Targeting gemcitabine containing liposomes to CD44 expressing pancreatic adenocarcinoma cells causes an increase in the antitumoral activity

Biochim Biophys Acta. 2013 May;1828(5):1396-404. doi: 10.1016/j.bbamem.2013.01.020. Epub 2013 Feb 4.

Abstract

Pancreatic adenocarcinoma is often diagnosed when metastatic events have occurred. The early spread of circulating cancer cells expressing the CD44 receptor may play a crucial role in this process. In this study, we have investigated the cellular delivery ability and both in vitro and in vivo anti-tumoral activity of liposomes conjugated with two different low molecular weight hyaluronic acids (HA 4.8kDa and HA 12kDa), the primary ligand of CD44, and containing a lipophilic gemcitabine (GEM) pro-drug. By confocal microscopy and flow cytometry analyses, we demonstrate that the cellular uptake into a highly CD44-expressing pancreatic adenocarcinoma cell line is higher with HA-conjugated (12kDa>4.8kDa) than non-conjugated liposomes. Consistently, in vitro cytotoxic assays display an increased sensitivity towards GEM containing HA-liposomes, compared to non-conjugated liposomes. Conversely, CD44 non-expressing normal cells show a similar uptake and in vitro cytotoxicity with both HA-conjugated and non-conjugated liposomes. Furthermore, we demonstrate that the HA-liposomes are taken up into the cells via lipid raft-mediated endocytosis. All the liposome formulations containing GEM show a higher antitumoral activity than free GEM in a mouse xenograft tumor model of human pancreatic adenocarcinoma. The 12kDa HA-liposomes have the strongest efficiency, while non-conjugated liposomes and the 4.8kDa HA-liposomes are similarly active. Taken together, our results provide a strong rationale for further development of HA-conjugated liposomes to treat pancreatic adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1,2-Dipalmitoylphosphatidylcholine / chemistry
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Animals
  • Antimetabolites, Antineoplastic / chemistry
  • Antimetabolites, Antineoplastic / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cholesterol / chemistry
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / chemistry
  • Deoxycytidine / pharmacology
  • Flow Cytometry
  • Humans
  • Hyaluronan Receptors / metabolism
  • Hyaluronic Acid / chemistry
  • Hyaluronic Acid / metabolism
  • Liposomes / chemistry*
  • Liposomes / metabolism
  • Mice
  • Mice, Nude
  • Microscopy, Confocal
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Phosphatidylethanolamines / chemistry
  • Prodrugs / chemistry
  • Prodrugs / pharmacology
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antimetabolites, Antineoplastic
  • Hyaluronan Receptors
  • Liposomes
  • Phosphatidylethanolamines
  • Prodrugs
  • Deoxycytidine
  • 1,2-Dipalmitoylphosphatidylcholine
  • 1,2-dipalmitoyl-3-phosphatidylethanolamine
  • Hyaluronic Acid
  • Cholesterol
  • gemcitabine