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Hyaluronan-conjugated liposomes encapsulating gemcitabine for breast cancer stem cells
Na-Kyung Han1, Dae Hwan Shin1, Jung Seok Kim1
1Research Center for Cell Fate Control (RCCFC) and College of Pharmacy, Sookmyung Women's University, Seoul, Korea.
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.
Insights
Hyaluronan-conjugated liposomes loaded with gemcitabine effectively target breast cancer stem cells (BCSCs), enhancing drug efficacy and reducing systemic toxicity for improved breast cancer therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Breast cancer stem cells (BCSCs) drive tumor relapse and metastasis.
- Targeted drug delivery systems are crucial for effective BCSCs therapy.
- Hyaluronan (HA) is a ligand for CD44, a marker overexpressed on BCSCs.
Purpose of the Study:
- To develop and evaluate HA-conjugated liposomes encapsulating gemcitabine (GEM) for targeted BCSCs therapy.
- To assess the in vitro and in vivo efficacy and safety of this novel drug delivery system.
Main Methods:
- Enriched BCSCs were obtained from MCF-7 cells cultured in nonadherent conditions.
- MCF-7 derived BCSCs were treated with HA-conjugated liposomes encapsulating GEM.
- In vitro cytotoxicity, migration, and colony formation assays were performed.
- Pharmacokinetic and antitumor efficacy studies were conducted in a xenograft mouse model.
Main Results:
- HA-conjugated liposomes significantly enhanced GEM's cytotoxicity, anti-migration, and anti-colony formation against BCSCs.
- Pharmacokinetic studies showed a 3.5-fold increase in the area under the curve (AUC) for liposomal GEM compared to free GEM.
- In vivo studies demonstrated a 3.3-fold higher antitumor effect of liposomal GEM versus free GEM with reduced systemic toxicity.
Conclusions:
- HA-conjugated liposomes encapsulating GEM represent a promising strategy for targeting BCSCs.
- This targeted liposomal formulation enhances GEM's stability, efficacy, and reduces its systemic toxicity.
- The developed system shows potential for improved breast cancer treatment by targeting CD44-expressing BCSCs.
