title: Multistep targeted nano drug delivery system aiming at leukemic stem cells and minimal residual disease.
abstract: Refractory leukemia remains the most common therapeutic problem in clinical treatment of leukemia. The key therapy of refractory leukemia is to kill, thoroughly, the minimal residual disease and leukemia stem cells in the highly vascularized red marrow areas. In this study, two new conjugates, alendronate-polyethylene glycol (100) monostearate and folate-polyethylene glycol (100) monostearate, were synthesized to develop a multistep targeting nanostructured lipid carriers by enhancing drug transport to the high bone turnover areas adjacent to the red marrow and targeting the minimal residual disease and leukemia stem cells. This dual targeting system demonstrated a great binding affinity to hydroxyapatite, a model component of bone minerals, and higher cell uptake (in the form of carriers but not drug) and cytotoxicity in the K562 cell line, a leukemia cell line with overexpressed folate receptors, were observed in vitro compared to unmodified carriers, especially when the cells were pretreated and the receptors were up-regulated by all-trans retinoic acid. The comodel test of K562 cells and HA showed that this dual targeting system could desorb from bone surface and be taken up by leukemia cells. For the in vivo study, this dual targeting system exhibited a significant increase in plasma half-life and could specifically accumulate in the bone tissue of rats or mice after intravenous injection. Ex vivo imaging of mice femurs and confocal laser scanning microscope imaging of mice femur slices further confirmed that this dual targeting system could favorably deposit to the osteoblast-enriched areas of high bone turnover in regions of trabecular bone surrounded by red marrow. In vivo antitumor activity in K562/BALB/c-nu leukemia mice showed that the treatment of this dual targeting system significantly reduced the white blood cell (WBC) number in peripheral blood and bone marrow to the normal level. In conclusion, this dual targeting system could precisely target to the regions where the minimal residual disease and leukemia stem cells are located and then be specifically uptaken in large amounts, which is a valuable target for refractory leukemia therapy.
authors: Department of Pharmaceutics, Key Lab of State Natural Medicine, China Pharmaceutical University, Nanjing 210009, PR China.
authors: Yongping
authors: Y
authors: Shi
authors: Zhigui
authors: Z
authors: Su
authors: Sai
authors: S
authors: Li
authors: Yinan
authors: Y
authors: Chen
authors: Xi
authors: X
authors: Chen
authors: Yanyu
authors: Y
authors: Xiao
authors: Minjie
authors: M
authors: Sun
authors: Qineng
authors: Q
authors: Ping
authors: Li
authors: L
authors: Zong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D017886:Durapatite / Q000737:chemistry; D005492:Folic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D007962:Leukocytes / Q000187:drug effects; D051379:Mice; D008942:Mitoxantrone / Q000008:administration & dosage / Q000627:therapeutic use; D018365:Neoplasm, Residual / Q000188:drug therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; C552831:poly(ethylene glycol)-folate; D011092:Polyethylene Glycols; D017886:Durapatite; D005492:Folic Acid; D008942:Mitoxantrone