Chemical and Biological Evaluations of an 111In-Labeled RGD-Peptide Targeting Integrin Alpha(V) Beta(3) in a Preclinical Tumor Model

In multiple myeloma, malignant plasma cells are localized in marrow and rarely circulate in peripheral blood. To investigate the role of adhesion proteins in this process, we determined the expression and function of adhesion molecules on cell lines derived from patients with myeloma. The U266, ARH-77, IM-9, and HS-Sultan cell lines strongly expressed beta 1 and alpha 4 integrins (89% to 98% positive), confirming that VLA-4 is the principal integrin on these cell lines. The U266 and IM-9 cell lines also expressed alpha 3 integrin on 15% to 20% cells. In contrast, all lines lacked cell surface alpha 2, alpha 5, and alpha 6 integrin expression (< 5% positive). These cell lines adhered to fibronectin (20% to 40% specific binding), without significant binding to either collagen or laminin. Adhesion of these cell lines to fibronectin was partially blocked with either anti-beta 1 integrin monoclonal antibody (MoAb) (75% inhibition), anti-alpha 4 integrin MoAb (75% inhibition), or RGD peptide (50% inhibition), but was unaffected by anti-alpha v beta 3 or anti-alpha IIb beta 3 MoAbs. Moreover, the combination of anti-beta 1 plus RGD peptide or anti-alpha 4 plus RGD peptide inhibited binding to fibronectin by 80% and 95%, respectively. Finally, pretreatment and coculture of the IM-9 cell line with interleukin-6 (IL-6) resulted in a 52% decrease in specific binding to fibronectin (30% +/- 6% to 15% +/- 6%; P = .001), associated with a decrease in the number of cells expressing VLA-4 and a decrease in intensity of VLA-4 expression. These data suggest that myeloma cells adhere to fibronectin through VLA-4 as well as through RGD-dependent mechanisms, and that this binding can be downregulated by IL-6. Future studies of binding of both myeloma cell lines and freshly isolated tumor cells to extracellular matrix proteins and to marrow stroma may enhance our understanding of localization and trafficking of cells within the bone marrow microenvironment.

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Characterization of adhesion molecules on human myeloma cell lines

Blood ◽

10.1182/blood.v80.9.2306.2306 ◽

1992 ◽

Vol 80 (9) ◽

pp. 2306-2314 ◽

Cited By ~ 95

Author(s):

H Uchiyama ◽

BA Barut ◽

D Chauhan ◽

SA Cannistra ◽

KC Anderson

Keyword(s):

Adhesion Molecules ◽

Cell Lines ◽

Plasma Cells ◽

Specific Binding ◽

Myeloma Cell ◽

Rgd Peptide ◽

Beta 1 Integrin ◽

Marrow Stroma ◽

And Function ◽

Alpha V Beta 3

Abstract In multiple myeloma, malignant plasma cells are localized in marrow and rarely circulate in peripheral blood. To investigate the role of adhesion proteins in this process, we determined the expression and function of adhesion molecules on cell lines derived from patients with myeloma. The U266, ARH-77, IM-9, and HS-Sultan cell lines strongly expressed beta 1 and alpha 4 integrins (89% to 98% positive), confirming that VLA-4 is the principal integrin on these cell lines. The U266 and IM-9 cell lines also expressed alpha 3 integrin on 15% to 20% cells. In contrast, all lines lacked cell surface alpha 2, alpha 5, and alpha 6 integrin expression (< 5% positive). These cell lines adhered to fibronectin (20% to 40% specific binding), without significant binding to either collagen or laminin. Adhesion of these cell lines to fibronectin was partially blocked with either anti-beta 1 integrin monoclonal antibody (MoAb) (75% inhibition), anti-alpha 4 integrin MoAb (75% inhibition), or RGD peptide (50% inhibition), but was unaffected by anti-alpha v beta 3 or anti-alpha IIb beta 3 MoAbs. Moreover, the combination of anti-beta 1 plus RGD peptide or anti-alpha 4 plus RGD peptide inhibited binding to fibronectin by 80% and 95%, respectively. Finally, pretreatment and coculture of the IM-9 cell line with interleukin-6 (IL-6) resulted in a 52% decrease in specific binding to fibronectin (30% +/- 6% to 15% +/- 6%; P = .001), associated with a decrease in the number of cells expressing VLA-4 and a decrease in intensity of VLA-4 expression. These data suggest that myeloma cells adhere to fibronectin through VLA-4 as well as through RGD-dependent mechanisms, and that this binding can be downregulated by IL-6. Future studies of binding of both myeloma cell lines and freshly isolated tumor cells to extracellular matrix proteins and to marrow stroma may enhance our understanding of localization and trafficking of cells within the bone marrow microenvironment.

