Abstract PO-097: Selective targeting and imaging of orthotopic glioblastoma after a single systemic dose of a novel hydoxyl dendrimer radionuclide

• Published in: Clinical cancer research Vol. 27; no. 8_Supplement; p. PO-097
• Main Authors: Sharma, Rishi, Sun, Minghao, Appiani, Santiago, Coelho, Richard, McConville, Patrick, Alters, Susan, Cleland, Jeffrey L.
• Format: Journal Article
• Language: English
• Published: 15-04-2021
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1557-3265.RADSCI21-PO-097

Abstract
Previous studies have demonstrated hydroxyl dendrimers (HDs) are selectively taken up by tumor associated macrophages (TAMs) after a single administration. HDs have also been observed to cross the blood brain barrier in six animal species including dogs and monkeys. The treatment of brain tumors and metastases is hampered by the inability to deliver radiotherapy or cancer agents selectively to the tumor. HDs of two different generations were prepared (HD4 and HD6; both smaller than antibodies) and DOTA was conjugated to the HD through linker arms attached to the hydroxyls on the dendrimer surface. 111In radiolabeling of HD4- and HD6-DOTA resulted in >95% radiochemical purity in both cases and specific activities of 0.621 mCi/mg and 0.638 mCi/mg, respectively. GL-261-luc cells, a syngeneic glioblastoma, were implanted intracranially in 8 female albino C57.bl/6 mice. Tumors were 15-60 mm3 at time of dosing. Mice received a single administration of HD4-DOTA-111In or HD6-DOTA-111In at a dose of approximately 0.5 mg/mouse and 0.3 mCi/mouse. Whole body SPECT/CT imaging was done over time up to 6 days post-dose in 3 animals per compound. The biodistribution and uptake in the brain tumor and other tissues was quantitatively measured using VivoQuant 4.0 (Invicro, Boston). Both HDs rapidly distributed in the systemic circulation after administration. Clearance appeared to be primarily via the kidneys based upon the fraction of injected dose observed in the bladder over time. The % injected dose (%ID)/g in the brain tumor was 2.67 ± 0.45 and 7.05 ± 0.53 at 24 h post-dose for the HD4 and HD6 compounds, respectively. The %ID/g in the contralateral brain section was 0.37 ± 0.17 and 0.90 ± 0.20 at 24 h post-dose for the HD4 and HD6 compounds, respectively. Tumor associated radioactivity persisted for the duration of the study (last time points: HD4, 96 h, 5.27 ± 2.04 %ID/g; HD6, 144 h, 3.20 ± 1.02 %ID/g). These results confirm previous studies in this model demonstrating selective tumor uptake and persistence with 58 fold greater radioactivity at the last time point in brain tumor compared to contralateral brain. The selectivity and prolonged duration of HDs in TAMs will enable the use of the same HD-DOTA constructs to deliver radiotherapeutic 90Y to brain tumors. The HD radiotherapy approach may eliminate the off-target toxicity of current ligand-based approaches.
Citation Format: Rishi Sharma, Minghao Sun, Santiago Appiani, Richard Coelho, Patrick McConville, Susan Alters, Jeffrey L. Cleland. Selective targeting and imaging of orthotopic glioblastoma after a single systemic dose of a novel hydoxyl dendrimer radionuclide [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-097.