Evaluation of an I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers.

Radiopharmaceutical therapy (RPT) is an attractive strategy for treatment of disseminated cancers including those overexpressing the HER2 receptor including breast, ovarian and gastroesophageal carcinomas. Single-domain antibody fragments (sdAbs) exemplified by the HER2-targeted VHH_1028 evaluated herein are attractive for RPT because they rapidly accumulate in tumor and clear faster from normal tissues than intact antibodies. In this study, VHH_1028 was labeled using the residualizing prosthetic agent N-succinimidyl 3-guanidinomethyl 5-[I]iodobenzoate (iso-[I]SGMIB) and its tissue distribution evaluated in the HER2-expressing SKOV-3 ovarian and BT474 breast carcinoma xenograft models.

Improved radiosynthesis of I-MAPi, an auger theranostic agent.

Purpose: I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently, I-MAPi is synthesized using multistep synthesis that results in modest yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials.

Poly(ADP-Ribose)Polymerase (PARP) Inhibitors and Radiation Therapy.

Poly(ADP-ribose)polymerase-1 (PARP1) is a DNA repair enzyme highly expressed in the nuclei of mammalian cells, with a structure and function that have attracted interest since its discovery. PARP inhibitors, moreover, can be used to induce synthetic lethality in cells where the homologous recombination (HR) pathway is deficient. Several small molecule PARP inhibitors have been approved by the FDA for multiple cancers bearing this deficiency These PARP inhibitors also act as radiosensitizing agents by delaying single strand break (SSB) repair and causing subsequent double strand break (DSB) generation, a concept that has been leveraged in various preclinical models of combination therapy with PARP inhibitors and ionizing radiation.

Targeted Brain Tumor Radiotherapy Using an Auger Emitter.

Purpose: Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades.

Experimental Design: I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger- and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells' DNA.

Discriminating radiation injury from recurrent tumor with [F]PARPi and amino acid PET in mouse models.

Background: Radiation injury can be indistinguishable from recurrent tumor on standard imaging. Current protocols for this differential diagnosis require one or more follow-up imaging studies, long dynamic acquisitions, or complex image post-processing; despite much research, the inability to confidently distinguish between these two entities continues to pose a significant dilemma for the treating clinician. Using mouse models of both glioblastoma and radiation necrosis, we tested the potential of poly(ADP-ribose) polymerase (PARP)-targeted PET imaging with [F]PARPi to better discriminate radiation injury from tumor.