Dataset Information

Targeted therapy for glioma using cyclic RGD-entrapped polyionic complex nanomicelles.

ABSTRACT:

Background

The purpose of this study was to test the efficacy of cyclic Arg-Gly-Asp (RGD) peptide conjugated with polyionic complex nanomicelles as targeted therapy for glioma.

Methods

A stable cyclic RGD polyionic complex nanostructure, ie, a c(RGDfC) polyionic complex micelle, was synthesized and its biocompatibility with cultured neurons was assessed using a cell viability assay. Targeted binding to cultured glioma cells was evaluated by the CdTe quantum dot marking technique and a cell viability assay. The inhibitory effect of the nanomicelles against glioma cells was also evaluated, and their targeted migration into rat brain glioma cells and apoptotic effects were traced by the CdTe quantum dot marking and immunohistochemical staining.

Results

c(RGDfC) polyionic complex micelles did not affect the growth of neurons but bonded selectively to and inhibited proliferation of glioma cells in vitro. When tested in vivo, the micelles migrated into glioma cells, inducing apoptosis in the rat brain.

Conclusion

The c(RGDfC) polyionic complex micelle is an effective targeted therapy against glioma.

SUBMITTER: Liu X

PROVIDER: S-EPMC3383325 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Targeted therapy for glioma using cyclic RGD-entrapped polyionic complex nanomicelles.

Liu Xiaoying X Cui Wenguo W Li Bo B Hong Zhen Z

International journal of nanomedicine 20120611

<h4>Background</h4>The purpose of this study was to test the efficacy of cyclic Arg-Gly-Asp (RGD) peptide conjugated with polyionic complex nanomicelles as targeted therapy for glioma.<h4>Methods</h4>A stable cyclic RGD polyionic complex nanostructure, ie, a c(RGDfC) polyionic complex micelle, was synthesized and its biocompatibility with cultured neurons was assessed using a cell viability assay. Targeted binding to cultured glioma cells was evaluated by the CdTe quantum dot marking technique a ...[more]

PMID: 22745548

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Project description:PurposeWe previously showed that intravitreal injection of the sFLT morpholino-oligomer (FLT-MO) suppresses laser-induced choroidal neovascularization (CNV) in mice by decreasing the membrane bound form of Flt-1 while increasing the soluble form of Flt-1 via alternative splicing shift. In this study, we examined whether cyclic RGD peptide (cRGD) can promote morpholino-oligomer accumulation in CNV following tail vein injection, and whether systemic cRGD conjugated FLT-MO (cRGD-FLT-MO) suppresses CNV growth.MethodscRGD conjugated fluorescent morpholino-oligomer (cRGD-F-MO) was injected via tail vein into mice with previous retinal laser photocoagulation and examined for cRGD-F-MO accumulation in CNV. To examine whether cRGD-FLT-MO suppresses CNV growth, mice were tail-vein injected with cRGD-FLT-MO, cRGD conjugated standard morpholino-oligomer (cRGD-STD-MO), or Dulbecco's Phosphate-Buffered Saline (DPBS) 1 and 4 days postlaser photocoagulation. Seven days postlaser photocoagulation, eyes were harvested and laser CNV was stained with isolectin GS-IB4, allowing quantification of CNV size by confocal microscopy.ResultscRGD-F-MO accumulation in CNV commenced immediately after tail vein injection and could be observed even 1 day after injection. cRGD-FLT-MO tail vein injection significantly suppressed CNV size (2.7 × 105 ± 0.3 × 105 ?m3, P < 0.05 by Student's t-test) compared with controls (DPBS: 5.1 × 105 ± 0.6 × 105 ?m3 and cRGD-STD-MO: 5.5 × 105 ± 0.8 × 105 ?m3).ConclusionscRGD peptide facilitates morpholino-oligomer accumulation in CNV following systemic delivery. cRGD-FLT-MO suppressed CNV growth after tail-vein injection, demonstrating the potential utility of cRGD peptide for morpholino-oligomer delivery to CNV.Translational relevanceCurrent therapy for neovascular age-related macular degeneration involves intravitreal injection of anti-vascular endothelial growth factor drugs. Our results indicate that CNV can be treated systemically, thus eliminating risks and hazards associated with intravitreal injection.

Project description:BackgroundThe interactions between nanoparticles (NPs) and plasma proteins form a protein corona around NPs after entering the biological environment, which provides new biological properties to NPs and mediates their interactions with cells and biological barriers. Given the inevitable interactions, we regard nanoparticle‒protein interactions as a tool for designing protein corona-mediated drug delivery systems. Herein, we demonstrate the successful application of protein corona-mediated brain-targeted nanomicelles in the treatment of glioma, loading them with paclitaxel (PTX), and decorating them with amyloid β-protein (Aβ)-CN peptide (PTX/Aβ-CN-PMs). Aβ-CN peptide, like the Aβ1-42 peptide, specifically binds to the lipid-binding domain of apolipoprotein E (ApoE) in vivo to form the ApoE-enriched protein corona surrounding Aβ-CN-PMs (ApoE/PTX/Aβ-CN-PMs). The receptor-binding domain of the ApoE then combines with low-density lipoprotein receptor (LDLr) and LDLr-related protein 1 receptor (LRP1r) expressed in the blood-brain barrier and glioma, effectively mediating brain-targeted delivery.MethodsPTX/Aβ-CN-PMs were prepared using a film hydration method with sonication, which was simple and feasible. The specific formation of the ApoE-enriched protein corona around nanoparticles was characterized by Western blotting analysis and LC-MS/MS. The in vitro physicochemical properties and in vivo anti-glioma effects of PTX/Aβ-CN-PMs were also well studied.ResultsThe average size and zeta potential of PTX/Aβ-CN-PMs and ApoE/PTX/Aβ-CN-PMs were 103.1 nm, 172.3 nm, 7.23 mV, and 0.715 mV, respectively. PTX was efficiently loaded into PTX/Aβ-CN-PMs, and the PTX release from rhApoE/PTX/Aβ-CN-PMs exhibited a sustained-release pattern in vitro. The formation of the ApoE-enriched protein corona significantly improved the cellular uptake of Aβ-CN-PMs on C6 cells and human umbilical vein endothelial cells (HUVECs) and enhanced permeability to the blood-brain tumor barrier in vitro. Meanwhile, PTX/Aβ-CN-PMs with ApoE-enriched protein corona had a greater ability to inhibit cell proliferation and induce cell apoptosis than taxol. Importantly, PTX/Aβ-CN-PMs exhibited better anti-glioma effects and tissue distribution profile with rapid accumulation in glioma tissues in vivo and prolonged median survival of glioma-bearing mice compared to those associated with PMs without the ApoE protein corona.ConclusionsThe designed PTX/Aβ-CN-PMs exhibited significantly enhanced anti-glioma efficacy. Importantly, this study provided a strategy for the rational design of a protein corona-based brain-targeted drug delivery system. More crucially, we utilized the unfavorable side of the protein corona and converted it into an advantage to achieve brain-targeted drug delivery.

Dataset Information

Targeted therapy for glioma using cyclic RGD-entrapped polyionic complex nanomicelles.

Background

Methods

Results

Conclusion

Publications

Targeted therapy for glioma using cyclic RGD-entrapped polyionic complex nanomicelles.

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