title: 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.
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7571, USA. satterle@email.unc.edu.|UNC and NCSU Joint Department of Biomedical Engineering, Chapel Hill, NC, 27599, USA. satterle@email.unc.edu.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Satterlee
authors.affiliation: UNC and NCSU Joint Department of Biomedical Engineering, Chapel Hill, NC, 27599, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Attayek
authors.affiliation: Translational Pathology Laboratory, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7571, USA.
authors.forename: Bentley
authors.initials: B
authors.lastname: Midkiff
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7571, USA. leafh@unc.edu.|UNC and NCSU Joint Department of Biomedical Engineering, Chapel Hill, NC, 27599, USA. leafh@unc.edu.
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D001918:Brachytherapy / Q000379:methods*; D045744:Cell Line, Tumor; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D008187:Lutetium / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D008962:Models, Theoretical; D053758:Nanoparticles; D009374:Neoplasms, Experimental / Q000532:radiotherapy*; D011868:Radioisotopes / Q000493:pharmacokinetics*; D011874:Radiometry / Q000379:methods*; D011880:Radiotherapy Planning, Computer-Assisted
chemical_list: D011868:Radioisotopes; D008187:Lutetium
keywords: Dosimetry; Heterogeneous; Internal Radiation Therapy; Nanoparticle; Tumor