Development of 5-FU and Doxorubicin-Loaded Cationic Liposomes against Human Pancreatic Cancer: Implications for Tumor Vascular Targeting
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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.
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.
Targeting human pancreatic cancer with PCLs may represent a rational alternative to conventional strategies.
Key wordscationic liposomes doxorubicin hydrochloride drug delivery pancreatic cancer 5-fluorouracil
- Capan-1 and HPAF-II
human pancreatic cancer cells
endothelial cell basal medium
human microvascular endothelial cells
human umbilical vein endothelial cell
eagle’s minimum essential medium
phosphate buffer saline
PEGylated cationic liposomes
severe combined immunodeficient
- 7.R. Wilkowski, M. Thoma, C. Bruns, E. Duhmke, and V. Heinemann. Combined chemoradiotherapy for isolated local recurrence after primary resection of pancreatic cancer. JOP 11:34–40 (2006).Google Scholar
- 9.M. Reni, S. Cordio, C. Milandri, P. Passoni, E. Bonetto, C. Oliani, G. Luppi, R. Nicoletti, L. Galli, R. Bordanaro, A. Passardi, A. Zerbi, G. Balzano, L. Aldrighetti, C. Straudacher, E. Villa, and V. Di Carlo. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentrre phase III trial. Lancet Oncol. 6:352–353 (2005).CrossRefGoogle Scholar
- 10.D. A. Karlin, J. R. Stroehlein, R. W. Bennetts, R. D. Jones, L. J. Heifetz, and P. S. Mahal. Phase I–II study of the combination of 5-FU, doxorubicin, mitomycin, and semustine IFAMMe) in the treatment of adenocarcinoma of the stomach, gastroesophageal junction, and pancreas. Cancer Treat. Rep. 66:1613–1617 (1982).PubMedGoogle Scholar
- 11.D. J. Wagener, Q. van Hoesel, G. S. H. Yap, W. J. Hoogenraad, T. Wobbes, and S. P. Strijk. Phase II trial of 5-fluorouracil, adriamycin and cisplatin (FAP) followed by radiation and 5-fluorouracil in locally advanced pancreatic cancer. Cancer Chemother. Pharmacol. 25:131–134 (1989).PubMedCrossRefGoogle Scholar
- 15.J. Folkman. The role of angiogenesis in tumor growth. Semin. Cancer Biol. 3:65–71 (1992).Google Scholar
- 16.C. M. Lee, T. Tanaka, T. Murai, M. Kondo, J. Kimura, W. Su, T. Kitagawa, T. Ito, H. Matsuda, and M. Miyasaka. Novel chondroitin sulfate-binding cationic liposomes loaded with cisplatin efficiently suppress the local growth and liver metastasis of tumor cells in vivo. Cancer Res. 62:4282–4288 (2002).PubMedGoogle Scholar
- 17.R. Kunstfeld, G. Weckenhauser, U. Michaelis, M. Teifel, W. Umek, K. Naujoks, K. Wolff, and P. Petzelbauer. Paclitaxel encapsulated in cationic liposomes diminishes tumor angiogenesis and melanoma growth in a “humanized” SCID mouse model. J. Invest. Dermatol. 120:476–82 (2003).PubMedCrossRefGoogle Scholar
- 23.J. W. McLean, E. A. Fox, P. Baluk, P. B. Bolton, A. Haskell, R. Pearlman, G. Thurston, E. Y. Umemoto, and D. M. McDonald. Organ-specific endothelial cell uptake of cationic liposome-DNA complexes in mice. Am. J. Physiol. 273:387–404 (1997).Google Scholar
- 31.D. Papahadjopoulos, T. Allen, A. Gabizon, E. Mayhew, K. Matthay, S. K. Huang, K. D. Lee, M. C. Woddle, D. D. Lasic, C. Redemann, and F. J. Martin. Sterically stabilized liposomes: improvements in pharmacokinetics and anti-tumor efficacy. Proc. Natl. Acad. Sci. USA 88:11460–11464 (1991).PubMedCrossRefGoogle Scholar
- 35.J. Denekamp. Vasculature as a target for tumor therapy. Prog. Appl. Microcirc. 4:28–38 (1984).Google Scholar