Alpha Nanotherapy to Target Metastatic Cancer

Objective

Targeted alpha therapy, a treatment that relies on targeting pharmaceuticals labeled with ⍺ emitters, has produced complete cures of metastatic cancer patients with refractory diseases in clinical trials. However, targeted alpha therapy is limited by the release of radioisotopes from the pharmaceuticals. In ⍺ emissions, the decay products break the chemical bonds by which they are bound to the radiopharmaceutical, and once liberated, they spread all over the body, causing off-target radiopoisoning. Thus, preventing radioisotope release is a fundamental step to improve targeted alpha therapy safety and extend its use beyond terminal cases. In AlphaTar, I will completely change how ⍺ emitters (particularly 212Pb) are delivered to metastatic tumors. This will be done by developing a novel therapeutic regime that employs targeted ultra-small nanoformulations as carriers. These nanoformulations will conceal the radiometals and their decay products and minimize side effects, while displaying enhanced therapeutic activity. Most clinical nanomedicine formulations are large (>50 nm) and display long-term accumulations in the liver and spleen, making them unsuitable for targeted alpha therapy, since those cause radiopoisoning. My approach will rely on formulations with sizes below the renal clearance cutoff (<10 nm), which can be rapidly and completely excreted through the urine with minimal off-target accumulation. Imaging-based strategies will be developed to identify patients who are likely to respond to AlphaTar, and genomic screening will be performed to assess safety. Local and systemic responses will be improved via combination therapy with immune checkpoint inhibitors, and physical and pharmacological priming will be used to enhance nanomedicine extravasation, penetration, and retention in tumors. The outcomes of AlphaTar will be highly impactful, as they contribute to overcoming fundamental challenges in metastatic cancer therapy in a realistic manner.