The design of polyvalent scaffolds for targeted delivery☆

Vance, David J.; Martin, Jacob T.; Patke, Sanket; Kane, Ravi S.

doi:10.1016/j.addr.2009.06.002

Cited by 44 publications

(38 citation statements)

References 97 publications

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“…It is well established that polyvalency, the presentation of multiple bioactive binding sites, significantly enhances binding strength for biological interactions, a phenomenon known as avidity (38). This phenomenon has a natural basis, vital to the function of binding proteins such as IgM with 10 binding sites (39) or the biological adhesion of many viruses (40), and even the extracellular matrix is polyvalent (41).…”

Section: Discussionmentioning

confidence: 99%

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair

Webber

Tongers

Newcomb

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

295

268

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There is great demand for the development of novel therapies for ischemic cardiovascular disease, a leading cause of morbidity and mortality worldwide. We report here on the development of a completely synthetic cell-free therapy based on peptide amphiphile nanostructures designed to mimic the activity of VEGF, one of the most potent angiogenic signaling proteins. Following self-assembly of peptide amphiphiles, nanoscale filaments form that display on their surfaces a VEGF-mimetic peptide at high density. The VEGF-mimetic filaments were found to induce phosphorylation of VEGF receptors and promote proangiogenic behavior in endothelial cells, indicated by an enhancement in proliferation, survival, and migration in vitro. In a chicken embryo assay, these nanostructures elicited an angiogenic response in the host vasculature. When evaluated in a mouse hind-limb ischemia model, the nanofibers increased tissue perfusion, functional recovery, limb salvage, and treadmill endurance compared to controls, which included the VEGF-mimetic peptide alone. Immunohistological evidence also demonstrated an increase in the density of microcirculation in the ischemic hind limb, suggesting the mechanism of efficacy of this promising potential therapy is linked to the enhanced microcirculatory angiogenesis that results from treatment with these polyvalent VEGF-mimetic nanofibers.

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Section: Discussionmentioning

confidence: 99%

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair

Webber

Tongers

Newcomb

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

295

268

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“…Among the factors impacting the design of NCs and therapeutic agents are: (i) binding affinity (18); (ii) multivalency or the average number of receptor-ligand bonds per bound NC (19)(20)(21)(22)(23); and (iii) in vivo targeting, measured as percentage of injected dose accumulated after intravenous injection (18).…”

mentioning

confidence: 99%

Computational model for nanocarrier binding to endothelium validated using in vivo, in vitro, and atomic force microscopy experiments

Liu

Weller²,

Zern

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

118

179

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A computational methodology based on Metropolis Monte Carlo (MC) and the weighted histogram analysis method (WHAM) has been developed to calculate the absolute binding free energy between functionalized nanocarriers (NC) and endothelial cell (EC) surfaces. The calculated NC binding free energy landscapes yield binding affinities that agree quantitatively when directly compared against analogous measurements of specific antibodycoated NCs (100 nm in diameter) to intracellular adhesion molecule-1 (ICAM-1) expressing EC surface in in vitro cell-culture experiments. The effect of antibody surface coverage (σ s ) of NC on binding simulations reveals a threshold σ s value below which the NC binding affinities reduce drastically and drop lower than that of single anti-ICAM-1 molecule to ICAM-1. The model suggests that the dominant effect of changing σ s around the threshold is through a change in multivalent interactions; however, the loss in translational and rotational entropies are also important. Consideration of shear flow and glycocalyx does not alter the computed threshold of antibody surface coverage. The computed trend describing the effect of σ s on NC binding agrees remarkably well with experimental results of in vivo targeting of the anti-ICAM-1 coated NCs to pulmonary endothelium in mice. Model results are further validated through close agreement between computed NC rupture-force distribution and measured values in atomic force microscopy (AFM) experiments. The three-way quantitative agreement with AFM, in vitro (cell-culture), and in vivo experiments establishes the mechanical, thermodynamic, and physiological consistency of our model. Hence, our computational protocol represents a quantitative and predictive approach for model-driven design and optimization of functionalized nanocarriers in targeted vascular drug delivery.absolute binding free energy | Monte Carlo | targeted drug delivery | multivalent interactions | antibody surface coverage T argeted delivery of functionalized nanocarriers (i.e., NCs coated with specific targeting ligands) to endothelium remains an important design challenge in pharmacological and biomedical sciences. The use of functionalized NCs offers a wide range of targeting options through tunable design parameters (size, shape, type, method of functionalization, etc.). This necessitates a multiparameter optimization for achieving efficacious targeting in drug delivery applications (1) including vascular-targeting in oncology (2-4).Rational design of functionalized NCs faces many challenges owing to the complexities of molecular and geometric parameters surrounding receptor-ligand interactions and NCs (5-9), lack of accurate characterization of hydrodynamic, physico-chemical barriers for NC uptake/arrest (10-14), and uncertainty in targeting environment in vivo (15)(16)(17).Among the factors impacting the design of NCs and therapeutic agents are: (i) binding affinity (18) Recently the binding affinity of functionalized NCs to ICAM-1 expressing EC surface has been studied experim...

