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Pharmaceutical Research

, Volume 23, Issue 12, pp 2809–2817 | Cite as

Development of 5-FU and Doxorubicin-Loaded Cationic Liposomes against Human Pancreatic Cancer: Implications for Tumor Vascular Targeting

  • Ashish V. Kalra
  • Robert B. Campbell
Research Paper

Abstract

Purpose

Human pancreatic adenocarcinoma is a major leading cause of cancer mortality in the United States. Given that current strategies are relatively ineffective against this disease, new treatments are being developed. Liposomes possessing relatively high cationic lipid content preferentially accumulate in tumor angiogenic vessels compared to vessels in normal tissues. We therefore seek to develop cationic liposomes for targeting pancreatic tumor vessels.

Materials and Methods

We report development of 5-fluorouracil (5-FU) and doxorubicin hydrochloride (DOX) loaded in PEGylated cationic liposomes (PCLs). We evaluate cell association, intracellular fate, and cytotoxicity. Human pancreatic cancer cells HPAF-II and Capan-1, and endothelial cells HMEC-1 and HUVEC were used in this study. Intratumoral distribution of PCLs in (HPAF-II) tumors was determined by intravital microscopy.

Results

HUVEC and HMEC-1 were most susceptible to 5-FU after 24 and 48 h, compared to HPAF-II and Capan-1. We observed >90% incorporation of 5-FU and DOX in PCLs for 3–20 mol% preparations, with reduced incorporation for >20 mol% formulations. PCLs showed significantly higher association with human endothelial versus pancreatic cancer cells, and improved growth inhibitory properties of DOX. Intravital microscopy revealed distribution of PCLs along HPAF-II vessels.

Conclusions

Targeting human pancreatic cancer with PCLs may represent a rational alternative to conventional strategies.

Key words

cationic liposomes doxorubicin hydrochloride drug delivery pancreatic cancer 5-fluorouracil 

Abbreviations

Capan-1 and HPAF-II

human pancreatic cancer cells

Chol

cholesterol

DOPC

1,2-dioleoyl-sn-glycerol-phosphatidylcholine

DOPE-PEG

1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-5000

DOTAP

1,2-dioleoyl-3-trimethylammonium-propane

DOX

doxorubicin hydrochloride

EBM-2

endothelial cell basal medium

FITC-dextran

fluorescein isothiocyanate-dextran

HMEC-1

human microvascular endothelial cells

HUVEC

human umbilical vein endothelial cell

MEME

eagle’s minimum essential medium

PBS

phosphate buffer saline

PCLs

PEGylated cationic liposomes

Rhodamine-DPPE

1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine

SCID

severe combined immunodeficient

5-FU

5-fluorouracil

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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, Bouvé College of Health SciencesNortheastern UniversityBostonUSA

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