vascular
endothelial cells were coupled to the distal end of PEG on the liposomes sterically stabilized with PEG (long circulating
liposomes, LCL). The liposome delivery system was characterized in terms of size, lamellarity, ligand density, drug loading,
and leakage properties. Targeting nature of the delivery system was evaluated in vitro using cultured human umbilical vein
endothelial cells (HUVEC). Electron microscopic observations of the formulations revealed presence of small unilamellar liposomes
of ∼120 nm in diameter. High performance liquid chromatography determination of ligand coupling to the liposome surface indicated
that more than 99% of the RGD peptides were reacted with maleimide groups on the liposome surface. Up to 3 mg/mL of stable
liposomal combretastatin A4 loading was achieved with ∼80% of this being entrapped within the liposomes. In the in vitro cell
culture studies, targeted liposomes showed significantly higher binding to their target cells than non-targeted liposomes,
presumably through specific interaction of the RGD with its receptors on the cell surface. It was concluded that the targeting
properties of the prepared delivery system would potentially improve the therapeutic benefits of combretastatin A4 compared
with nontargeted liposomes or solution dosage forms. |
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Keywords: | targeted liposome delivery system combretastatin A4 tumor vasculature targeting liposome characterization |
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