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“…Previous studies have observed that nanoparticles between 25-50 nm in diameters were internalized most efficiently. 26 This implies that it could be beneficial to increase the size of the Gd 2 O 3 nanoparticles to make them more efficient for intracellular labeling. However, magnetic and relaxation properties might not be favored if particle size is increased.…”

Section: Dovepressmentioning

confidence: 99%

Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement

Hedlund

Ahrén²,

Gustafsson³

et al. 2011

IJN

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As the utility of magnetic resonance imaging (MRI) broadens, the importance of having specific and efficient contrast agents increases and in recent time there has been a huge development in the fields of molecular imaging and intracellular markers. Previous studies have shown that gadolinium oxide (Gd2O3) nanoparticles generate higher relaxivity than currently available Gd chelates: In addition, the Gd2O3 nanoparticles have promising properties for MRI cell tracking. The aim of the present work was to study cell labeling with Gd2O3 nanoparticles in hematopoietic cells and to improve techniques for monitoring hematopoietic stem cell migration by MRI. Particle uptake was studied in two cell lines: the hematopoietic progenitor cell line Ba/F3 and the monocytic cell line THP-1. Cells were incubated with Gd2O3 nanoparticles and it was investigated whether the transfection agent protamine sulfate increased the particle uptake. Treated cells were examined by electron microscopy and MRI, and analyzed for particle content by inductively coupled plasma sector field mass spectrometry. Results showed that particles were intracellular, however, sparsely in Ba/F3. The relaxation times were shortened with increasing particle concentration. Relaxivities, r1 and r2 at 1.5 T and 21°C, for Gd2O3 nanoparticles in different cell samples were 3.6–5.3 s-1 mM-1 and 9.6–17.2 s-1 mM-1, respectively. Protamine sulfate treatment increased the uptake in both Ba/F3 cells and THP-1 cells. However, the increased uptake did not increase the relaxation rate for THP-1 as for Ba/F3, probably due to aggregation and/or saturation effects. Viability of treated cells was not significantly decreased and thus, it was concluded that the use of Gd2O3 nanoparticles is suitable for this type of cell labeling by means of detecting and monitoring hematopoietic cells. In conclusion, Gd2O3 nanoparticles are a promising material to achieve positive intracellular MRI contrast; however, further particle development needs to be performed.

funding agencies|Swedish Research Council| 621-2007-3810 621-2009-5148 521-2009-3423 |VINNOVA| 2009-00194 |Center in Nanoscience and Technology at LiTH (CeNano)||

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The design of polyvalent scaffolds for targeted delivery☆

Cited by 44 publications

References 97 publications

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair

Computational model for nanocarrier binding to endothelium validated using in vivo, in vitro, and atomic force microscopy experiments

Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement

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