The effect of hyaluronic acid functionalized carbon nanotubes loaded with salinomycin on gastric cancer stem cells.

Gastric cancer stem cells (CSCs) play a crucial role in the initiation, development, relapse and metastasis of gastric cancer because they are resistant to a standard chemotherapy and the residual CSCs are able to proliferate indefinitely. Therefore, eradication of this cell population is a primary objective in gastric cancer therapy. Here, we report a gastric CSCs-specifically targeting drug delivery system (SAL-SWNT-CHI-HA complexes) based on chitosan(CHI) coated single wall carbon nanotubes (SWNTs) loaded with salinomycin (SAL) functionalized with hyaluronic acid (HA) can selectively eliminate gastric CSCs. Gastric CSCs were identified as CD44+ cells and cultured in serum-free medium. SAL-SWNT-CHI-HA complexes were capable of inhibiting the self-renewal capacity of CD44+ population, and decrease mammosphere- and colon-formation of CSCs. In addition, the migration and invasion of gastric CSCs were significantly blocked by SAL-SWNT-CHI-HA complexes. Quantitative and qualitative analysis of cellular uptake demonstrated that HA functionalization facilitated the uptake of SWNTs in gastric CSCs while free HA competitively inhibited cellular uptake of SAL-SWNT-CHI-HA delivery system, revealing the mechanism of CD44 receptor-mediated endocytosis. The SAL-SWNT-CHI-HA complexes showed the strongest antitumor efficacy in gastric CSCs by inducing apoptosis, and in CSCs mammospheres by penetrating deeply into the core. Taken altogether, our studies demonstrated that this gastric CSCs-targeted SAL-SWNT-CHI-HA complexes would provide a potential strategy to selectively target and efficiently eradicate gastric CSCs, which is promising to overcome the recurrence and metastasis of gastric cancer and improve gastric cancer treatment.

[1]  He Lian,et al.  Dual targeting folate-conjugated hyaluronic acid polymeric micelles for paclitaxel delivery. , 2011, International journal of pharmaceutics.

[2]  James R. Smith,et al.  Novel biocompatible chitosan decorated single-walled carbon nanotubes (SWNTs) for biomedical applications: theoretical and experimental investigations. , 2010, Physical chemistry chemical physics : PCCP.

[3]  F. Szoka,et al.  Anticancer therapeutics: targeting macromolecules and nanocarriers to hyaluronan or CD44, a hyaluronan receptor. , 2008, Molecular pharmaceutics.

[4]  Yang Liu,et al.  A potential target associated with both cancer and cancer stem cells: a combination therapy for eradication of breast cancer using vinorelbine stealthy liposomes plus parthenolide stealthy liposomes. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[5]  Ravi R. Patel,et al.  Chitosan mediated targeted drug delivery system: a review. , 2010, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[6]  Y. Miao,et al.  CD44v6 in peripheral blood and bone marrow of patients with gastric cancer as micro-metastasis. , 2006, World journal of gastroenterology.

[7]  Kiyoko Kato,et al.  The inhibitory effect of salinomycin on the proliferation, migration and invasion of human endometrial cancer stem-like cells. , 2013, Gynecologic oncology.

[8]  A. Fattorossi,et al.  Hyaluronic acid–paclitaxel: effects of intraperitoneal administration against CD44(+) human ovarian cancer xenografts , 2011, Cancer Chemotherapy and Pharmacology.

[9]  D. Peer,et al.  Loading mitomycin C inside long circulating hyaluronan targeted nano‐liposomes increases its antitumor activity in three mice tumor models , 2004, International journal of cancer.

[10]  Hoguen Kim,et al.  Prognostic significance of CD44 and nm23 expression in patients with stage II and stage IIIA gastric carcinoma , 1999, Journal of surgical oncology.

[11]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[12]  Xiaoke Zhang,et al.  Targeted delivery and controlled release of doxorubicin to cancer cells using modified single wall carbon nanotubes. , 2009, Biomaterials.

[13]  S. Howell,et al.  CD44-targeted microparticles for delivery of cisplatin to peritoneal metastases. , 2010, Molecular pharmaceutics.

[14]  Toshiaki Watanabe,et al.  Predictive Value of Cancer Stem-Like Cells and Cancer-Associated Genetic Markers for Peritoneal Recurrence of Colorectal Cancer in Patients after Curative Surgery , 2010, Oncology.

