title: Targeted delivery of a combination therapy consisting of combretastatin A4 and low-dose doxorubicin against tumor neovasculature.
abstract: The present study demonstrates the applicability of a novel strategy that employs targeted delivery of combined treatment against tumor neovasculature. Briefly, a ligand of integrins, cyclic arginine-glycine-aspartic acid-tyrosine-lysine pentapeptide (cRGDyK), was conjugated to the PEG end of polyethylene glycol-b-poly lactic acid (PEG-b-PLA), and doxorubicin was chemically linked to the PLA end of PEG-b-PLA. The targeted dual-drug micelle system was prepared by mixing combretastatin A4 (an antivascular agent), PEG-b-PLA, and the above two conjugates using a solution-casting method. The targeted micelles significantly enhanced cellular uptake of the drug by B16-F10 cells and human umbilical vein endothelial cells through a receptor-mediated endocytosis. The cRGDyK-modified dual-drug system achieved an optimal antitumor effect, lifespan increase, antineovasculature, antiproliferation, and apoptosis induction, revealing the advantage of active targeting and the modified combination therapy. In conclusion, the integration of targeted delivery and combination therapy against tumor neovasculature represents a promising approach for cancer treatment.
  
  
  BACKGROUND
  A ligand of integrins was conjugated to PEG-b-PLA, and doxorubicin was chemically linked to the PLA. Efficiency was demonstrated in a cancer model. The integration of targeted delivery and combination therapy against tumor neovasculature represents a promising approach for cancer treatment.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Tingyuan
authors.initials: T
authors.lastname: Yang
authors.forename: Yiguang
authors.initials: Y
authors.lastname: Wang
authors.forename: Zaiquan
authors.initials: Z
authors.lastname: Li
authors.forename: Wenbing
authors.initials: W
authors.lastname: Dai
authors.forename: Jie
authors.initials: J
authors.lastname: Yin
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.forename: Xue
authors.initials: X
authors.lastname: Ying
authors.forename: Shufeng
authors.initials: S
authors.lastname: Zhou
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Wang
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007773:Lactates / Q000737:chemistry* / Q000627:therapeutic use; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010456:Peptides, Cyclic / Q000737:chemistry / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000627:therapeutic use; D013267:Stilbenes / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D007773:Lactates; D008823:Micelles; D010456:Peptides, Cyclic; D013267:Stilbenes; C550210:cyclo(Arg-Gly-Asp-Tyr-Lys); C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; D004317:Doxorubicin; C058728:fosbretabulin