Improved therapeutic responses for liposomal doxorubicin targeted via thrombospondin peptidomimetics versus untargeted doxorubicin.
New therapies in cancer treatment are focusing on multifaceted approaches to starve and kill tumors utilizing both antiangiogenic and chemotherapeutic compounds. In this work, we searched for a peptide vector that would home liposomes both to endothelial and tumor cells. [Abu6]TSPB and [Abu6]TSPA, aspartimide analogs of natural sequences of TSP-1 and TSP-2, respectively, were tested for adhesion of tumor and endothelial cells, in vivo and in vitro antiangiogenic effects, and in vivo antitumor action. Both peptides support the adhesion of both types of cells, but only [Abu6]TSPA inhibits the angiogenesis in vivo, and [Abu6]TSPA-targeted L-DOX decreases by 58% (P < 0.008) the HT29 tumor growth in nude mice. The improvement in the doxorubicin antitumor effect should be attributed to the antiangiogenic effect of [Abu6]TSPA, since [Abu6]TSPB, despite being a good ligand for both cell types, had no effect on tumor growth.
Rivera-Fillat
M P
MP
Pathology and Experimental Therapeutics Group, CSIC-ICCC, Barcelona, Spain.
Reig
F
F
Martínez
E M
EM
Grau-Oliete
M R
MR
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells; D006801:Humans; D008081:Liposomes / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D018716:Molecular Mimicry; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D019699:Thrombospondins / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D004337:Drug Carriers; D008081:Liposomes; D019699:Thrombospondins; D004317:Doxorubicin