Enhancement of anticancer activity in antineovascular therapy is based on the intratumoral distribution of the active targeting carrier for anticancer drugs.
We previously observed the enhanced anticancer efficacy of anticancer drugs encapsulated in Ala-Pro-Arg-Pro-Gly-polyethyleneglycol-modified liposome (APRPG-PEG-Lip) in tumor-bearing mice, since APRPG peptide was used as an active targeting tool to angiogenic endothelium. This modality, antineovascular therapy (ANET), aims to eradicate tumor cells indirectly through damaging angiogenic vessels. In the present study, we examined the in vivo trafficking of APRPG-PEG-Lip labeled with [2-(18)F]2-fluoro-2-deoxy-D-glucose ([2-(18)F]FDG) by use of positron emission tomography (PET), and observed that the trafficking of this liposome was quite similar to that of non-targeted long-circulating liposome (PEG-Lip). Then, histochemical analysis of intratumoral distribution of both liposomes was performed by use of fluorescence-labeled liposomes. In contrast to in vivo trafficking, intratumoral distribution of both types of liposomes was quite different: APRPG-PEG-Lip was colocalized with angiogenic endothelial cells that were immunohistochemically stained for CD31, although PEG-Lip was localized around the angiogenic vessels. These results strongly suggest that intratumoral distribution of drug carrier is much more important for therapeutic efficacy than the total accumulation of the anticancer drug in the tumor, and that active delivery of anticancer drugs to angiogenic vessels is useful for cancer treatment.
Maeda
Noriyuki
N
Department of Medical Biochemistry and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, Yada, Shizuoka, Japan.
Miyazawa
Souichiro
S
Shimizu
Kosuke
K
Asai
Tomohiro
T
Yonezawa
Sei
S
Kitazawa
Sadaya
S
Namba
Yukihiro
Y
Tsukada
Hideo
H
Oku
Naoto
N
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D019788:Fluorodeoxyglucose F18; D008081:Liposomes; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009842:Oligopeptides / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D049268:Positron-Emission Tomography
D000970:Antineoplastic Agents; D008081:Liposomes; D009842:Oligopeptides; C490869:alanyl-prolyl-arginyl-prolyl-glycine; D019788:Fluorodeoxyglucose F18; D011092:Polyethylene Glycols; D004317:Doxorubicin