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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1573-1585
Number of pages13
JournalMolecular pharmaceutics
Volume16
Issue number4
Early online date25-Feb-2019
DOIs
Publication statusPublished - Apr-2019

Keywords

  • 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

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