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01.12.2017 | Research | Ausgabe 1/2017 Open Access

Radiation Oncology 1/2017

A dosimetric model for the heterogeneous delivery of radioactive nanoparticles In vivo: a feasibility study

Zeitschrift:
Radiation Oncology > Ausgabe 1/2017
Autoren:
Andrew B. Satterlee, Peter Attayek, Bentley Midkiff, Leaf Huang
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13014-017-0794-z) contains supplementary material, which is available to authorized users.

Abstract

Accurate and quantitative dosimetry for internal radiation therapy can be especially challenging, given the heterogeneity of patient anatomy, tumor anatomy, and source deposition. Internal radiotherapy sources such as nanoparticles and monoclonal antibodies require high resolution imaging to accurately model the heterogeneous distribution of these sources in the tumor. The resolution of nuclear imaging modalities is not high enough to measure the heterogeneity of intratumoral nanoparticle deposition or intratumoral regions, and mathematical models do not represent the actual heterogeneous dose or dose response. To help answer questions at the interface of tumor dosimetry and tumor biology, we have modeled the actual 3-dimensional dose distribution of heterogeneously delivered radioactive nanoparticles in a tumor after systemic injection.

Methods

24 h after systemic injection of dually fluorescent and radioactive nanoparticles into a tumor-bearing mouse, the tumor was cut into 342 adjacent sections and imaged to quantify the source distribution in each section. The images were stacked to generate a 3D model of source distribution, and a novel MATLAB code was employed to calculate the dose to cells on a middle section in the tumor using a low step size dose kernel.

Results

The average dose calculated by this novel 3D model compared closely with standard ways of calculating average dose, and showed a positive correlation with experimentally determined cytotoxicity in vivo. The high resolution images allowed us to determine that the dose required to initiate radiation-induced H2AX phosphorylation was approximately one Gray. The nanoparticle distribution was further used to model the dose distribution of two other radionuclides.

Conclusions

The ability of this model to quantify the absorbed dose and dose response in different intratumoral regions allows one to investigate how source deposition in different tumor areas can affect dose and cytotoxicity, as well as how characteristics of the tumor microenvironment, such as hypoxia or high stromal areas, may affect the potency of a given dose.
Zusatzmaterial
Additional file 1: MIRD calculations and Pharmacokinetic calculations. Contains Table S1 and Figure S1 (177Lu-LCP Pharmacokinetics), Figure S2 (Overall dose rate for 177Lu-LCP), and Figure S3 (Fraction of Volume Populated by Cell Nuclei). (DOCX 2072 kb)
13014_2017_794_MOESM1_ESM.docx
Additional file 2: Standalone File for Table S1: 177Lu-LCP Pharmacokinetics. The fraction of 177Lu-LCP that has left circulation at each time point is tabulated.(PNG 12 kb)
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Additional file 3: Standalone File for Figure S1: 177Lu-LCP Pharmacokinetics. Graphical representation of 177Lu PK shown in Table S1. The fast distribution phase is modeled by a linear equation (Eq 5) and the slower elimination phase is modeled by a logarithmic equation (Eq 6). (PNG 99 kb)
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Additional file 4: Table S2 (Dose Kernels for 177Lu, 90Y, and 33P) and S3 (Interpolated Dose Kernels for 177Lu, 90Y, and 33P). (XLSX 78 kb)
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Additional file 5: Table S4: Depiction of Dose Kernel Interpolation. (PNG 58 kb)
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Additional file 6: Standalone File for Figure S3: Fraction of Volume Populated by Cell Nuclei. A) 10x magnification image of DAPI-stained nuclei in an area in section 171; B) Binary representation of nuclear distribution used to quantify nuclear density. Cell nuclei populated ~40% of the total image area. Nuclear radius measured to be an average of ~5 μm. (PNG 401 kb)
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Literatur
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