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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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The progressive development of the malignant mass is depicted at four different time points, namely 6, 12, 18 and 24 days post tumor inception.Three characteristic tumor regions can be identified as the viable (red), hypoxic (blue), and necrotic (brown) tissue. Pre-existing vessels (straight brown lines) are laid out in a regular grid, maintaining normoxic conditions in the surrounding tissue. New vessels (irregular brown lines) are sprouting from the pre-existing vasculature in response to a net balance of pro-angiogenic factors released by hypoxic cells in the interior of the tumor. Field of view is 2×2 mm.
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pone-0056876-g002: The progressive development of the malignant mass is depicted at four different time points, namely 6, 12, 18 and 24 days post tumor inception.Three characteristic tumor regions can be identified as the viable (red), hypoxic (blue), and necrotic (brown) tissue. Pre-existing vessels (straight brown lines) are laid out in a regular grid, maintaining normoxic conditions in the surrounding tissue. New vessels (irregular brown lines) are sprouting from the pre-existing vasculature in response to a net balance of pro-angiogenic factors released by hypoxic cells in the interior of the tumor. Field of view is 2×2 mm.

Mentions: Four different time points in the evolution of the malignant mass are considered in detail, namely 6, 12, 18 and 24 days post inception. Representative panels (2×2 mm) depicting the tumor evolution over time are presented in Figure 2. The pre-existing vessels are laid out in a regular grid with vessels located every 250 µm along each dimension (brown lines in Figure 2) establishing normoxic conditions within the surrounding tissue cross-section, as demonstrated previously [17], [19]. At time zero, an avascular tumor nodule of radius ∼50 µm is placed in the center of the regular grid. With time, the nodule grows and develops three identifiable regions: the viable tissue developing at the front of the expanding mass (red); the necrotic tissue located deeper inside the tumor (brown); and the hypoxic tissue intermediately located between the viable and necrotic areas (blue). Also, irregular vessels are seen to sprout from the normal vessels in response to a net balance of pro-angiogenic factors produced by the hypoxic tissue within the tumor. Figure 2 shows the progressive enlargement of the malignant mass with a continuous growth of the volume ratio associated with the necrotic and hypoxic tissues, as well as of the tumor vascular density.


A computational model for predicting nanoparticle accumulation in tumor vasculature.

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

The progressive development of the malignant mass is depicted at four different time points, namely 6, 12, 18 and 24 days post tumor inception.Three characteristic tumor regions can be identified as the viable (red), hypoxic (blue), and necrotic (brown) tissue. Pre-existing vessels (straight brown lines) are laid out in a regular grid, maintaining normoxic conditions in the surrounding tissue. New vessels (irregular brown lines) are sprouting from the pre-existing vasculature in response to a net balance of pro-angiogenic factors released by hypoxic cells in the interior of the tumor. Field of view is 2×2 mm.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0056876-g002: The progressive development of the malignant mass is depicted at four different time points, namely 6, 12, 18 and 24 days post tumor inception.Three characteristic tumor regions can be identified as the viable (red), hypoxic (blue), and necrotic (brown) tissue. Pre-existing vessels (straight brown lines) are laid out in a regular grid, maintaining normoxic conditions in the surrounding tissue. New vessels (irregular brown lines) are sprouting from the pre-existing vasculature in response to a net balance of pro-angiogenic factors released by hypoxic cells in the interior of the tumor. Field of view is 2×2 mm.
Mentions: Four different time points in the evolution of the malignant mass are considered in detail, namely 6, 12, 18 and 24 days post inception. Representative panels (2×2 mm) depicting the tumor evolution over time are presented in Figure 2. The pre-existing vessels are laid out in a regular grid with vessels located every 250 µm along each dimension (brown lines in Figure 2) establishing normoxic conditions within the surrounding tissue cross-section, as demonstrated previously [17], [19]. At time zero, an avascular tumor nodule of radius ∼50 µm is placed in the center of the regular grid. With time, the nodule grows and develops three identifiable regions: the viable tissue developing at the front of the expanding mass (red); the necrotic tissue located deeper inside the tumor (brown); and the hypoxic tissue intermediately located between the viable and necrotic areas (blue). Also, irregular vessels are seen to sprout from the normal vessels in response to a net balance of pro-angiogenic factors produced by the hypoxic tissue within the tumor. Figure 2 shows the progressive enlargement of the malignant mass with a continuous growth of the volume ratio associated with the necrotic and hypoxic tissues, as well as of the tumor vascular density.

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