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.

Multifunctional polymersomes for cytosolic delivery of gemcitabine and doxorubicin to cancer cells

“…In order to overcome these limitations, gemcitabine has been delivered by employing various carriers, e.g., theranostic nanoparticles [5], targeted liposomes [6], micelles [7], and microbubbles [8]. Recent clinical studies demonstrate that gemcitabine, in combination with other antineoplastic agents, is more effective for treating pancreatic cancer [9–13].…”

Trilayer micelles for combination delivery of rapamycin and siRNA targeting Y-box binding protein-1 (siYB-1)

“…It is also important to keep in mind that the bw did not change drastically because the tumors were not allowed to grow to extreme volumes (e.g. 1000–2000 mm 3 [57,58],) to avoid tumor necrosis, often characteristic of large tumors. None of the animals died during the course of the experiments and they were all promptly euthanized by day 10.…”

Targeting Hyaluronic Acid Family for Cancer Chemoprevention and Therapy

“…The uptake of these nanoparticles or liposomes by tumor cells occurs through HA-receptor-mediated internalization, since incubation of tumor cells with soluble HA inhibits uptake of these materials. This suggests that the delivery of these nanoparticles is occurring through HA-receptor-mediated internalization of nanoparticles and liposomes (Dalla Pozza et al, 2013; Ganesh, Iyer, Gattacceca, Morrissey, & Amiji, 2013). …”