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A computational model for predicting nanoparticle accumulation in tumor vasculature.

Frieboes HB, Wu M, Lowengrub J, Decuzzi P, Cristini V - PLoS ONE (2013)

Bottom Line: It is shown that an optimal vascular affinity can be identified providing the proper balance between accumulation dose and uniform spatial distribution of the NPs.This balance depends on the stage of tumor development (vascularity and endothelial receptor expression) and the NP properties (size, ligand density and ligand-receptor molecular affinity).Also, it is demonstrated that for insufficiently developed vascular networks, NPs are transported preferentially through the healthy, pre-existing vessels, thus bypassing the tumor mass.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, University of Louisville, Louisville, Kentucky, USA. hbfrie01@louisville.edu

ABSTRACT
Vascular targeting of malignant tissues with systemically injected nanoparticles (NPs) holds promise in molecular imaging and anti-angiogenic therapies. Here, a computational model is presented to predict the development of tumor neovasculature over time and the specific, vascular accumulation of blood-borne NPs. A multidimensional tumor-growth model is integrated with a mesoscale formulation for the NP adhesion to blood vessel walls. The fraction of injected NPs depositing within the diseased vasculature and their spatial distribution is computed as a function of tumor stage, from 0 to day 24 post-tumor inception. As the malignant mass grows in size, average blood flow and shear rates increase within the tumor neovasculature, reaching values comparable with those measured in healthy, pre-existing vessels already at 10 days. The NP vascular affinity, interpreted as the likelihood for a blood-borne NP to firmly adhere to the vessel walls, is a fundamental parameter in this analysis and depends on NP size and ligand density, and vascular receptor expression. For high vascular affinities, NPs tend to accumulate mostly at the inlet tumor vessels leaving the inner and outer vasculature depleted of NPs. For low vascular affinities, NPs distribute quite uniformly intra-tumorally but exhibit low accumulation doses. It is shown that an optimal vascular affinity can be identified providing the proper balance between accumulation dose and uniform spatial distribution of the NPs. This balance depends on the stage of tumor development (vascularity and endothelial receptor expression) and the NP properties (size, ligand density and ligand-receptor molecular affinity). Also, it is demonstrated that for insufficiently developed vascular networks, NPs are transported preferentially through the healthy, pre-existing vessels, thus bypassing the tumor mass. The computational tool described here can effectively select an optimal NP formulation presenting high accumulation doses and uniform spatial intra-tumor distributions as a function of the development stage of the malignancy.

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Related in: MedlinePlus

Highlight of a blood vessel network lined by endothelial cells (blue) transporting red blood cells (red), leukocytes (white) and nanoparticles (grey) within a tumor.Some of the nanoparticles are shown firmly adhering to the endothelial cells while experiencing intra-vascular flow.
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pone-0056876-g001: Highlight of a blood vessel network lined by endothelial cells (blue) transporting red blood cells (red), leukocytes (white) and nanoparticles (grey) within a tumor.Some of the nanoparticles are shown firmly adhering to the endothelial cells while experiencing intra-vascular flow.

Mentions: We simulate the transport and progressive accumulation of NPs within the tumor microvasculature, as schematically shown in Figure 1. The systemically injected NPs reach the malignant mass through the pre-existing vascular network and the more chaotic neovasculature originating over time within the tumor. Spherical NPs with three different sizes, namely 100, 600 and 1,000 nm, are considered. The surface density and molecular affinity of the ligand molecules decorating the NPs, as well as the receptor molecules expressed on the tumor endothelium, are systematically varied through the parameters α and β, as described in the Methods. The objective of this analysis is to characterize variations in the vascular accumulation of NPs depending on the tumor development stage and the expression of vascular endothelial receptors.


A computational model for predicting nanoparticle accumulation in tumor vasculature.

Frieboes HB, Wu M, Lowengrub J, Decuzzi P, Cristini V - PLoS ONE (2013)

Highlight of a blood vessel network lined by endothelial cells (blue) transporting red blood cells (red), leukocytes (white) and nanoparticles (grey) within a tumor.Some of the nanoparticles are shown firmly adhering to the endothelial cells while experiencing intra-vascular flow.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585411&req=5

pone-0056876-g001: Highlight of a blood vessel network lined by endothelial cells (blue) transporting red blood cells (red), leukocytes (white) and nanoparticles (grey) within a tumor.Some of the nanoparticles are shown firmly adhering to the endothelial cells while experiencing intra-vascular flow.
Mentions: We simulate the transport and progressive accumulation of NPs within the tumor microvasculature, as schematically shown in Figure 1. The systemically injected NPs reach the malignant mass through the pre-existing vascular network and the more chaotic neovasculature originating over time within the tumor. Spherical NPs with three different sizes, namely 100, 600 and 1,000 nm, are considered. The surface density and molecular affinity of the ligand molecules decorating the NPs, as well as the receptor molecules expressed on the tumor endothelium, are systematically varied through the parameters α and β, as described in the Methods. The objective of this analysis is to characterize variations in the vascular accumulation of NPs depending on the tumor development stage and the expression of vascular endothelial receptors.

Bottom Line: It is shown that an optimal vascular affinity can be identified providing the proper balance between accumulation dose and uniform spatial distribution of the NPs.This balance depends on the stage of tumor development (vascularity and endothelial receptor expression) and the NP properties (size, ligand density and ligand-receptor molecular affinity).Also, it is demonstrated that for insufficiently developed vascular networks, NPs are transported preferentially through the healthy, pre-existing vessels, thus bypassing the tumor mass.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, University of Louisville, Louisville, Kentucky, USA. hbfrie01@louisville.edu

ABSTRACT
Vascular targeting of malignant tissues with systemically injected nanoparticles (NPs) holds promise in molecular imaging and anti-angiogenic therapies. Here, a computational model is presented to predict the development of tumor neovasculature over time and the specific, vascular accumulation of blood-borne NPs. A multidimensional tumor-growth model is integrated with a mesoscale formulation for the NP adhesion to blood vessel walls. The fraction of injected NPs depositing within the diseased vasculature and their spatial distribution is computed as a function of tumor stage, from 0 to day 24 post-tumor inception. As the malignant mass grows in size, average blood flow and shear rates increase within the tumor neovasculature, reaching values comparable with those measured in healthy, pre-existing vessels already at 10 days. The NP vascular affinity, interpreted as the likelihood for a blood-borne NP to firmly adhere to the vessel walls, is a fundamental parameter in this analysis and depends on NP size and ligand density, and vascular receptor expression. For high vascular affinities, NPs tend to accumulate mostly at the inlet tumor vessels leaving the inner and outer vasculature depleted of NPs. For low vascular affinities, NPs distribute quite uniformly intra-tumorally but exhibit low accumulation doses. It is shown that an optimal vascular affinity can be identified providing the proper balance between accumulation dose and uniform spatial distribution of the NPs. This balance depends on the stage of tumor development (vascularity and endothelial receptor expression) and the NP properties (size, ligand density and ligand-receptor molecular affinity). Also, it is demonstrated that for insufficiently developed vascular networks, NPs are transported preferentially through the healthy, pre-existing vessels, thus bypassing the tumor mass. The computational tool described here can effectively select an optimal NP formulation presenting high accumulation doses and uniform spatial intra-tumor distributions as a function of the development stage of the malignancy.

Show MeSH
Related in: MedlinePlus