[15]  Huan Yang,et al.  Identification of CD44+CD24+ gastric cancer stem cells , 2011, Journal of Cancer Research and Clinical Oncology.

[16]  M. Zheng,et al.  Salinomycin Selectively Targets ‘CD133+’ Cell Subpopulations and Decreases Malignant Traits in Colorectal Cancer Lines , 2011, Annals of Surgical Oncology.

[17]  Eun-Kyung Lim,et al.  Hyaluronan-modified magnetic nanoclusters for detection of CD44-overexpressing breast cancer by MR imaging. , 2011, Biomaterials.

[18]  T. Mizushima,et al.  Effect of claudin expression on paracellular permeability, migration and invasion of colonic cancer cells. , 2009, Biological & pharmaceutical bulletin.

[19]  Yan Zhang,et al.  The antitumor efficacy of functional paclitaxel nanomicelles in treating resistant breast cancers by oral delivery. , 2011, Biomaterials.

[20]  Eric S. Lander,et al.  Identification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening , 2009, Cell.

[21]  D. Peer,et al.  Hyaluronan-coated nanoparticles: the influence of the molecular weight on CD44-hyaluronan interactions and on the immune response. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[22]  M. Bahrani,et al.  Expression of cell adhesion molecule CD44 in gastric adenocarcinoma and its prognostic importance. , 2008, World journal of gastroenterology.

[23]  H. Krug,et al.  Carbon nanotubes show no sign of acute toxicity but induce intracellular reactive oxygen species in dependence on contaminants. , 2007, Toxicology letters.

[24]  Lu,et al.  Fullerene pipes , 1998, Science.

[25]  Yi Wang.  Effects of salinomycin on cancer stem cell in human lung adenocarcinoma A549 cells. , 2011, Medicinal chemistry (Shariqah (United Arab Emirates)).

[26]  S. Vinogradov,et al.  Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for the targeting of CD44-positive and drug-resistant tumors. , 2013, Bioconjugate chemistry.

[27]  Amit Jain,et al.  The intracellular drug delivery and anti tumor activity of doxorubicin loaded poly(gamma-benzyl L-glutamate)-b-hyaluronan polymersomes. , 2010, Biomaterials.

[28]  Mingwu Shen,et al.  Hyaluronic acid-modified hydrothermally synthesized iron oxide nanoparticles for targeted tumor MR imaging. , 2014, Biomaterials.

[29]  Kevin Struhl,et al.  Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. , 2009, Cancer research.

[30]  Justin C. Grindley,et al.  Tumour-initiating cells: challenges and opportunities for anticancer drug discovery , 2009, Nature Reviews Drug Discovery.

[31]  H. Krug,et al.  Oops they did it again! Carbon nanotubes hoax scientists in viability assays. , 2006, Nano letters.

[32]  Xiaoke Zhang,et al.  Cell behaviors on polysaccharide-wrapped single-wall carbon nanotubes: a quantitative study of the surface properties of biomimetic nanofibrous scaffolds. , 2009, ACS nano.

[33]  Hong-Mao Wu,et al.  An investigation on dispersion of carbon nanotubes in chitosan aqueous solutions , 2010 .

[34]  Dong Wang,et al.  Biodegradable self-assembled nanoparticles of poly (D,L-lactide-co-glycolide)/hyaluronic acid block copolymers for target delivery of docetaxel to breast cancer. , 2014, Biomaterials.

[35]  T. Wang,et al.  Identification of Gastric Cancer Stem Cells Using the Cell Surface Marker CD44 , 2009, Stem cells.

[36]  Maurizio Prato,et al.  Targeting Carbon Nanotubes Against Cancer , 2012 .

[37]  Michael Dean,et al.  Tumour stem cells and drug resistance , 2005, Nature Reviews Cancer.

[38]  Mao Sun,et al.  CD44+ gastric cancer cells with stemness properties are chemoradioresistant and highly invasive , 2013, Oncology letters.

[39]  Kun Yang,et al.  Identification and expansion of cancer stem cells in tumor tissues and peripheral blood derived from gastric adenocarcinoma patients , 2011, Cell Research.

[40]  G. Opelz,et al.  Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells. , 2010, Biochemical and biophysical research communications.

[41]  Xinli Liu,et al.  Characterization of CD44-mediated cancer cell uptake and intracellular distribution of hyaluronan-grafted liposomes. , 2011, Molecular pharmaceutics.