A simple strategy to reduce the salivary gland and kidney uptake of PSMA-targeting small molecule radiopharmaceuticals

Abstract

Purpose: Peptide-based prostate-specific membrane antigen (PSMA) targeted radionuclide therapy (TRT) agent [¹⁷⁷Lu]-PSMA-617 has emerged as leading TRT candidate for treatment of castration-resistant prostate cancer (mCRPC). [¹⁷⁷Lu]-PSMA-617 and other small molecule-based PSMA ligands have shown efficacy in reducing the tumor burden in mCRPC patients but irradiation to the salivary gland and kidneys is a concern and dose-limiting factor. Therefore, methods to reduce non-target organ toxicity are needed to safely treat patients and preserve their quality of life. Herein, we report that addition of cold PSMA ligand PSMA-11 can aid in reducing the uptake of [¹⁷⁷Lu]-PSMA-617 in the salivary glands and kidneys.

Methods: Groups of athymic nude mice (n = 4) bearing PC3-PIP (PSMA+) tumor xenografts were administered with [¹⁷⁷Lu]-PSMA-617 along with 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 and biodistribution studies were performed at 1 h.

Results: Biodistribution studies at 1 h post-administration revealed that [¹⁷⁷Lu]-PSMA-617 uptake in PC3-PIP tumors was 21.71 ± 6.13, 18.7 ± 2.03, 26.44 ± 2.94, 16.21 ± 3.5, 13.52 ± 3.68, and 12.03 ± 1.96 %ID/g when 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 were added, respectively. Corresponding uptake values in kidney were 123.14 ± 52.52, 132.31 ± 47.4, 84.29 ± 78.25, 2.12 ± 1.88, 1.16 ± 0.36, and 0.64 ± 0.23 %ID/g, respectively. Corresponding salivary gland uptake values were 0.48 ± 0.11, 0.45 ± 0.15, 0.38 ± 0.3, 0.08 ± 0.03, 0.09 ± 0.07, and 0.05 ± 0.02 % ID/g, respectively.

Conclusion: The uptake of [¹⁷⁷Lu]-PSMA-617 in the salivary gland and kidney can be substantially reduced without significantly impacting tumor uptake by adding cold PSMA-11.

Keywords: Dose reduction; Kidneys; PSMA TRT; PSMA-617; Salivary glands; Specific activity.

Fig. 1. Relative levels of PSMA mRNA in patient samples.

PSMA mRNA levels in prostate cancer samples analyzed from the Yu prostate data set (4). A total of 112 samples including 23 normal prostate, 64 prostate carcinoma, and 25 metastatic prostate cancer samples were analyzed on Affymetrix U95A-C microarrays; 8603 gene transcripts were analyzed and the PSMA (FOLH1) mRNA expression data was plotted using Graphpad Prism. P value calculated by unpaired student t test. P-trends were analyzed by one-way ANOVA.

Fig. 2. PSMA Ligands.

Representative structures of peptide-based PSMA-targeted radiopharmaceuticals currently being evaluated in several clinical and preclinical studies.

Fig 3.. Tumor to organ ratios of uptake of [¹⁷⁷Lu]-PSMA-617 in salivary gland and kidneys as a function of mass of PSMA-11 added to the preparation.

The uptake of [¹⁷⁷Lu]-PSMA-617 in salivary glands and kidneys normalized to tumor uptake at 1 h post-administration was plotted as a function of mass of PSMA-11 administered to the animal. The data is presented as mean ± SD and student t-test was used to analyze statistically whether effective molar activity affects relative uptake of [¹⁷⁷Lu]-PSMA-617 in organs. t -test was performed using normalized uptake at 0 pmoles addition of PSMA-11 per mouse as a control. P-value was marked in each group as asterisk (* p <0.05, ** p < 0.01, *** p < 0.005, **** p < 0.001). It is clear from the graph that we observe statistically significant improvements in tumor to organ ratios with addition of PSMA-11 at 500 and 100 pmoles for kidneys and salivary glands respectively.