Meng study hopes to advance radiopharmaceutical therapeutics with multi-isotope molecular imaging

11/30/2021

Phillip Kisubika

Meng study hopes to advance radiopharmaceutical therapeutics with multi-isotope molecular imaging

NPRE professor Ling-Jian Meng has recently been awarded a $3.8M Biomedical Research Partnership (BRP/U01) grant from the National Institute of Biomedical Imaging and Bioengineering (NIBIB), entitled “High Energy and Spatial Resolution Multi-Isotope SPECT imaging of Targeted Alpha-Emitters and their Daughters.”

The overarching goal of this project is to develop the next-generation clinical SPECT imaging platform (will be referred to as Alpha-SPECT) that incorporates cutting-edge CZT imaging-spectrometers and a synthetic compound-eye (SCE) game-camera design to offer a dramatically improved spatial resolution, energy resolution, sensitivity, and multi-isotope imaging capability, and apply the Alpha-SPECT technology to accelerate the development and translation to the clinical practice of α-particle radiopharmaceutical therapeutics (α-RPTs).

“α-RPTs have great potential for patients with metastatic cancer, who have diminished prospects for long-term survival compared to patients whose cancer remains localized,” Meng said. “This group of patients represents a major challenge for cancer therapy. In patients with late-stage metastatic cancer, conventional chemotherapy is highly toxic and rarely effective. Targeted biologic therapies that inhibit signaling pathways associated with maintaining the cancer phenotype have shown dramatic initial responses but typically fail over the long term. By contrast, α-particles cause highly disruptive and largely irreparable DNA double-strand breaks capable of killing a cell with as few as one to two tracks through the nucleus. Since α-particles travel a short distance (50-100 mm), this damage is confined to the vicinity of targeted cells or cell clusters. In clinical and preclinical studies, α-RPTs have been highly effective against disseminated cancer.”

In human studies that have progressed beyond Phase I, α-emitters have yielded significant survival results in adult leukemia, glioblastoma multiforme, and hormone-refractory metastatic prostate cancer, all cancers for which there are few or no treatment options. The inclusion of αRPTs in the drug development pipeline of large pharmaceutical companies such as Bayer, Genentech Roche, and Johnson & Johnson also suggests that prior obstacles regarding availability and radiochemistry have been overcome and that this approach is poised for widespread clinical use.

Dosimetry is the key to understanding the toxicity and efficacy profiles of α-RPTs. Accurate knowledge of the distribution of the parent and daughter radionuclides is essential for accurate dosimetry. For conventional radiopharmaceuticals, SPECT or PET imaging provides a means to measure the biodistribution of radionuclides in vivo. However, there are challenges in doing this for alpha emitters. The energy spectrum of typical alpha emitters is very complicated, often being limited to characteristic x-rays or high energy photons. In addition, the presence of daughters with their own emissions makes the energy spectrum very complicated. Since some daughters are long-lived on the scale of physiological processes, it is desirable to obtain the distribution of both parent and daughter radionuclides. We hope the upcoming Alpha-SPECT system would provide a unique spectral imaging capability of imaging both the primary alpha-emitter, such as Ac-225 and Ra-223 and their daughters, and therefore allow for in vivo assessment of the delivery of α-RPTs in cancer patients.    

This project will be carried out by a large interdisciplinary research team led by Meng and Dr. George Sgouros from Johns Hopkins University School of Medicine.