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

Abstract

ᅟ: 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.

Keywords: Dosimetry; Heterogeneous; Internal Radiation Therapy; Nanoparticle; Tumor.

Fig. 1

Intratumoral DiI-¹⁷⁷Lu-LCP Distribution: a) two-channel image of DAPI nuclear stain (blue) and DiI (red) in section 171; b) Isolated and background-subtracted DiI signal; c) 3D stack of 342 adjacent tumor sections

Fig. 2

Dose Kernel Distribution; data recorded every 0.01 mm: a) Volume of each annulus with inner diameter on x-axis; b) Number of nuclei per annulus as calculated in Methods section; c) Total absorbed dose per annulus in J/Bq-h; d) Absorbed dose per nucleus in J/Bq-h

Fig. 3

Dose Map: a) Map of total dose in Gy from ¹⁷⁷Lu in all sections onto cells in section 171; b) Image of cell nuclei stained with DAPI; c) Overlay of dose map onto the cell nucleus image. The black areas in b and c are areas of low cell density that therefore have no DAPI stain

Fig. 4

Correlating Dose Map with Cytotoxicity: a) ¹⁷⁷Lu Dose Map; b) Distribution of p-H2AX positive cells; Blue = DAPI; Red = p-H2AX immunostain; c) Histogram showing the number of cells that received a given dose of radiation according to the dose map; d) Number of p-H2AX positive cells that received a given dose; e) Percent of p-H2AX positive cells that received a given dose, taken from bins with > 1000 total cells as seen in c. As cells received a higher dose of radiation, a higher percent of those cells stained positive for DNA double-stranded break repair, beginning around 1 Gy over 24 h

Fig. 5

Dose Map for ¹⁷⁷Lu, ³³P, and ⁹⁰Y given identical source distribution: a-c) Dose maps and individual scale bars (in Gy) for ¹⁷⁷Lu, ³³P, and ⁹⁰Y, respectively; d-f) Cell distribution overlay for dose maps in a-c; g-i) Dose maps for ¹⁷⁷Lu, ³³P, and ⁹⁰Y using the same scale bar min and max

Fig. 6

Dose Contributions for ¹⁷⁷Lu, ³³P, and ⁹⁰Y at Different Distances from a Given Cell: a-c) Contributions to a cell’s total absorbed dose from ¹⁷⁷Lu, ³³P, and ⁹⁰Y, respectively; d-f) Contributions with normalized x- and y-axes