TY - JOUR
T1 - The effect of liposomal size on the targeted delivery of doxorubicin toIntegrin αvβ3-expressing tumor endothelial cells
AU - Kibria, Golam
AU - Hatakeyama, Hiroto
AU - Ohga, Noritaka
AU - Hida, Kyoko
AU - Harashima, Hideyoshi
N1 - Funding Information:
This study was supported in parts by grants from the Special Education and Research Expenses of the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) ; as well as by a Grant-in-Aid for Research on Medical Device Development from the Ministry of Health, Labour and Welfare of Japan (MHLW) . We thank Dr. Milton S. Feather for editing the manuscript.
PY - 2013/7
Y1 - 2013/7
N2 - Size of the liposomes (LPs) specially governs its biodistribution. In this study, LPs were developed with controlled sizes, where variation in LP size dictates the ligand-receptor interaction, cellular internalization and its distribution within the tumor microenvironment. The therapeutic efficacies of doxorubicin (DOX)-loaded RGD modified small size (~100nm in diameter, dnm) and large size (~300dnm) PEGylated LPs (RGD-PEG-LPs) were compared to that of Doxil (a clinically used DOX-loaded PEG-LP, ~100dnm) in DOX resistant OSRC-2 (Renal cell carcinoma, RCC) tumor xenografts. Doxil, which accumulated in tumor tissue via the enhanced permeability and retention (EPR) effect, failed to suppress tumor growth. Small size RGD-PEG-LP, that targets the tumor endothelial cells (TECs) and extravasates to tumor cells, failed to provide anti-tumor effect. Large size RGD-PEG-LP preferentially targets the TECs via minimization of the EPR effect, and significantly reduced the tumor growth, which was exerted through its strong anti-angiogenic activity on the tumor vasculature rather than having a direct effect on DOX resistant RCC. The prepared large size RGD-PEG-LP that targets the TECs via interacting with Integrin αvβ3, is a potentially effective and alternate therapeutic strategy for the treatment of DOX resistant tumor cells by utilizing DOX, in cases where Doxil is ineffective.
AB - Size of the liposomes (LPs) specially governs its biodistribution. In this study, LPs were developed with controlled sizes, where variation in LP size dictates the ligand-receptor interaction, cellular internalization and its distribution within the tumor microenvironment. The therapeutic efficacies of doxorubicin (DOX)-loaded RGD modified small size (~100nm in diameter, dnm) and large size (~300dnm) PEGylated LPs (RGD-PEG-LPs) were compared to that of Doxil (a clinically used DOX-loaded PEG-LP, ~100dnm) in DOX resistant OSRC-2 (Renal cell carcinoma, RCC) tumor xenografts. Doxil, which accumulated in tumor tissue via the enhanced permeability and retention (EPR) effect, failed to suppress tumor growth. Small size RGD-PEG-LP, that targets the tumor endothelial cells (TECs) and extravasates to tumor cells, failed to provide anti-tumor effect. Large size RGD-PEG-LP preferentially targets the TECs via minimization of the EPR effect, and significantly reduced the tumor growth, which was exerted through its strong anti-angiogenic activity on the tumor vasculature rather than having a direct effect on DOX resistant RCC. The prepared large size RGD-PEG-LP that targets the TECs via interacting with Integrin αvβ3, is a potentially effective and alternate therapeutic strategy for the treatment of DOX resistant tumor cells by utilizing DOX, in cases where Doxil is ineffective.
KW - Anti-angiogenic effect
KW - Drug-resistant cancer
KW - Ligand multivalency
KW - Size of liposomes
KW - Tumor vasculature targeting
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U2 - 10.1016/j.biomaterials.2013.03.094
DO - 10.1016/j.biomaterials.2013.03.094
M3 - Article
C2 - 23623323
AN - SCOPUS:84877609222
SN - 0142-9612
VL - 34
SP - 5617
EP - 5627
JO - Biomaterials
JF - Biomaterials
IS - 22
ER -
