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Selective photodetection and photodynamic therapy for prostate cancer through targeting of proteolytic activity
Maria-Fernanda Zuluaga1, Nawal Sekkat, Doris Gabriel
1Department of Pharmaceutics and Biopharmaceutics, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
Abstract:
Frequent side effects of radical treatment modalities and the availability of novel diagnostics have raised the interest in focal therapies for localized prostate cancer. To improve the selectivity and therapeutic efficacy of such therapies, we developed a minimally invasive procedure based on a novel polymeric photosensitizer prodrug sensitive to urokinase-type plasminogen activator (uPA). The compound is inactive in its prodrug form and accumulates passively at the tumor site by the enhanced permeability and retention effect. There, the prodrug is selectively converted to its photoactive form by uPA, which is overexpressed by prostate cancer cells. Irradiation of the activated photosensitizer exerts a tumor-selective phototoxic effect. The prodrug alone (8 μmol/L) showed no toxic effect on PC-3 cells, but upon irradiation the cell viability was reduced by 90%. In vivo, after systemic administration of the prodrug, PC-3 xenografts became selectively fluorescent. This is indicative of the prodrug accumulation in the tumor and selective local enzymatic activation. Qualitative analysis of the activated compound confirmed that the enzymatic cleavage occurred selectively in the tumor, with only trace amounts in the neighboring skin or muscle. Subsequent photodynamic therapy studies showed complete tumor eradication of animals treated with light (150 J/cm(2) at 665 nm) 16 hours after the injection of the prodrug (7.5 mg/kg). These promising results evidence the excellent selectivity of our prodrug with the potential to be used for both imaging and therapy for localized prostate cancer.
Insights
A novel polymeric photosensitizer prodrug targets localized prostate cancer. Activated by urokinase-type plasminogen activator (uPA), it enables tumor-selective photodynamic therapy and imaging with high efficacy.
Area of Science:
- Biomedical Engineering
- Oncology
- Photodynamic Therapy
Background:
- Radical treatments for localized prostate cancer have significant side effects.
- Novel diagnostics are increasing interest in focal therapy approaches.
- There is a need for more selective and effective focal therapies for prostate cancer.
Purpose of the Study:
- To develop a minimally invasive focal therapy for localized prostate cancer.
- To create a novel polymeric photosensitizer prodrug activated by urokinase-type plasminogen activator (uPA).
- To enhance the selectivity and therapeutic efficacy of prostate cancer treatments.
Main Methods:
- A novel polymeric photosensitizer prodrug was synthesized.
- The prodrug's accumulation and activation in tumors were assessed using enhanced permeability and retention (EPR) effect and uPA sensitivity.
- In vitro cytotoxicity assays and in vivo studies on PC-3 xenografts were performed.
- Photodynamic therapy (PDT) was conducted following prodrug administration and light irradiation.
Main Results:
- The prodrug showed no toxicity alone but reduced PC-3 cell viability by 90% upon irradiation.
- In vivo, the prodrug selectively accumulated and was activated in PC-3 xenografts, confirmed by fluorescence and enzymatic cleavage analysis.
- Complete tumor eradication was achieved in animals treated with the prodrug and photodynamic therapy.
Conclusions:
- The developed photosensitizer prodrug demonstrates excellent tumor selectivity for localized prostate cancer.
- This novel approach holds potential for both diagnostic imaging and therapeutic applications.
- The uPA-activated prodrug offers a promising minimally invasive focal therapy option.
