Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate

Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to prostate cancer cells. In this study, we performed the synthesis of a novel small-molecule PSMA-targeted conjugate based on abiraterone. Cytotoxicity, the induction of intracellular reactive oxygen species, and P450-cytochrome species inhibition were investigated for this conjugate PSMA-abiraterone. The conjugate demonstrated a preferential effect on prostate tumor cells, remaining inactive at up to 100 µM in human fibroblast cells. In addition, it revealed preferential efficacy, specifically on PSMA-expressing lines with a 65% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts after 14-fold oral administration of PSMA-Abi at a single dose of 500 mg/kg (7.0 g/kg total dose) was observed. This compound showed significantly reduced acute toxicity with comparable efficacy compared to AbiAc.

[1]  I. Uddin,et al.  Targeted non AR mediated smart delivery of abiraterone to the prostate cancer , 2022, PloS one.

[2]  Mahfoozur Rahman,et al.  Systematic Development of Solid Lipid Nanoparticles of Abiraterone Acetate with Improved Oral Bioavailability and Anticancer Activity for Prostate Carcinoma Treatment , 2022, ACS omega.

[3]  M. Riyazuddin,et al.  Augmented experimental design for bioavailability enhancement: a robust formulation of abiraterone acetate , 2022, Journal of liposome research.

[4]  G. Baretton,et al.  Impact of Androgen Receptor Activity on Prostate-Specific Membrane Antigen Expression in Prostate Cancer Cells , 2022, International journal of molecular sciences.

[5]  D. Basak,et al.  Comparison of Anticancer Drug Toxicities: Paradigm Shift in Adverse Effect Profile , 2021, Life.

[6]  A. Zamyatnin,et al.  Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin E Conjugate. , 2021, Journal of medicinal chemistry.

[7]  V. Pokrovsky,et al.  PSMA-targeted small-molecule docetaxel conjugate: Synthesis and preclinical evaluation. , 2021, European journal of medicinal chemistry.

[8]  M. Pomper,et al.  Targeted delivery of cytotoxic proteins to prostate cancer via conjugation to small molecule urea-based PSMA inhibitors , 2021, Scientific Reports.

[9]  K. Herrmann,et al.  The salivary glands as a dose limiting organ of PSMA- targeted radionuclide therapy: A review of the lessons learnt so far. , 2021, Nuclear medicine and biology.

[10]  O. Dontsova,et al.  Synthesis and Biological Evaluation of PSMA Ligands with Aromatic Residues and Fluorescent Conjugates Based on Them. , 2021, Journal of medicinal chemistry.

[11]  P. Real,et al.  Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation , 2021, Cancers.

[12]  M. Pomper,et al.  Prostate-specific membrane antigen (PSMA)-targeted photodynamic therapy enhances the delivery of PSMA-targeted magnetic nanoparticles to PSMA-expressing prostate tumors , 2021, Nanotheranostics.

[13]  Pramod C. Nair,et al.  Slow-, Tight-Binding Inhibition of CYP17A1 by Abiraterone Redefines Its Kinetic Selectivity and Dosing Regimen , 2020, The Journal of Pharmacology and Experimental Therapeutics.

[14]  Y. Korchev,et al.  In vitro and in vivo Electrochemical Measurement of ROS After Treatment with Anticancer Drugs. , 2020, Analytical chemistry.

[15]  Dave A. Miller,et al.  Improved Dissolution and Pharmacokinetics of Abiraterone through KinetiSol® Enabled Amorphous Solid Dispersions , 2020, Pharmaceutics.

[16]  Wen-Bin Yang,et al.  CYP17A1 Maintains the Survival of Glioblastomas by Regulating SAR1-Mediated Endoplasmic Reticulum Health and Redox Homeostasis , 2019, Cancers.

[17]  Tanya Stoyanova,et al.  Second-Generation Antiandrogens: From Discovery to Standard of Care in Castration Resistant Prostate Cancer , 2019, Front. Oncol..

[18]  J. Reddy,et al.  Prostate-Specific Membrane Antigen-Specific Antitumor Activity of a Self-Immolative Tubulysin Conjugate. , 2019, Bioconjugate chemistry.

