A nephron-based model of the kidneys for macro-to-micro α-particle dosimetry

Abstract

Targeted α-particle therapy is a promising treatment modality for cancer. Due to the short path-length of α-particles, the potential efficacy and toxicity of these agents is best evaluated by microscale dosimetry calculations instead of whole-organ, absorbed fraction-based dosimetry. Yet time-integrated activity (TIA), the necessary input for dosimetry, can still only be quantified reliably at the organ or macroscopic level. We describe a nephron-and cellular-based kidney dosimetry model for α-particle radiopharmaceutical therapy, more suited to the short range and high linear energy transfer of α-particle emitters, which takes as input kidney or cortex TIA and through a macro to micro model-based methodology assigns TIA to micro-level kidney substructures. We apply a geometrical model to provide nephron-level S-values for a range of isotopes allowing for pre-clinical and clinical applications according to the medical internal radiation dosimetry (MIRD) schema. We assume that the relationship between whole-organ TIA and TIA apportioned to microscale substructures as measured in an appropriate pre-clinical mammalian model also applies to the human. In both, the pre-clinical and the human model, microscale substructures are described as a collection of simple geometrical shapes akin to those used in the Cristy-Eckerman phantoms for normal organs. Anatomical parameters are taken from the literature for a human model, while murine parameters are measured ex vivo. The murine histological slides also provide the data for volume of occupancy of the different compartments of the nephron in the kidney: glomerulus versus proximal tubule versus distal tubule. Monte Carlo simulations are run with activity placed in the different nephron compartments for several α-particle emitters currently under investigation in radiopharmaceutical therapy. The S-values were calculated for the α-emitters and their descendants between the different nephron compartments for both the human and murine models. The renal cortex and medulla S-values were 3 Author to whom any correspondence should be addressed.

(2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy

“…Microscale S values for 211 At decays in these regions were multiplied by the total number of decays to yield the absorbed doses to proximal tubules and glomeruli. The S values were calculated according to a previously created Monte Carlo-based kidney nephron model (25).…”

Testis dosimetry in individual patients by combining a small-scale dosimetry model and pharmacokinetic modeling-application of111In-Ibritumomab Tiuxetan (Zevalin®)

“…Owing to the small extension of the testes compared to other body regions it was considered important to make explicit attenuation correction, and was achieved using a pixel-based quantification scheme where an X-ray scout image is used as attenuation correction map. The internal dosimetry community continuously discusses the necessity for improvements to bring about more detailed tissue and cellular dosimetry (Hobbs et al 2012;Howell et al 2006;ICRU 2002;Sgouros and Hobbs 2014;Sgouros et al 2009). One direction has been the development of detailed small-scale dosimetry models but the practical use is so far unfortunately limited due to the difficulties in determining detailed activity localization for the tissue in question.…”

Targeted and Nontargeted α-Particle Therapies

“…These methods were initially developed to estimate the radiation risk of radiolabeled diagnostic imaging agents; accordingly, they provide estimates of the mean absorbed dose for normal organ volumes defined by reference anatomies, and not for individual patients. Dosimetry methods for therapy and, in particular, therapy with α-particle emitters require consideration of tissue subregions that are defined, in part, by the distribution of the agent at the millimeter scale for β-particle emitters and at the submillimeter scale for α-particle emitters (34, 35). To relate the absorbed dose from α-particle-emitting radionuclides, the RBE of α-particles must be used to account for their greater biological efficacy per unit absorbed dose.…”