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VEGF₁₂₁-conjugated mesoporous silica nanoparticle: a tumor targeted drug delivery system.

Goel S, Chen F, Hong H, Valdovinos HF, Hernandez R, Shi S, Barnhart TE, Cai W - ACS Appl Mater Interfaces (2014)

Bottom Line: Although a number of anti-VEGFR therapies have been conceived, inefficient drug administration still limits their therapeutic efficacy and raises concerns of potential side effects.Our results demonstrated that a significantly higher amount of sunitinib could be delivered to the U87MG tumor by targeting VEGFR when compared with the non-targeted counterparts.The as-developed VEGF121-conjugated MSN could become another attractive nanoplatform for the design of future theranostic nanomedicine.

View Article: PubMed Central - PubMed

Affiliation: Materials Science Program, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.

ABSTRACT
The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling cascade plays a critical role in tumor angiogenesis and metastasis and has been correlated with several poorly prognostic cancers such as malignant gliomas. Although a number of anti-VEGFR therapies have been conceived, inefficient drug administration still limits their therapeutic efficacy and raises concerns of potential side effects. In the present work, we propose the use of uniform mesoporous silica nanoparticles (MSNs) for VEGFR targeted positron emission tomography imaging and delivery of the anti-VEGFR drug (i.e., sunitinib) in human glioblastoma (U87MG) bearing murine models. MSNs were synthesized, characterized and modified with polyethylene glycol, anti-VEGFR ligand VEGF121 and radioisotope (64)Cu, followed by extensive in vitro, in vivo and ex vivo studies. Our results demonstrated that a significantly higher amount of sunitinib could be delivered to the U87MG tumor by targeting VEGFR when compared with the non-targeted counterparts. The as-developed VEGF121-conjugated MSN could become another attractive nanoplatform for the design of future theranostic nanomedicine.

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Synthesis and characterization of 64Cu-NOTA-MSN(SUN)-VEGF121. (A) Schematic illustration of 64Cu-NOTA-MSN(SUN)-VEGF121 nanoconjugate. (B) Transmissionelectron microscopy (TEM) image of pure MSN before surface modification.(C) TEM image of NOTA-MSN(SUN)-VEGF121. (D) UV–visspectrum of pure MSN (black line) and sunitinib loaded MSN, or MSN(SUN)(red line). (E) In vitro drug release profile of MSN(SUN) in PBS withdifferent pH values. (F) Elution profile of 64Cu-NOTA-MSN-VEGF121 after the 64Cu labeling. Inset shows the digitalphoto and PET imaging of 64Cu-NOTA-MSN-VEGF121 (3.5–4.0 mL fraction).
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fig1: Synthesis and characterization of 64Cu-NOTA-MSN(SUN)-VEGF121. (A) Schematic illustration of 64Cu-NOTA-MSN(SUN)-VEGF121 nanoconjugate. (B) Transmissionelectron microscopy (TEM) image of pure MSN before surface modification.(C) TEM image of NOTA-MSN(SUN)-VEGF121. (D) UV–visspectrum of pure MSN (black line) and sunitinib loaded MSN, or MSN(SUN)(red line). (E) In vitro drug release profile of MSN(SUN) in PBS withdifferent pH values. (F) Elution profile of 64Cu-NOTA-MSN-VEGF121 after the 64Cu labeling. Inset shows the digitalphoto and PET imaging of 64Cu-NOTA-MSN-VEGF121 (3.5–4.0 mL fraction).

Mentions: Inspired by the pivotalrole of the VEGF/VEGFR signaling pathwayin cancer and the advantages offered by MSNs, in this paper, we proposea VEGF pathway targeting potentially theranostic nanoplatform (Figure 1A) based on surface engineering of MSN for simultaneousnoninvasive PET imaging and in vivo enhanced delivery of anti-VEGFRdrug, sunitinib (SUN). Human glioblastoma (U87MG) bearing mice withsuitable tumor sizes (∼60 mm3, having high VEGFRexpression) were selected for in vivo active targeting study. Uniformsized MSN was first surface modified with amino groups, followed bychelator (e.g., S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triaceticacid, or NOTA) conjugation, PEGylation, VEGF121 linkageand radioisotope (64Cu, t1/2 = 12.7 h) labeling. The mesoporous scaffolds were loaded with asmall molecule hydrophobic drug to assess their drug loading and deliveryefficacy. Sunitinib was chosen because it is a potent receptor tyrosinekinase inhibitor (including all VEGFRs) and has been clinically successfulin providing improved progression free survival and tumor responsesin a range of cancers.27−31 To the best of our knowledge, this is the first study documentingthe use of MSNs for VEGFR targeted PET imaging and in vivo enhanceddrug delivery.