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RGD Peptide–mediated Molecular Imaging for Targeting Integrin Alpha(v) Beta(3) in Tumors: A Review

Current Medical Imaging Formerly Current Medical Imaging Reviews ◽

10.2174/1573405613666161209102928 ◽

2018 ◽

Vol 14 (2) ◽

pp. 186-195 ◽

Cited By ~ 2

Author(s):

Su Hu ◽

Ling yang ◽

Feng-lin Dong ◽

Chen-Fei Yao ◽

Xi-Ming Wang ◽

...

Keyword(s):

Molecular Imaging ◽

Rgd Peptide ◽

Alpha V Beta 3

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Preparation and characterization of a dual-receptor mesoporous silica nanoparticle–hyaluronic acid–RGD peptide targeting drug delivery system

RSC Advances ◽

10.1039/c6ra03113g ◽

2016 ◽

Vol 6 (46) ◽

pp. 40427-40435 ◽

Cited By ~ 18

Author(s):

Haixing Xu ◽

Zhihui Wang ◽

Yan Li ◽

Yufeng Guo ◽

Huimin Zhou ◽

...

Keyword(s):

Drug Delivery ◽

Hyaluronic Acid ◽

Mesoporous Silica ◽

Mesoporous Silica Nanoparticles ◽

Silica Nanoparticle ◽

Rgd Peptide ◽

Mesoporous Silica Nanoparticle ◽

System P ◽

Peptide Targeting

Novel mesoporous silica nanoparticles conjugated with hyaluronic acid and RGD peptide were developed for dual-receptor mediated targeting drug delivery.

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Experimental study of dendrimer-based nanoparticles with RGD-peptide for anticancer radionuclide therapy

Bulletin of Russian State Medical University ◽

10.24075/brsmu.2018.089 ◽

2018 ◽

pp. 113-119 ◽

Cited By ~ 1

Author(s):

Yu.V. Stukalov ◽

E.Yu. Grigorieva ◽

A.V. Smirnova ◽

A.A. Lipengolts ◽

I.Yu. Kubasova ◽

...

Keyword(s):

Tumor Cells ◽

Therapeutic Efficacy ◽

Radionuclide Therapy ◽

Tumor Model ◽

Rgd Peptide ◽

Significant Inhibition ◽

Great Promise ◽

Multiple Metastases ◽

Delivery Platform ◽

Normal Ratio

Radionuclide therapy (RNT) is an effective modality for treating multiple metastases in patients with cancer. The list of malignancies that can be managed with RNT expands with the arrival of novel tumoritropic radiopharmaceuticals (RP). A versatile delivery platform capable of carrying various therapeutic and diagnostic radionuclides, as well as vector molecules needed to achieve sufficient specificity to tumor cells and ensure therapeutic efficacy may hold great promise for radiation therapy. The aim of this work was to assess the performance of a delivery system based on the original dendrimer. The dendrimer demonstrated low toxicity in mice (LD50 was 779 ± 111 mg/kg). To study the specificity of the dendrimer to tumor cells and its therapeutic efficacy, we used a nanostructure (NS) composed of the dendrimer itself, the RGD peptide and 188Re (188Re-NS). Lewis lung carcinoma LLC1 was used as a tumor model. The biodistribution analysis revealed that the compound effectively accumulated in the tumor demonstrating a tumor-to-normal ratio >1 (relative to healthy organs and tissues) and retention time of at least 6 hours. Injections of 185 MBq/kg 188Re-NS caused a statistically significant inhibition of tumor growth (p < 0.05) by day 7 following the injection (Т/С = 5%), which remained stable for 6 days. Our findings suggest that the proposed dendrimer is a promising platform for RP delivery.

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