The effect of liposomal size on the targeted delivery of doxorubicin toIntegrin αvβ3-expressing tumor endothelial cells

Golam Kibria; Hiroto Hatakeyama; Noritaka Ohga; Kyoko Hida; Hideyoshi Harashima

doi:10.1016/j.biomaterials.2013.03.094

The effect of liposomal size on the targeted delivery of doxorubicin toIntegrin αvβ3-expressing tumor endothelial cells

Golam Kibria, Hiroto Hatakeyama, Noritaka Ohga, Kyoko Hida, Hideyoshi Harashima^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

100 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	5617-5627
Number of pages	11
Journal	Biomaterials
Volume	34
Issue number	22
DOIs	https://doi.org/10.1016/j.biomaterials.2013.03.094
State	Published - Jul 2013

Funding

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.

Keywords

Anti-angiogenic effect
Drug-resistant cancer
Ligand multivalency
Size of liposomes
Tumor vasculature targeting

ASJC Scopus subject areas

Mechanics of Materials
Ceramics and Composites
Bioengineering
Biophysics
Biomaterials

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.biomaterials.2013.03.094

Cite this

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title = "The effect of liposomal size on the targeted delivery of doxorubicin toIntegrin αvβ3-expressing tumor endothelial cells",

abstract = "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.",

keywords = "Anti-angiogenic effect, Drug-resistant cancer, Ligand multivalency, Size of liposomes, Tumor vasculature targeting",

author = "Golam Kibria and Hiroto Hatakeyama and Noritaka Ohga and Kyoko Hida and Hideyoshi Harashima",

note = "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. ",

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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

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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.

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KW - Drug-resistant cancer

KW - Ligand multivalency

KW - Size of liposomes

KW - Tumor vasculature targeting

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ER -

The effect of liposomal size on the targeted delivery of doxorubicin toIntegrin αvβ3-expressing tumor endothelial cells

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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