Abstract 4412: Assessing protease inhibition enhanced delivery of prostate tumor targeted peptide receptor based radiotherapy
Authors: Rold Tammy L. , Bernskoetter Nicole E. , Berendzen Ashley F. , Hoffman Timothy J. 
Published: August 2015

Abstract
Purpose: Peptide receptor targeted therapy for treatment of castration resistant prostate cancer (CRPC) has been explored by several groups including our own. However limitations in tumor drug delivery and transient retention at the tumor site has resulted in non-optimal therapeutic effectiveness of Lu-177 based peptide therapies.Marsouvanidis and co-workers (Cancer Biotherapy and Radiopharmaceuticals, 2014; DOI: 10.1089/cbr.2014.1706) recently demonstrated that co-administration of a neutral endopeptidase (NEP) inhibitor could enhance prostate tumor directed Lu-177-BB2r agonist drug delivery in excess of 300%. Based on this report, we hypothesized that similar enhancement of drug delivery might be possible for BB2r antagonist vectors currently under evaluation in our laboratory.
Methods: As a model system, we commercially synthesized DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (RM2), a potent BB2r antagonist, and radiolabeled with Lu-177 to create the theranostic radiopharmaceutical. Male SCID mice (4 week old) were bi-laterally flank inoculated with PC-3 prostate cancer cells (5×106/flank). Pharmacokinetic studies were conducted 4 weeks post cell implantation using Lu-177-RM2 alone or co-injected with 300ug of phosphoramidon (PA). Drug biodistribution studies were conducted between 15 min and 336 hrs post drug administration and Lu-177 content was determined. Concurrent SPECT/CT images were obtained.
Results: Enhancement of Lu-177-RM2 tumor uptake was noted within 1 hour post injection (9.7+/-2.6%ID/g vs 6.8+/-2.5%ID/g for Lu-177-RM2 + PA vs Lu-177-RM2 alone) and persisted for 24 hours post injection (9.6+/-2.5%ID/g vs 5.3+/-1.1%ID/g for Lu-177-RM2 + PA vs Lu-177-RM2 alone). The delayed time points demonstrated that the initial drug delivery enhancement achieved by co-injection of PA was transient, and by 48 hours post injection there was no statistical significance between the Lu-177-RM2 + PA vs Lu-177-RM2 alone treatment groups.
Summary: In vivo enzyme inhibition of NEP results in short term transient improvement of theranostic drug delivery when employing high affinity BB2r peptide antagonist targeting vectors. Although a nearly 80% improvement in BB2r positive tumor xenograft targeting was achieved, prolonged retention (beyond 24 hours post administration) of the drug at the tumor site was not observed. These results suggest that the benefits of combination NEP inhibitors with theranostic radiopharmaceuticals needs to be assessed on a case by case basis.
Citation Format: Tammy L. Rold, Nicole E. Bernskoetter, Ashley F. Berendzen, Timothy J. Hoffman. Assessing protease inhibition enhanced delivery of prostate tumor targeted peptide receptor based radiotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4412. doi:10.1158/1538-7445.AM2015-4412