Alpha Particles In Tissue Research Articles

Abstract 6034: PSMA targeted alpha radiopharmaceutical [211At]PSAt-3 inhibits tumor growth in a preclinical model of prostate cancer

Abstract Introduction: Prostate cancer continues to be a highly prevalent cancer diagnosis among men and a leading cause of cancer related deaths worldwide. With the introduction[177Lu]Lu-PSMA-617, targeted radionuclide therapy has proven successful in increasing survival time for patients with metastasized castration resistant prostate cancer. However, despite encouraging results, such patients tend to develop progressive disease, and thus, enhanced efficacy is warranted. To this end, the use of radiopharmaceuticals harnessing alpha-emitters is a promising venue due to the potent energy deposition and short range of alpha particles in tissue. Here, we employ the PSMA targeting vector, [211At]PSAt-3, for targeted alpha radionuclide therapy in a preclinical prostate cancer model. Methods: [211At]PSAt-3, a structural derivative of PSMA-617, in which the L-2-naphtylalanine was replaced by L-3-[211At]astato-phenylalanine, was obtained by electrophilic [211At]astatodesilylation. Evaluation of [211At]PSAt-3 was conducted in male inbred nude mice of Balb/c background xenografted subcutaneously with human prostate cancer cells (LNCaP). Prior biodistribution studies were carried out with approximately 100 kBq intravenous injections, and subsequent biodistribution 2, 6 and 24h post injection (P.I.). For establishment of therapeutic effect, a single intravenous dose of [211At]PSAt-3 was administered. To asses hematological toxicity, blood cell composition was assessed weekly. Results: Favorable tumor uptake of 15.2±6 %ID/g was observed 2h after injection of [211At]PSAt-3 in LNCaP xenografted nude mice, with subsequent 9±5.1% ID/g and 6.4±2.4% ID/g 6 and 24h P.I., respectively. [211At]PSAt-3 cleared mainly by the kidneys, in which uptake was 72, 38 and 6% ID/g at 2, 6 and 24h P.I., respectively. Thyroid/throat uptake remained low at ~0.1% ID for all timepoints investigated, indicating a low degree of de-astatination. Initial efficacy studies using a single intravenous dose of 0.5 MBq (~20 MBq/kg) demonstrated significant growth delay and tumor volume reduction compared with control mice (saline). Blood platelet count was reduced after administration of [211At]PSAt-3 and subsequently recovered. No signs of severe toxicity, and no significant weight loss between control and treated mice was observed, suggesting that the treatment is well tolerated. Conclusion: 0.5 MBq [211At]PSAt-3 was well tolerated in mice and demonstrated tumor volume reduction and significant delay of tumor growth. These findings suggest [211At]PSAt-3 as a promising candidate for clinical translation. Citation Format: Lars Hvass, Marius Müller, Anne Clausen, Matthias Herth, Andreas Kjaer. PSMA targeted alpha radiopharmaceutical [211At]PSAt-3 inhibits tumor growth in a preclinical model of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6034.

Microscopic dose to lung from inhaled alpha emitters in humans

Because of the short range of alpha particles in tissue, the degree of uniformity of irradiation of the lung varies greatly depending on the form of the inhaled material. Animal studies have shown that the degree of dose uniformity influences the risk of lung cancer. This study investigates the radiation dose distribution of plutonium in human lung. Numerical maps of tissue configuration and target cell locations are obtained from histological sections of human lung tissue stained to enhance the identification of putative cell types for parenchymal lung cancers, i.e. alveolar type II cells and Clara cells. Monte Carlo simulations are used to obtain dose distribution around individual particles, and these distributions are used to compute dose distribution in volumes of lung tissue. Lung dose is characterised both by the degree of non-uniformity of irradiation and the relative degree of irradiation of all tissue versus the special cells of interest.

Absorbed dose delivered by alpha particles calculated in cylindrical geometry

The present work aims to develop a semi-analytical method to calculate the absorbed dose delivered by alpha particles in a cylindrical geometry. This method will be employed to reproduce the dose conversion coefficients or absorbed fraction of alpha particles in sensitive cells of the tracheobronchial tree obtained by NRC and ICRP, respectively. The difference caused by using water stopping power and tissue stopping power will also be investigated. Linear stopping powers for alpha particles in tissue and air were calculated, and the dependences of stopping powers on the traveled distance were established. A geometry model is set up for our calculations, and two different cases have been considered, namely the near-wall and far-wall cases. The total energy imparted to a unit-diameter sphere around a point is shown to be obtainable from a triple integral, which can be solved numerically. The absorbed dose is found to be independent of the diameter of the sphere being considered and additional assumptions about its diameter were not needed. The results obtained are in good agreement with those obtained previously by NRC and ICRP66. Using the semi-analytical method developed in the present work, the dose conversion coefficients or absorbed fraction previously obtained by NRC and ICRP, respectively, have been satisfactorily reproduced. Using the tissue stopping power instead of the water stopping power can slightly lower the values for dose conversion coefficients in the bronchial region.

