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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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In vivo enhanced drug delivery study.(A) Schematic illustrationshowing the synthesis of NOTA-MSN(SUN)-PEG-VEGF121 forin vivo enhanced drug delivery. Ex vivo optical images of sunitinibin major organs at 3 h p.i. of (B) NOTA-MSN(SUN)-PEG-VEGF121 (targeted group), (C) NOTA-MSN(SUN)-PEG (non-targeted group) inU87MG bearing mice, and (D) pure MSN without the drug SUN (negativecontrol). All images were acquired using an IVIS spectrum in vivoimaging system (ex = 430 nm; em = 640 nm).
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fig6: In vivo enhanced drug delivery study.(A) Schematic illustrationshowing the synthesis of NOTA-MSN(SUN)-PEG-VEGF121 forin vivo enhanced drug delivery. Ex vivo optical images of sunitinibin major organs at 3 h p.i. of (B) NOTA-MSN(SUN)-PEG-VEGF121 (targeted group), (C) NOTA-MSN(SUN)-PEG (non-targeted group) inU87MG bearing mice, and (D) pure MSN without the drug SUN (negativecontrol). All images were acquired using an IVIS spectrum in vivoimaging system (ex = 430 nm; em = 640 nm).

Mentions: To achieve targeted SUN deliveryin vivo, MSN(SUN) was stepwiseconjugated to NOTA, PEG and VEGF121, as described earlier,to produce NOTA-MSN(SUN)-PEG-VEGF121 nanoconjugates (Figure 6A). A separate batch of NOTA-MSN(SUN)-PEG was alsosynthesized to serve as a non-targeted control. Equal concentrationsolutions of NOTA-MSN(SUN)-PEG-VEGF121 and NOTA-MSN(SUN)-PEG(∼500 μg/mL) were used for in vivo image-guided drugdelivery studies. The final dose of SUN was about 5 mg of SUN perkg of mouse. The U87MG bearing mice were sacrificed at 3 h p.i. Fluorescencefrom the drug was harnessed to image the tumor along with the majororgans, using an IVIS Spectrum imaging system (ex = 430 nm; em = 640nm). An equal concentration of MSNs without SUN was also injectedin a separate group of mice to serve as the negative control. Enhanceddelivery of SUN to U87MG tumors was achieved in targeted group whencompared with the non-targeted group (Figure 6C). Moreover, the negative control group showed only background levelsof fluorescence in all organs, lower than even the non-targeted group,indicating that autofluorescence from the organs was not responsiblefor the observed effects. The accumulation in RES organs, such asliver and spleen, appeared low, contrary to the PET imaging results.This anomaly can be explained on the basis of different absorptionand scattering of SUN emission (around 580 nm) signal by differenttissues. Therefore, dark colored organs, such as liver and spleen,may have strongly absorbed the emission wavelength from SUN, resultingin a weaker optical signal, compared to the light colored tumor tissues.As such, optical imaging cannot reliably measure the accurate absoluteuptake of MSN(SUN) in different organs. However, it can serve as ahandy tool to compare the drug uptake in U87MG tumors from the targetedand non-targeted groups. About a 2-fold difference was observed betweenthe two groups, clearly demonstrating the superiority of using VEGF121 targeted MSNs for enhanced delivery of anti-VEGFR drugsover passively targeted nanosystems.


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)

In vivo enhanced drug delivery study.(A) Schematic illustrationshowing the synthesis of NOTA-MSN(SUN)-PEG-VEGF121 forin vivo enhanced drug delivery. Ex vivo optical images of sunitinibin major organs at 3 h p.i. of (B) NOTA-MSN(SUN)-PEG-VEGF121 (targeted group), (C) NOTA-MSN(SUN)-PEG (non-targeted group) inU87MG bearing mice, and (D) pure MSN without the drug SUN (negativecontrol). All images were acquired using an IVIS spectrum in vivoimaging system (ex = 430 nm; em = 640 nm).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4262629&req=5

fig6: In vivo enhanced drug delivery study.(A) Schematic illustrationshowing the synthesis of NOTA-MSN(SUN)-PEG-VEGF121 forin vivo enhanced drug delivery. Ex vivo optical images of sunitinibin major organs at 3 h p.i. of (B) NOTA-MSN(SUN)-PEG-VEGF121 (targeted group), (C) NOTA-MSN(SUN)-PEG (non-targeted group) inU87MG bearing mice, and (D) pure MSN without the drug SUN (negativecontrol). All images were acquired using an IVIS spectrum in vivoimaging system (ex = 430 nm; em = 640 nm).
Mentions: To achieve targeted SUN deliveryin vivo, MSN(SUN) was stepwiseconjugated to NOTA, PEG and VEGF121, as described earlier,to produce NOTA-MSN(SUN)-PEG-VEGF121 nanoconjugates (Figure 6A). A separate batch of NOTA-MSN(SUN)-PEG was alsosynthesized to serve as a non-targeted control. Equal concentrationsolutions of NOTA-MSN(SUN)-PEG-VEGF121 and NOTA-MSN(SUN)-PEG(∼500 μg/mL) were used for in vivo image-guided drugdelivery studies. The final dose of SUN was about 5 mg of SUN perkg of mouse. The U87MG bearing mice were sacrificed at 3 h p.i. Fluorescencefrom the drug was harnessed to image the tumor along with the majororgans, using an IVIS Spectrum imaging system (ex = 430 nm; em = 640nm). An equal concentration of MSNs without SUN was also injectedin a separate group of mice to serve as the negative control. Enhanceddelivery of SUN to U87MG tumors was achieved in targeted group whencompared with the non-targeted group (Figure 6C). Moreover, the negative control group showed only background levelsof fluorescence in all organs, lower than even the non-targeted group,indicating that autofluorescence from the organs was not responsiblefor the observed effects. The accumulation in RES organs, such asliver and spleen, appeared low, contrary to the PET imaging results.This anomaly can be explained on the basis of different absorptionand scattering of SUN emission (around 580 nm) signal by differenttissues. Therefore, dark colored organs, such as liver and spleen,may have strongly absorbed the emission wavelength from SUN, resultingin a weaker optical signal, compared to the light colored tumor tissues.As such, optical imaging cannot reliably measure the accurate absoluteuptake of MSN(SUN) in different organs. However, it can serve as ahandy tool to compare the drug uptake in U87MG tumors from the targetedand non-targeted groups. About a 2-fold difference was observed betweenthe two groups, clearly demonstrating the superiority of using VEGF121 targeted MSNs for enhanced delivery of anti-VEGFR drugsover passively targeted nanosystems.

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