[19]  R. Kuefer,et al.  Expression of Prostate-Specific Membrane Antigen (PSMA) on Biopsies Is an Independent Risk Stratifier of Prostate Cancer Patients at Time of Initial Diagnosis , 2018, Front. Oncol..

[20]  A. Majouga,et al.  Synthesis of PSMA-targeted 131- and 152-substituted chlorin e6 derivatives and their biological properties , 2018, Journal of Porphyrins and Phthalocyanines.

[21]  Vasilis Ntziachristos,et al.  Synthesis and Preclinical Characterization of the PSMA-Targeted Hybrid Tracer PSMA-I&F for Nuclear and Fluorescence Imaging of Prostate Cancer , 2018, The Journal of Nuclear Medicine.

[22]  Mini Thomas,et al.  Evaluation of Novel Prostate-Specific Membrane Antigen-Targeted Near-Infrared Imaging Agent for Fluorescence-Guided Surgery of Prostate Cancer , 2018, Clinical Cancer Research.

[23]  E. Crawford,et al.  Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerations , 2018, Prostate Cancer and Prostatic Diseases.

[24]  Y. Korchev,et al.  Novel method for rapid toxicity screening of magnetic nanoparticles , 2018, Scientific Reports.

[25]  L. Smit,et al.  Physiologic distribution of PSMA-ligand in salivary glands and seromucous glands of the head and neck on PET/CT. , 2018, Oral surgery, oral medicine, oral pathology and oral radiology.

[26]  Hong-min Liu,et al.  Synthesis and biological evaluation of new steroidal pyridines as potential anti-prostate cancer agents. , 2018, European journal of medicinal chemistry.

[27]  J. Carles,et al.  The Phase 3 COU-AA-302 Study of Abiraterone Acetate Plus Prednisone in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Stratified Analysis Based on Pain, Prostate-specific Antigen, and Gleason Score. , 2017, European urology.

[28]  M. Pomper,et al.  A PSMA-targeted theranostic agent for photodynamic therapy. , 2017, Journal of photochemistry and photobiology. B, Biology.

[29]  A. D'Amico,et al.  Adverse effects of androgen deprivation therapy and strategies to mitigate them. , 2015, European urology.

[30]  S. Duensing,et al.  Comparison of different prostatic markers in lymph node and distant metastases of prostate cancer , 2015, Modern Pathology.

[31]  Martin G Pomper,et al.  Synthesis and biological evaluation of low molecular weight fluorescent imaging agents for the prostate-specific membrane antigen. , 2012, Bioconjugate chemistry.

[32]  F. Saad,et al.  Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. , 2012, The Lancet. Oncology.

[33]  J. Rosenberg,et al.  Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer , 2012, Drug design, development and therapy.

[34]  P. Low,et al.  Synthesis and biological analysis of prostate-specific membrane antigen-targeted anticancer prodrugs. , 2010, Journal of Medicinal Chemistry.

[35]  P. Choyke,et al.  Prostate specific membrane antigen- a target for imaging and therapy with radionuclides. , 2010, Discovery medicine.

[36]  D. Olmos,et al.  Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven. , 2009, Cancer research.

[37]  Bruce Montgomery,et al.  Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion , 2009, Nature Clinical Practice Urology.

[38]  S. Landas,et al.  Expression of Prostate-Specific Membrane Antigen in Normal and Malignant Human Tissues , 2006, World Journal of Surgery.

[39]  S. Balk,et al.  Androgen receptor: A key molecule in the progression of prostate cancer to hormone independence , 2004, Journal of cellular biochemistry.

[40]  K. Pienta,et al.  The Current State of Hormonal Therapy for Prostate Cancer , 2002, CA: a cancer journal for clinicians.

[41]  S. Schwartz,et al.  A new human prostate carcinoma cell line, 22Rv1 , 1999, In Vitro Cellular & Developmental Biology - Animal.

[42]  M. Bogaert,et al.  Cytochrome P450: genetic polymorphism and drug interactions. , 1996, Acta clinica Belgica.

[43]  M. Waterman,et al.  The role of cytochrome b5 in the biosynthesis of androgens by human P450c17. , 1995, Archives of biochemistry and biophysics.

[44]  J. Lechner,et al.  Establishment and characterization of a human prostatic carcinoma cell line (PC-3). , 1979, Investigative urology.