Lifespan studies in rats exposed to 239PuO2 aerosol.

Spatial-temporal dose-distribution patterns in the lung continually change following inhalation of radionuclides. Lung clearance, microdosimetry, and radiation dose were examined in female Wistar rats exposed to high-fired 169Yb2O3-239PuO2 aerosols. Whole-body counting for 169Yb at 14 d postexposure provided an accurate (r = 0.99) estimate of 239Pu lung content. Alpha irradiation of tracheal epithelium was at least 50 times less than for bronchiolar epithelium due principally to preferential retention of 239PuO2 in peribronchiolar alveoli as compared to other alveolar regions. The formation of large aggregates (> 25 particles) increased linearly with initial lung burden starting at 0.4 kBq; mean dose rate to these focal alveolar regions was 120 Gy d-1. Concentration of 239PuO2 in pulmonary macrophages and in aggregates, along with the limited penetration of alpha particles in tissue, resulted in a highly nonhomogeneous dose distribution pattern. Alveolar clearance was best represented by a biphasic clearance curve comprised of a rapid early phase (80% initial lung burden) and a slow late phase (20% initial lung burden). Studies with intratracheally instilled 237PuO2-239PuO2 and with inhaled 239PuO2 showed that alveolar clearance was inversely proportional to initial lung burden. A single clearance function was derived from experimentally determined clearance curves for inhaled 239PuO2 that was used to accurately estimate lung dose at all initial lung burden levels. Lung doses were calculated for 2,105 exposed lifespan rats based on individually determined initial lung burden, survival time, and individually computed clearance function.

Energy Loss of Alpha Particles in Tissue

Stopping powers of alpha particles have been measured for CO2, O2, N2, and CH4 over an energy range from 0.1 to 5.3 MeV. From these measurements atomic stopping cross sections of alpha particles in tissue (H, 10.1%; C, 12.1%; N, 4.0%; O, 73.6% by weight) have been evaluated. For energies less than 1 MeV the results are as much as 50% higher than those calculated by Neufeld and Snyder, assuming that the stopping power of an ion is given by the product of the proton specific stopping power and the average of the square of the charge of the ion. Possible explanations are presented to account for this discrepancy.

Experimental studies of relative biological effectiveness of 910-Mev alpha particles in mammalian cells.

The application of energetic heavy particles, such as neutrons, protons, and alpha particles for treatment of neoplastic and neurologic diseases is of recent development. These particles, as compared to electrons, are in fact very heavy, and they possess unique advantages over x-rays in depth of penetration and lack of scattering in tissues. As an example, 340-Mev protons and 910-Mev alpha particles from the Berkeley 184-inch cyclotron can be made to travel in a pencil-like beam which gives an almost uniform distribution of radiation along its path and can be made to result in destruction in a predetermined, small, deep-lying structure. Furthermore, these mono-energetic heavy particles have a uniform and well defined range of penetration, producing maximum ionization just before stopping in tissues, producing the so-called Bragg effect. The range of the 910-Mev alpha particles in tissue is about 22 gm./cm.2 The present report will describe a preliminary experimental investigation of the RBE of 910-Mev alpha particles from the Berkeley cyclotron, based on mouse ascites tumors. For this purpose, TA3 transplantable ascites tumor,3 which grows progressively in and finally kills A/HeJ and A/J inbred mice, was chosen. The tumor from a freshly killed animal was diluted with normal saline to a known concentration of cells, and the resulting suspension was placed in a test tube for irradiation. For Bragg peak studies, special plastic chambers 1 mm. in depth were used. After irradiation, the tumor suspension was recovered from the test tubes and the plastic chambers, counted, and transplanted into a group of 5 to 10 A/HeJ mice. Each intraperitoneal inoculum consisted of 500,000 irradiated tumor cells and 50 per cent tumor takes was used as the end point. The mice were fed with Simonson Laboratory white diet and water ad libitum and were observed for six weeks after tumor transplantation. Radiation and Dosimetry The roentgen radiation was from a Philips unit, with the following technical factors: 200 kv, 15 ma, added filtration 0.25 mm. Cu and 1 mm. Al, h.v.l. 1 mm. Cu. For the alpha particle irradiation the 910-Mev beam was deflected from the cyclotron, magnetically sorted, and collimated by the quadruple focusing method. Following its emergence from the vacuum collimating system into air, it consisted of nearly parallel streams of particles in a homogeneous beam nearly 2 inches in diameter. The dose rates ranged from 50 to 100 rads per minute for roentgen irradiation and 500 to 1,000 rads per minute for alpha irradiation. For oxygenated and anoxic experiments pure oxygen and nitrogen, respectively, were bubbled through the tumor suspension for approximately fifteen minutes before and continuously during the irradiation. Results The experimental data have been briefly summarized in Figure 1.