Abstract B066: Development of paired small-molecule drug conjugates for prostate cancer precision theranostics
Authors: Guan Bing , Wu Yunkou , Yang Jingyue , Xiong Yahong , Hsieh Jer-Tsong , Hao Guiyang , Sun Xiankai 
Published: February 2019

Objectives: Traditional cancer chemotherapy is normally associated with systemic toxicity due to the lack of tumor-targeting specificity. Recent efforts have therefore focused on targeted therapy to reduce such systemic toxicity. We have recently developed a pair of 18/19F-labeled theranostic small-molecule drug conjugates (18/19F-T-SMDCs) for prostate cancer precision theranostics, which consists of a prostate-specific membrane antigen (PSMA) specific ligand for prostate cancer targeting, a cytotoxic drug (DM1, with high antimitotic cytotoxicity at subnanomolar range) for chemotherapy, and an 18F imaging unit via a lysine-PEG trifunctional linker for PET imaging or a nonradioactive 19F unit for therapy in order to overcome the dosage gap between diagnostic and therapeutic agents. The18/19F-T-SMDCs have been demonstrated to retain the PSMA binding affinity, exhibit high cell uptake in PSMA-positive cells, display an appreciable level of internalization in a time-dependent manner, and be capable of specifically imaging PSMA-expressing cancer xenografts in mice. Here we evaluated the in vitro cytotoxicity and in vivo therapeutic potency of the18/19F-T-SMDCs.

Methods: The in vitro cytotoxicity of 19F-T-SMDC was measured by crystal violet cell growth assay in PSMA-positive LNCaP cells and PSMA-negative PC-3 cells. The DM1 free drug was included in the assay as an internal positive standard to compare the toxicity of 19F-T-SMDC in these two cell lines. In vivo treatment study was performed in SCID mice bearing PSMA-positive PC3-PIP subcutaneous tumors to evaluate both imaging and therapeutic performance of 18/19F-T-SMDCs (DM1). The treatment started when the average tumor volumes were in the range of 100 - 200 mm3 (length × width × height × 0.523), with intravenous injection of 15 or 40 nmol 19F-T-SMDC in 10% ethanol solution per mouse (n = 8) for three times a week for total four injections. The control group of mice received 10% ethanol solution plus 0.075 nmol 19F-T-SMDC (DM1) following the same injection schedule (n = 3). PET imaging with 18F-T-SMDC (DM1) was conducted before (Day 0: 18F-T-SMDC only) and during the 1st-dose treatment (Day 1: coinjection of 18/19F-T-SMDC) for both 15 and 40 nmol groups (n = 3). Besides the PET imaging with 18F-T-SMDC, concurrent FDG PET imaging was also conducted in the 15 nmol group mice (n = 3) before and post treatment (week 4) to monitor the treatment responses.

Results: The PSMA-positive LNCaP cells exhibited higher toxicity from 19F-T-SMDC (DM1) than PSMA-negative PC-3 cells. In comparison to free DM1 drug, the 19F-T-SMDC (DM1) was less toxic in both LNCaP and PC-3 cells. The reduced toxicity of the T-SMDC is desirable to alleviate the acute side effects of the drug (DM1) to normal tissues. For treatment study, 19F-T-SMDC (DM1) showed controllable acute toxicity, with the body weight loss all within 15%. While the 40-nmol group showed a greater body weight loss than the 15-nmol group, both groups started their body weight recovery from Day 18. In contrast, the control group showed no body weight loss until Day 10 when the tumor burden became severe. The average tumor sizes of both high- and low-dose treatment groups stopped increasing by Day 7. After then, all tumors started shrinking over the course of the treatment. Meanwhile, the control group was observed with fast and continuous tumor growth. Although the increased dose did not benefit the tumor reduction, the high-dose treatment group exhibited delayed tumor recurrence compared to the low-dose group.

Conclusions: The 18/19F-T-SMDCs retain PSMA binding affinity, exhibit PSMA-dependent toxicity, and are capable of specifically imaging PSMA-positive cancer xenografts in mice. They also show effective therapeutic performance in in vivo tumor treatment study, and can be served as a promising strategy for prostate cancer precision theranostics

Citation Format: Bing Guan, Yunkou Wu, Jingyue Yang, Yahong Xiong, Jer-Tsong Hsieh, Guiyang Hao, Xiankai Sun. Development of paired small-molecule drug conjugates for prostate cancer precision theranostics [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B066.