Intracellular Activation of a Prostate Specific Antigen-Cleavable Doxorubicin Prodrug: A Key Feature Towards Prodrug-Nanomedicine Design

Pereira, S. G. T., Hudoklin, S., Kreft, M. E., Kostevsek, N., Stuart, M. C. A. & Al-Jamal, W. T., Apr-2019, In : Molecular pharmaceutics. 16, 4, p. 1573-1585 13 p.

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  • Intracellular Activation of a Prostate Specific Antigen-Cleavable Doxorubicin Prodrug

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  • Sara G. T. Pereira
  • Samo Hudoklin
  • Mateja Erdani Kreft
  • Nina Kostevsek
  • Marc C. A. Stuart
  • Wafa T. Al-Jamal

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.

Original languageEnglish
Pages (from-to)1573-1585
Number of pages13
JournalMolecular pharmaceutics
Issue number4
Early online date25-Feb-2019
Publication statusPublished - Apr-2019


  • intracellular activation, pH-sensitive liposomes, prostate cancer, prostate-specific antigen-cleavable doxorubicin prodrug, PH-SENSITIVE LIPOSOMES, IN-VITRO, TARGETED THERAPY, CANCER, PEPTIDE, PSA, DELIVERY, INTERNALIZATION, MECHANISMS, CONJUGATE

ID: 77007293