A tumor vasculature targeted liposome delivery system for combretastatin A4

design, characterization, and in vitro evaluation.

Ramakrishna Nallamothu, George C. Wood, Christopher B. Pattillo, Robert C. Scott, Mohammad F. Kiani, Bob M. Moore, Laura A. Thoma

Research output: Contribution to journalArticle

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 alphavbeta3-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 approximately 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 approximately 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 nontargeted 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.

Original languageEnglish (US)
JournalAAPS PharmSciTech [electronic resource].
Volume7
Issue number2
StatePublished - Jul 24 2006

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polyethylene glycol
Liposomes
peptides
neoplasms
integrins
blood vessels
films (materials)
extrusion
phosphatidylcholines
endothelial cells
Neoplasms
cell culture
high performance liquid chromatography
cholesterol
electrons
cells
soybeans
drugs
therapeutics
receptors

All Science Journal Classification (ASJC) codes

  • Agronomy and Crop Science
  • Pharmaceutical Science
  • Drug Discovery

Cite this

A tumor vasculature targeted liposome delivery system for combretastatin A4 : design, characterization, and in vitro evaluation. / Nallamothu, Ramakrishna; Wood, George C.; Pattillo, Christopher B.; Scott, Robert C.; Kiani, Mohammad F.; Moore, Bob M.; Thoma, Laura A.

In: AAPS PharmSciTech [electronic resource]., Vol. 7, No. 2, 24.07.2006.

Research output: Contribution to journalArticle

Nallamothu, Ramakrishna ; Wood, George C. ; Pattillo, Christopher B. ; Scott, Robert C. ; Kiani, Mohammad F. ; Moore, Bob M. ; Thoma, Laura A. / A tumor vasculature targeted liposome delivery system for combretastatin A4 : design, characterization, and in vitro evaluation. In: AAPS PharmSciTech [electronic resource]. 2006 ; Vol. 7, No. 2.
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