Approach Aim 1. Preliminary work performed by Drs. Choyke and Lin have demonstrated that PSMA-targeted agents such as 18F-DCYPyL are taken up in salivary glands of rats and can reliably be detected via positron emission tomography (PET) imaging. Study animals will have their major salivary glands accessed by the NIDCR team via minimally-invasive cannulation of the excretory ducts of both the parotid (Stenson's duct) and the submandibular gland (Wharton's duct). Un-radiolabeled cold DCYPyL will then be infused retrograde into each gland using the methodology to be optimized in Project 1. Infusion of cold DCYPyL will be performed on either the right or left-sided glands only, which will then allow us to use the contralateral glands as a within-subject control. A 18F-DCYPyL PET scan will be performed using standard tail vein injection, and uptake of 18F-DCYPyL will be compared in the infused glands vs. the un-infused control glands on the contralateral side. Activity will be determined using the standardized uptake value (SUV) of a region of interest drawn around the parotid and submandibular glands. The goal of the study will be to demonstrate that the SUV of the infused glands will be significantly lower than the contralateral control glands, which would then indicate that selective inhibition of 18F-DCYPyL uptake (and by extension 225Ac-PSMA uptake) in the infused gland has been successfully achieved.
Aim 2. Preliminary work performed by Dr. Choyke have demonstrated that PSMA-targeted agents such as 18F-DCYPyL are taken up in salivary glands of humans and can reliably be detected via positron emission tomography (PET) imaging. If the pre-clinical data from Aim 1 prove promising, Aim 2 would strive to perform the same proof-of-concept experiment as in Aim 1 but using human subjects in a clinical trial. Dr. Choyke already has an IRB-approved protocol 17-C-0089: Evaluation of 18F-DCFPyL PSMA- versus 18F-NaF-PET Imaging for Detection of Metastatic Prostate Cancer, which would be a source of patient accrual for this project. An amendment will be made to protocol 17-C-0089 which will introduce the option of unilateral salivary gland cannulation in patients already scheduled to receive 18F-DCFPyL PET imaging. Similar to Aim 1, the goal of this study will be to demonstrate that selective inhibition of 18F-DCYPyL uptake (and by extension 225Ac-PSMA) can be achieved in the infused gland in humans.
Aim 3. This scientific aim is made possible by recent developments in microfluidics and micro-electronic sensors. A new ionizing radiation device has been developed by research teams at CERN called the Timepix sensor. This sensor has an active area of 1.4 cm x 1.4 cm and is composed of ionization sensing pixels with a 55 micron pitch. While originally developed for high-resolution detection of charged particles, the Timepix sensor can be used in combination with a custom-designed microfluidic chip for the direct detection and measurement of alpha particle activity in either solution or a thin slice of tissue. Samples would be held in the microfluidic chip and then brought close to the 12 micron thick Mylar sheet sensing window of the Timepix device. The thinness of the Mylar sheet covering and the proximity of the microfluidic chip would then allow alpha particles in the sample to cross into the Timepix and be detected/counted. This methodology will have two important applications to the 225Ac-PSMA project: 1) Improve the accuracy in measuring the dose and activity of treatment to be administered in either animal models or in humans, and 2) Allow us to perform more accurate dosimetry and bio-distribution studies on tissue samples obtained either from animals or from resected/biopsied human tissue samples. Although alpha-PSMA radionuclide therapy shows significant promise in efficacy, severe irreversible xerostomia is a major life-changing side effect which could affect the development of this promising agent. Having a minimally-invasive method to prevent xerostomia will significantly improve the clinical acceptance of alpha-PSMA targeted radionuclide therapy. Development of an accurate method to directly measure alpha particles will improve the practicality of using alpha emitters in clinical care.
