Journal
MOLECULAR PHARMACEUTICS
Volume 16, Issue 4, Pages 1573-1585Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.8b01257
Keywords
prostate cancer; prostate specific antigen-cleavable doxorubicin prodrug; pH-sensitive liposomes; intracellular activation
Funding
- Prostate Cancer UK [CDF12-002]
- Engineering and Physical Sciences Research Council (EPSRC) [EP/M008657/1]
- Slovenian Research Agency [J3-7494, P3-0108]
- EPSRC [EP/M008657/1] Funding Source: UKRI
- Prostate Cancer UK [CDF12-002] Funding Source: researchfish
Ask authors/readers for more resources
L-377,202 prodrug (Dox-PSA) was in phase I clinical trials 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 tumor 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, 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 tumor spheroids, due to deeper penetration within tumor spheroids. Our approach could open the doors for novel Dox-PSA nanomedicines with higher safety and efficacy to treat advanced and metastatic prostate cancer.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available