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Polyvalent oligonucleotide iron oxide nanoparticle "click" conjugates.

ABSTRACT: We have utilized the copper-catalyzed azide-alkyne reaction to form a dense monolayer of oligonucleotides on a superparamagnetic nanoparticle core. These particles exhibit the canonical properties of materials densely functionalized with DNA, which can be controlled by modulating the density of oligonucleotides on the surface of the particles. Furthermore, like their Au analogues, these particles can easily cross HeLa (cervical cancer) cell membranes without transfection agents due to their dense DNA shell. Importantly, this approach should be generalizable to other azide-functionalized particles.

SUBMITTER: Cutler JI

PROVIDER: S-EPMC2874426 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Polyvalent oligonucleotide iron oxide nanoparticle "click" conjugates.

Cutler Joshua I JI Zheng Dan D Xu Xiaoyang X Giljohann David A DA Mirkin Chad A CA

Nano letters 20100401 4

We have utilized the copper-catalyzed azide-alkyne reaction to form a dense monolayer of oligonucleotides on a superparamagnetic nanoparticle core. These particles exhibit the canonical properties of materials densely functionalized with DNA, which can be controlled by modulating the density of oligonucleotides on the surface of the particles. Furthermore, like their Au analogues, these particles can easily cross HeLa (cervical cancer) cell membranes without transfection agents due to their dens ...[more]

PMID: 20307079

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Project description:Angiogenesis is an essential component of tumour growth and, consequently, an important target both therapeutically and diagnostically. The cell adhesion molecule α(v)β(3) integrin is a specific marker of angiogenic vessels and the most prevalent vascular integrin that binds the amino acid sequence arginine-glycine-aspartic acid (RGD). Previous studies using RGD-targeted nanoparticles (20-50 nm diameter) of iron oxide (NPIO) for magnetic resonance imaging (MRI) of tumour angiogenesis, have identified a number of limitations, including non-specific extravasation, long blood half-life (reducing specific contrast) and low targeting valency. The aim of this study, therefore, was to determine whether conjugation of a cyclic RGD variant [c(RGDyK)], with enhanced affinity for α(v)β(3), to microparticles of iron oxide (MPIO) would provide a more sensitive contrast agent for imaging of angiogenic tumour vessels. Cyclic RGD [c(RGDyK)] and RAD [c(RADyK)] based peptides were coupled to 2.8 μm MPIO, and binding efficacy tested both in vitro and in vivo. Significantly greater specific binding of c(RGDyK)-MPIO to S-nitroso-n-acetylpenicillamine (SNAP)-stimulated human umbilical vein endothelial cells in vitro than PBS-treated cells was demonstrated under both static (14-fold increase; P < 0.001) and flow (44-fold increase; P < 0.001) conditions. Subsequently, mice bearing subcutaneous colorectal (MC38) or melanoma (B16F10) derived tumours underwent in vivo MRI pre- and post-intravenous administration of c(RGDyK)-MPIO or c(RADyK)-MPIO. A significantly greater volume of MPIO-induced hypointensities were found in c(RGDyK)-MPIO injected compared to c(RADyK)-MPIO injected mice, in both tumour models (P < 0.05). Similarly, administration of c(RGDyK)-MPIO induced a greater reduction in mean tumour T(2)* relaxation times than the control agent in both tumour models (melanoma P < 0.001; colorectal P < 0.0001). Correspondingly, MPIO density per tumour volume assessed immunohistochemically was significantly greater for c(RGDyK)-MPIO than c(RADyK)-MPIO injected animals, in both melanoma (P < 0.05) and colorectal (P < 0.0005) tumours. In both cases, binding of c(RGDyK)-MPIO co-localised with α(v)β(3) expression. Comparison of RGD-targeted and dynamic contrast enhanced (DCE) MRI assessment of tumour perfusion indicated sensitivity to different vascular features. This study demonstrates specific binding of c(RGDyK)-MPIO to α(v)β(3) expressing neo-vessels, with marked and quantifiable contrast and rapid clearance of unbound particles from the blood circulation compared to NPIO. Combination of this molecular MRI approach with conventional DCE MRI will enable integrated molecular, anatomical and perfusion tumour imaging.

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Polyvalent oligonucleotide iron oxide nanoparticle "click" conjugates.

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Polyvalent oligonucleotide iron oxide nanoparticle "click" conjugates.

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