Nanotech 2011

Engineering Viral Nanoparticles as Smart Devices for Nanomedicine (invited presentation)

N.F. Steinmetz
Case Western Reserve University, US

Keywords: viral nanoparticles, targeting, in vivo imaging

Abstract:

The use of nanomaterials has the potential to revolutionize materials science and medicine. Currently, a number of different nanoparticles are being investigated for applications in imaging and therapy. Viral nanoparticles (VNPs) derived from plants can be regarded as self-assembled bionanomaterials with defined sizes and shapes. For example, the icosahedral particles formed by Cowpea mosaic virus (CPMV) are 30 nm in diameter, while rod-shaped Tobacco mosaic virus particles have dimensions of 300 by 18 nm (see Figure 1). From a materials scientist’s point of view VNPs are attractive building blocks for several reasons: the particles are monodisperse, can be produced with ease on large scale in planta, are exceptionally stable, and biocompatible. Also, VNPs are “programmable” units, which can be specifically engineered using genetic modification or chemical bioconjugation methods.[1, 2] Based on the materials properties and engineering methodologies developed, VNPs offer highly tunable platforms for use in medicine. The structure of VNPs is known to atomic resolution, and modifications can be carried out with spatial precision at the atomic level, a level of control that, with current state-of-the-art technologies cannot be achieved using synthetic nanomaterials. A major goal in medicine is to develop smart devices for targeted and image-guided therapy. Chemotherapy for cancer is generally not targeted, thus many undesired side effects occur. Targeting drugs specifically to sites of disease while avoiding healthy tissues is expected to reduce toxic side effects, and increase the efficacy of chemotherapeutics. In order to develop VNPs for such applications one has to overcome the following obstacles: immune surveillance, non-specific cell interactions, retention, and accessibility. The first step toward achieving tissue-specificity is to overcome non-specific cell binding. We and others have shown that this can be facilitated through PEGylation of VNPs.[3-6] Next, to introduce tissue-specificity, targeting ligands directed toward tumor-specific receptors can be exploited. To devise complex VNP formulations displaying PEG and targeting ligands Cu(I)-catalyzed azide-alkyne cycloaddition reactions (‘click’ chemistry) or oxime ligation chemistry are used. Exploring these design principles, we showed that VNPs can be homed to cancer cells and solid tumors using the following receptor-ligand systems: i) F56 peptides were exploited to target VNPs to the vascular endothelial growth factor receptor-1 (VEGFR-1), ii) RGD peptides were used to deliver VNPs to integrins αvβ3 and αvβ5, and iii) bombesin peptides were used to accomplish targeting of gastrin-releasing peptide receptors; these receptors are specifically overexpressed in diseased tumor tissue.[7-15] We validated our designs and confirmed targeting specificity in vitro using flow cytometry and confocal microscopy. Tumor homing was evaluated using in vivo imaging of a mouse model with human tumor xenografts and the chick chorioallantoic membrane model.[16] (and manuscripts in review) I will highlight examples that demonstrate the feasibility of targeting VNPs to sites of disease using preclinical animal models (see Figure 2).
 

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