Hyaluronan-conjugated liposomes encapsulating gemcitabine for breast cancer stem cells

Abstract

Investigation of potential therapeutics for targeting breast cancer stem cells (BCSCs) is important because these cells are regarded as culprit of breast cancer relapse. Accomplishing this kind of strategy requires a specific drug-delivery system using the distinct features of liposomes. Studies on targeted liposomal delivery systems have indicated the conjugation of hyaluronan (HA), a primary ligand for CD44 surface markers, as an appropriate method for targeting BCSCs. For this study, enriched BCSCs were obtained by culturing MCF-7 breast cancer cells in nonadherent conditions. The enriched BCSCs were challenged with HA-conjugated liposomes encapsulating gemcitabine (2, 2-difluoro-2-deoxycytidine, GEM). In vitro study showed that the HA-conjugated liposomes significantly enhanced the cytotoxicity, anti-migration, and anti-colony formation abilities of GEM through targeting of CD44 expressed on BCSCs. In pharmacokinetic study, area under the drug concentration vs time curve (AUC) of the immunoliposomal GEM was 3.5 times higher than that of free GEM, indicating that the HA-conjugated liposomes enhanced the stability of GEM in the bloodstream and therefore prolonged its half-life time. The antitumor effect of the immunoliposomal GEM was 3.3 times higher than that of free GEM in a xenograft mouse model, probably reflecting the unique targeting of the CD44 receptor by HA and the increased cytotoxicity and stability through the liposomal formulation. Furthermore, marginal change in body weight demonstrated that the use of liposomes considerably reduced the systemic toxicity of GEM on normal healthy cells. Taken together, this study demonstrates that HA-conjugated liposomes encapsulating GEM show promise for the therapy of breast cancer in vitro and in a xenograft model by targeting the BCSCs.

Hyaluronic Acid in the 3^rd Millennium

“…HA can be also conjugated to phospholipids in order to develop surface-modified liposomes: the chemical modification can be performed prior to liposome formulation [184] or after, on the outside shell [185,186]. Moreover, HA can be also non-covalently linked on liposome surface: indeed, liposomes can be covered by HA through ionic interaction mechanism [187,188] or simple lipid film hydration technique [189].…”

“…Moreover, HA can be also non-covalently linked on liposome surface: indeed, liposomes can be covered by HA through ionic interaction mechanism [187,188] or simple lipid film hydration technique [189]. HA-modified liposomes appear promising carriers, as they have been shown to enhance the stability of drugs in the bloodstream, prolong their half-life time, reduce their systemic toxicity [186], enhance their tissue permeability, sustain their prolonged release [189] and ameliorate their therapeutic effects through synergistic actions [190]. HA-coated liposomes could improve the safety and the efficacy of antitumoral therapies: they appear proficient in mediating site-specific delivery of siRNA [191] and anticancer drugs such as doxorubicin [185], gemcitabine [186], imatinib mesylate [188] and docetaxel [184], via CD44 cell receptors.…”

“…HA-modified liposomes appear promising carriers, as they have been shown to enhance the stability of drugs in the bloodstream, prolong their half-life time, reduce their systemic toxicity [186], enhance their tissue permeability, sustain their prolonged release [189] and ameliorate their therapeutic effects through synergistic actions [190]. HA-coated liposomes could improve the safety and the efficacy of antitumoral therapies: they appear proficient in mediating site-specific delivery of siRNA [191] and anticancer drugs such as doxorubicin [185], gemcitabine [186], imatinib mesylate [188] and docetaxel [184], via CD44 cell receptors. Additionally, HA-surface-modified liposomes have been investigated as delivery systems also in ophthalmology [189], pneumology [190] and topical treatment of wounds and burns [40].…”

“…Many researches have shown that HA can act as drug carrier and targeting agent at the same time, under the form of polymer-antitumoral conjugates, or delivery systems encapsulating anticancer drugs [179]. Additionally, hyaluronan can be employed to design surface-modified nanoparticles [196][197][198] or liposomes [184][185][186][187][188]. After CD44 receptor-mediated cell internalization, all these HA derivatives are hydrolyzed by intracellular enzymes and, therefore, drugs are released inside the cancer target cells [179].…”

A Forecast of Targeting Leukemia Stem Cells by Nanomedicine

“…HA incorporated nanocarriers can deliver traditional chemotherapeutic drugs, such as doxorubicin and cyclosporine, to successfully target CD44 expressing CSCs both in vitro and in vivo [75]. This Nanomedicine based CSC targeting strategies have achieved prolonged survival in multiple animal cancer models including AML [76,[100][101][102][103]. Antibody incorporated nanocarriers have also been used for CSC targeting.…”