1. Intracellular Activation of a Prostate Specific Antigen-Cleavable Doxorubicin Prodrug
- Author
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Wafa' T Al-Jamal, Mateja Erdani Kreft, Nina Kostevšek, Samo Hudoklin, Marc C. A. Stuart, Sara Pereira, Stratingh Institute of Chemistry, and Electron Microscopy
- Subjects
Male ,medicine.medical_treatment ,Pharmaceutical Science ,02 engineering and technology ,PH-SENSITIVE LIPOSOMES ,urologic and male genital diseases ,prostate-specific antigen-cleavable doxorubicin prodrug ,030226 pharmacology & pharmacy ,Targeted therapy ,Prostate cancer ,PSA ,0302 clinical medicine ,TARGETED THERAPY ,Drug Discovery ,Tumor Cells, Cultured ,polycyclic compounds ,Prodrugs ,PEPTIDE ,Cytotoxicity ,Liposome ,Antibiotics, Antineoplastic ,Chemistry ,Prodrug ,021001 nanoscience & nanotechnology ,prostate cancer ,CANCER ,3. Good health ,Prostate-specific antigen ,Nanomedicine ,Systemic administration ,Molecular Medicine ,0210 nano-technology ,medicine.drug ,intracellular activation ,MECHANISMS ,03 medical and health sciences ,DELIVERY ,SDG 3 - Good Health and Well-being ,medicine ,Humans ,Doxorubicin ,CONJUGATE ,Prostatic Neoplasms ,IN-VITRO ,Prostate-Specific Antigen ,medicine.disease ,carbohydrates (lipids) ,Liposomes ,Cancer research ,Nanoparticles ,INTERNALIZATION - Abstract
L-377,202 prodrug (Dox-PSA) was in phase I Clinical trial for patients with metastatic castration-resistant prostate cancer (mCRPC). It consists of doxorubicin (Dox) conjugated to a prostate specific antigen (PSA)-cleavable peptide that can be selectively activated by secreted PSA at the tumour site. However, despite the initial promising results, further clinical testing with Dox-PSA was halted due to toxicity concerns emerging from non-PSA-specific cleavage, following systemic administration. In the present study, we have reported, and for the first time, the intracellular activation of Dox-PSA, where Dox nuclear uptake was specific to C4-2B (PSA-expressing) cells, which agreed with the cytotoxicity studies. This finding was confirmed by encapsulating Dox-PSA prodrug into pH-sensitive liposomes to enable prodrug intracellular release, followed by its enzymatic activation. Interestingly, our results demonstrated that Dox-PSA loaded into pH-responsive nanoparticles exhibited cytotoxicity comparable to free prodrug in C4-2B monolayers, with superior activity in tumour spheroids, due to deeper penetration within tumour spheroids. Our approach could open the doors for novel Dox-PSA nanomedicines with higher safety and efficacy to treat advanced and metastatic prostate cancer.
- Published
- 2019
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