Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of alpha (α) particles in tissue, cancer cells can be significantly damaged while causing minimal toxicity to surrounding healthy cells. Recent clinical studies have demonstrated the remarkable efficacy of TAT in the treatment of metastatic, castration-resistant prostate cancer. In this comprehensive review, we discuss the current consensus regarding the properties of the α-particle-emitting radionuclides that are potentially relevant for use in the clinic; the TAT-mediated mechanisms responsible for cell death; the different classes of targeting moieties and radiometal chelators available for TAT development; current approaches to calculating radiation dosimetry for TATs; and lead optimization via medicinal chemistry to improve the TAT radiopharmaceutical properties. We have also summarized the use of TATs in pre-clinical and clinical studies to date.

New effective therapies are greatly needed for metastatic uveal melanoma which has a very poor prognosis with a median survival of less than one year. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanoma metastases, and a MC1R specific ligand (MC1RL) with high affinity and selectivity for MC1R was previously developed. Methods: The ²²⁵Ac-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity, tested in vitro for biostability, MC1R-specific cytotoxicity in uveal melanoma cells, and the La-DOTA-MC1RL analog was tested for binding affinity. Non-tumor bearing BALB/c mice were tested for maximum tolerated dose and biodistribution. Severe combined immunodeficient (SCID) mice bearing uveal melanoma tumors, or engineered MC1R positive and negative tumors were studied for biodistribution and efficacy. Radiation dosimetry was calculated using mouse biodistribution data and blood clearance kinetics from Sprague-Dawley rat data. Results: High biostability, MC1R-specific cytotoxicity and high binding affinity were observed. Limiting toxicities were not observed at even the highest administered activities. Pharmacokinetics and biodistribution studies revealed rapid blood clearance (<15 min), renal and hepatobillary excretion, MC1R specific tumor uptake and minimal retention in other normal tissues. Radiation dosimetry calculations determined pharmacokinetics parameters and absorbed α-emission dosages from ²²⁵Ac and its daughters. Efficacy studies demonstrated significantly prolonged survival and decreased metastasis burden following a single administration of ²²⁵Ac-DOTA-MC1RL in treated mice relative to controls. Conclusion: These results suggest significant potential for the clinical translation of ²²⁵Ac-DOTA-MC1RL as a novel therapy for metastatic uveal melanoma.

Evaluation of radiofluorinated carboximidamides as potential IDO-targeted PET tracers for cancer imaging

To increase the achievement of negative R0 surgical margins and increase the low survival rates of pancreatic cancer, improvements in assessing tumor margins during surgical resections are needed. This can be accomplished by using pancreatic cancer–targeted fluorescence molecular imaging agents to intraoperatively detect tumor margins in real time. Because Toll-like receptor 2 (TLR2) is broadly expressed among many cancer types including pancreatic adenocarcinomas, a high-affinity TLR2-targeted fluorescence molecular imaging agent (TLR2L-800) was developed. We investigate the potential for increased survival by employing real-time intraoperative tumor detection in a preclinical orthotopic human pancreatic xenograft tumor model using TLR2L-800. Three cohorts of nude mice bearing orthotopic human pancreatic xenograft tumors were intravenously injected with TLR2L-800. At 24 hours postinjection, one cohort underwent in vivo fluorescence-guided surgical removal of tumors using a real-time fluorescence imaging platform, a second cohort underwent visible light surgery (VLS), and a third cohort did not undergo surgery. A fourth, nontumor-bearing cohort was administered TLR2L-800 with no surgery. At 41 days postsurgery, the survival rates were 53% for the fluorescence-guided surgery (FGS) group and 0% for both the VLS and the tumor-bearing no-surgery group. The overall 200-day survival rate of 35% for the FGS group was significant compared with 0% for the VLS group (P value = 0.0018). This study demonstrates the potential of increasing disease-free survival for patients with pancreatic cancer by increasing the attainment of R0 margins using a novel tumor-targeted lipopeptide ligand-based fluorescence molecular imaging agent, TLR2L-800, during real-time FGS. Significance: Human TLR2 is broadly expressed among pancreatic adenocarcinomas, and the highly specific TLR2L-800 fluorescence molecular imaging agent has potential for use in fluorescence-guided surgery to increase R0 margins and improve patient survival.