An α-particle, a 4He nucleus, is exquisitely cytotoxic, and indifferent to many limitations associated with conventional chemo- and radiotherapy. The exquisite cytotoxicity of α radiation, the result of its high mean energy deposition (high linear energy transfer, LET) and limited range in tissue, provides for a highly controlled therapeutic modality that can be targeted to selected malignant cells (targeted α-therapy (TAT)) with minimal normal tissue effects. There is a burgeoning interest in the development of TAT that is buoyed by the increasing number of ongoing clinical trials worldwide. The short path length renders α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking, hematological cancers, infections, and compartmental cancers such as ovarian cancer or neoplastic meningitis. Yet, despite decades of study of high-LET radiation, the mechanistic pathways of the effects of this modality remain not well defined. The modality is effectively presumed to follow a simple therapeutic mechanism centered on catastrophic double strand (ds) DNA breaks without full examination of the actual molecular pathways and targets that are activated that directly impact cell survival or death. This Molecular Pathways article provides an overview of the mechanisms and pathways that are involved in the response to and repair of TAT induced DNA damage as currently understood. Finally, this article highlights the current state of clinical translation of TAT as well as other high-LET radionuclide radiation therapy using α-emitters such as 225Ac, 211At, 213Bi, 212Pb and 223Ra.

Alpha-particle emitters have a high linear energy transfer and short range, offering the potential for treating micrometastases while sparing normal tissues. We developed a urea-based, 211 At-labeled small molecule targeting prostate-specific membrane antigen (PSMA) for the treatment of micrometastases due to prostate cancer (PC). Methods: PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-211 At-astatobenzamido) pentyl)ureido)-pentanedioic acid ( 211 At-6) was synthesized. Cellular uptake and clonogenic survival were tested in PSMA-positive (PSMA1) PC3 PIP and PSMA-negative (PSMA−) PC3 flu human PC cells after 211 At-6 treatment. The antitumor efficacy of 211 At-6 was evaluated in mice bearing PSMA1 PC3 PIP and PSMA-PC3 flu flank xenografts at a 740-kBq dose and in mice bearing PSMA1, luciferase-expressing PC3-ML micrometastases. Biodistribution was determined in mice bearing PSMA1 PC3 PIP and PSMA-PC3 flu flank xenografts. Suborgan distribution was evaluated using α-camera images, and microscale dosimetry was modeled. Longterm toxicity was assessed in mice for 12 mo. Results: 211 At-6 treatment resulted in PSMA-specific cellular uptake and decreased clonogenic survival in PSMA1 PC3 PIP cells and caused significant tumor growth delay in PSMA1 PC3 PIP flank tumors. Significantly improved survival was achieved in the newly developed PSMA1 micrometastatic PC model. Biodistribution showed uptake of 211 At-6 in PSMA1 PC3 PIP tumors and in kidneys. Microscale kidney dosimetry based on α-camera images and a nephron model revealed hot spots in the proximal renal tubules. Long-term toxicity studies confirmed that the dose-limiting toxicity was late radiation nephropathy. Conclusion: PSMA-targeted 211 At-6 α-particle radiotherapy yielded significantly improved survival in mice bearing PC micrometastases after systemic administration. 211 At-6 also showed uptake in renal proximal tubules resulting in late nephrotoxicity, highlighting the importance of long-term toxicity studies and microscale dosimetry.

Cetuximab is a recombinant, human/mouse chimeric IgG1, monoclonal antibody (mAb) that binds to the epidermal growth factor receptor (EGFR/HER1). Cetuximab is approved for the treatment of patients with HER1-expressing metastatic colorectal cancer. Limitations in currently reported radiolabeled cetuximab for PET applications prompted the development of 86Y-CHX-A”-DTPA-cetuximab as an alternative for imaging HER1-expressing cancer. 86Y-CHX-A”-DTPA-cetuximab can also serve as a surrogate marker for 90Y therapy. Methods Bifunctional chelate, CHX-A”-DTPA was conjugated to cetuximab and radiolabeled with 86Y. In vitro immunoreactivity was assessed in HER1-expressing A431 cells. In vivo biodistribution, PET imaging and non-compartmental pharmacokinetics were performed on mice bearing HER1-expressing human colorectal (LS-174T and HT29), prostate (PC-3 and DU145), ovarian (SKOV3) and pancreatic (SHAW) tumor xenografts. Receptor blockage was demonstrated by co-injection of either 0.1 or 0.2 mg cetuximab. Results 86Y-CHX-A”-DTPA-cetuximab was routinely prepared with a specific activity of 1.5– 2 GBq/mg and in vitro immunoreactivity ranging from 65–75 %. Biodistribution and PET imaging studies demonstrated high HER1-specific tumor uptake of the radiotracer and clearance from non-specific organs. In LS-174T tumor bearing mice injected with the 86Y-CHX-A”-DTPA-cetuximab alone, 86Y-CHX-A”-DTPA-cetuximab plus 0.1 mg cetuximab or 0.2 mg cetuximab, the tumor uptake values at 3 d were 29.3 ± 4.2, 10.4 ± 0.5 and 6.4 ± 0.3 % ID/g, respectively, demonstrating dose-dependent blockage of the target. Tumors were clearly visualized 1 d after injecting 3.8–4.0 MBq 86Y-CHX-A”-DTPA-cetuximab. Quantitative PET revealed highest tumor uptake in LS-174T (29.55 ± 2.67 % ID/cc) and lowest tumor uptake in PC-3 (15.92 ± 1.55 % ID/cc) xenografts at 3 d after injection. Tumor uptake values quantified by PET were closely correlated (r2= 0.9, n=18) to values determined by biodistribution studies. Conclusion This study demonstrates the feasibility in preparation of high specific activity 86Y-CHX-A”-DTPA-cetuximab and its application for quantitative non-invasive PET imaging of HER1-expressing tumors. 86Y-CHX-A”-DTPA-cetuximab offers an attractive alternative to previously labeled cetuximab for PET and warrants further investigation for clinical translation.