VEGF₁₂₁-conjugated mesoporous silica nanoparticle: a tumor targeted drug delivery system.

Goel S, Chen F, Hong H, Valdovinos HF, Hernandez R, Shi S, Barnhart TE, Cai W - ACS Appl Mater Interfaces (2014)

Synthesis and characterization of 64Cu-NOTA-MSN(SUN)-VEGF121. (A) Schematic illustration of 64Cu-NOTA-MSN(SUN)-VEGF121 nanoconjugate. (B) Transmissionelectron microscopy (TEM) image of pure MSN before surface modification.(C) TEM image of NOTA-MSN(SUN)-VEGF121. (D) UV–visspectrum of pure MSN (black line) and sunitinib loaded MSN, or MSN(SUN)(red line). (E) In vitro drug release profile of MSN(SUN) in PBS withdifferent pH values. (F) Elution profile of 64Cu-NOTA-MSN-VEGF121 after the 64Cu labeling. Inset shows the digitalphoto and PET imaging of 64Cu-NOTA-MSN-VEGF121 (3.5–4.0 mL fraction).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4262629&req=5

fig1: Synthesis and characterization of 64Cu-NOTA-MSN(SUN)-VEGF121. (A) Schematic illustration of 64Cu-NOTA-MSN(SUN)-VEGF121 nanoconjugate. (B) Transmissionelectron microscopy (TEM) image of pure MSN before surface modification.(C) TEM image of NOTA-MSN(SUN)-VEGF121. (D) UV–visspectrum of pure MSN (black line) and sunitinib loaded MSN, or MSN(SUN)(red line). (E) In vitro drug release profile of MSN(SUN) in PBS withdifferent pH values. (F) Elution profile of 64Cu-NOTA-MSN-VEGF121 after the 64Cu labeling. Inset shows the digitalphoto and PET imaging of 64Cu-NOTA-MSN-VEGF121 (3.5–4.0 mL fraction).
Mentions: Inspired by the pivotalrole of the VEGF/VEGFR signaling pathwayin cancer and the advantages offered by MSNs, in this paper, we proposea VEGF pathway targeting potentially theranostic nanoplatform (Figure 1A) based on surface engineering of MSN for simultaneousnoninvasive PET imaging and in vivo enhanced delivery of anti-VEGFRdrug, sunitinib (SUN). Human glioblastoma (U87MG) bearing mice withsuitable tumor sizes (∼60 mm3, having high VEGFRexpression) were selected for in vivo active targeting study. Uniformsized MSN was first surface modified with amino groups, followed bychelator (e.g., S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triaceticacid, or NOTA) conjugation, PEGylation, VEGF121 linkageand radioisotope (64Cu, t1/2 = 12.7 h) labeling. The mesoporous scaffolds were loaded with asmall molecule hydrophobic drug to assess their drug loading and deliveryefficacy. Sunitinib was chosen because it is a potent receptor tyrosinekinase inhibitor (including all VEGFRs) and has been clinically successfulin providing improved progression free survival and tumor responsesin a range of cancers.27−31 To the best of our knowledge, this is the first study documentingthe use of MSNs for VEGFR targeted PET imaging and in vivo enhanceddrug delivery.

Bottom Line: Although a number of anti-VEGFR therapies have been conceived, inefficient drug administration still limits their therapeutic efficacy and raises concerns of potential side effects.Our results demonstrated that a significantly higher amount of sunitinib could be delivered to the U87MG tumor by targeting VEGFR when compared with the non-targeted counterparts.The as-developed VEGF121-conjugated MSN could become another attractive nanoplatform for the design of future theranostic nanomedicine.

View Article: PubMed Central - PubMed

Affiliation: Materials Science Program, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.

ABSTRACT
The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling cascade plays a critical role in tumor angiogenesis and metastasis and has been correlated with several poorly prognostic cancers such as malignant gliomas. Although a number of anti-VEGFR therapies have been conceived, inefficient drug administration still limits their therapeutic efficacy and raises concerns of potential side effects. In the present work, we propose the use of uniform mesoporous silica nanoparticles (MSNs) for VEGFR targeted positron emission tomography imaging and delivery of the anti-VEGFR drug (i.e., sunitinib) in human glioblastoma (U87MG) bearing murine models. MSNs were synthesized, characterized and modified with polyethylene glycol, anti-VEGFR ligand VEGF121 and radioisotope (64)Cu, followed by extensive in vitro, in vivo and ex vivo studies. Our results demonstrated that a significantly higher amount of sunitinib could be delivered to the U87MG tumor by targeting VEGFR when compared with the non-targeted counterparts. The as-developed VEGF121-conjugated MSN could become another attractive nanoplatform for the design of future theranostic nanomedicine.

Show MeSH
Related in: MedlinePlus