title: Targeting gemcitabine containing liposomes to CD44 expressing pancreatic adenocarcinoma cells causes an increase in the antitumoral activity.
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.
authors: Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
authors: Elisa
authors: E
authors: Dalla Pozza
authors: Carlotta
authors: C
authors: Lerda
authors: Chiara
authors: C
authors: Costanzo
authors: Massimo
authors: M
authors: Donadelli
authors: Ilaria
authors: I
authors: Dando
authors: Elisa
authors: E
authors: Zoratti
authors: Maria Teresa
authors: MT
authors: Scupoli
authors: Stefania
authors: S
authors: Beghelli
authors: Aldo
authors: A
authors: Scarpa
authors: Elias
authors: E
authors: Fattal
authors: Silvia
authors: S
authors: Arpicco
authors: Marta
authors: M
authors: Palmieri
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000737:chemistry; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D018960:Hyaluronan Receptors; D008081:Liposomes; D010714:Phosphatidylethanolamines; D011355:Prodrugs; D003841:Deoxycytidine; D015060:1,2-Dipalmitoylphosphatidylcholine; C007510:1,2-dipalmitoyl-3-phosphatidylethanolamine; D006820:Hyaluronic Acid; D002784:Cholesterol; D000093542:Gemcitabine