Nonthermal Ablation by Using Intravascular Oxygen Radical Generation with WST11: Dynamic Tissue Effects and Implications for Focal Therapy

Kimm, Simon; Tarin, Tatum; Monette, Sébastien; Srimathveeravalli, Govindarajan; Gerber, Daniel; Durack, Jeremy C.; Solomon, Stephen B.; Scardino, Peter T.; Scherz, Avigdor; Coleman, Jonathan

doi:10.1148/radiol.2016141571

Cited by 25 publications

(27 citation statements)

References 41 publications

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“…In a phase III clinical trial, the treatment was found to be a promising alternative to active surveillance of early stage prostate tumors 6 . PDT with padeliporfin has also proven successful in preclinical in vivo studies with application to renal and urethral tumors 7 , 8 . Furthermore, other photosensitizers were tested for treatment of, amongst others, pancreatic cancer 9 and brain gliomas 10 .…”

Section: Introductionmentioning

confidence: 99%

Detection of Treatment Success after Photodynamic Therapy Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Schreurs¹,

Jacobs²,

Nicolay³

et al. 2017

Theranostics

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Early evaluation of response to therapy is crucial for selecting the optimal therapeutic follow-up strategy for cancer patients. PDT is a photochemistry-based treatment modality that induces tumor tissue damage by cytotoxic oxygen radicals, generated by a pre-injected photosensitive drug upon light irradiation of tumor tissue. Vascular shutdown is an important mechanism of tumor destruction for most PDT protocols. In this study, we assessed the suitability of Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) to evaluate treatment efficacy within a day after photodynamic therapy (PDT), using the tumor vascular response as a biomarker for treatment success.Methods: DCE-MRI at 7 T was used to measure the micro-vascular status of subcutaneous colon carcinoma tumors before, right after, and 24 h after PDT in mice. Maps of the area under the curve (AUC) of the contrast agent concentration were calculated from the DCE-MRI data. Besides, tracer kinetic parameters including Ktrans were calculated using the standard Tofts-Kermode model. Viability of tumor tissue at 24 h after PDT was assessed by histological analysis.Results: PDT led to drastic decreases in AUC and Ktrans or complete loss of enhancement immediately after treatment, indicating a vascular shutdown in treated tumor regions. Histological analysis demonstrated that the treatment induced extensive necrosis in the tumors. For PDT-treated tumors, the viable tumor fraction showed a strong correlation (ρ ≥ 0.85) with the tumor fraction with Ktrans > 0.05 min-1 right after PDT. The viable tumor fraction also correlated strongly with the enhanced fraction, the average Ktrans, and the fraction with Ktrans > 0.05 min-1 at 24 h after PDT. Images of the viability stained tumor sections were registered to the DCE-MRI data, demonstrating a good spatial agreement between regions with Ktrans > 0.05 min-1 and viable tissue regions. Finally, 3D post-treatment viability detection maps were constructed for the tumors of three mice by applying a threshold (0.05 min-1) to Ktrans at 24 h after PDT. As a proof of principle, these maps were compared to actual tumor progression after one week. Complete tumor response was correctly assessed in one animal, while residual viable tumor tissue was detected in the other two at the locations where residual tumor tissue was observed after one week.Conclusion: This study demonstrates that DCE-MRI is an effective tool for early evaluation of PDT tumor treatment.

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Section: Introductionmentioning

confidence: 99%

Detection of Treatment Success after Photodynamic Therapy Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Schreurs¹,

Jacobs²,

Nicolay³

et al. 2017

Theranostics

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“…12 Moreover, cellular necrosis was complete in contrast to residual cellular viability seen following thermal based ablation influenced by heat sink effects. 12 WST11-VTP differs from classical PDT 20-26 and offers major advantages, including absence of prolonged skin photosensitivity, which has been a major barrier to widespread utilization of traditional PDT. 22-24 WST11-VTP has been successfully and safely applied in phase II clinical trials for tissue ablation in cancer bearing organs.…”

Section: Discussionmentioning

confidence: 99%

Treatment Effects of WST11 Vascular Targeted Photodynamic Therapy for Urothelial Cell Carcinoma in Swine

et al. 2016

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Purpose Surgical management of upper tract urothelial carcinoma requires removal of kidney and ureter, compromising renal function. Non-surgical alternatives have potentially prohibitive safety concerns. We examine the feasibility and safety of ablation of the ureter and renal pelvis using endoluminal vascular-targeted photodynamic therapy in a porcine model and report efficacy of WST11 vascular-targeted photodynamic therapy in a murine model. Materials and Methods Following approval, we performed 28 endoluminal ablations in the ureters and renal pelvis of 18 swine. Intravenous infusion of WST11 (4mg/kg) followed by laser illumination (10 minutes) was performed via percutaneous access or retrograde ureteroscopic approach. Animals were followed clinically with laboratory testing, imaging and histology was evaluated at several post-ablation time points. A murine xenograft was created with the 5637 human urothelial cell carcinoma line to determine sensitivity to this therapy. Results At 24 hours, 50 mW/cm laser fluence produced superficial necrosis of the ureter and deeper necrosis (penetrating the muscularis propria or adventitia) was produced by treatment with 200 mW/cm in the ureter and renal pelvis. At 4 weeks, superficial urothelium had regenerated over the treatment site. No symptomatic obstruction, clinically relevant hydronephrosis, or abnormality of lab testing was noted up to 4 weeks. In mice, 80% had no evidence of tumor at 19 days after WST11 vascular-targeted photodynamic therapy. Conclusions Urothelial cell carcinoma appears to be sensitive to WST11 vascular-targeted photodynamic therapy. Depth of WST11 vascular-targeted photodynamic therapy treatment effects can be modulated in a dose-dependent manner by titration of light intensity. Moreover, this treatment modality, applied to the porcine upper urinary tract, is feasible via antegrade and retrograde access.

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“…Dose escalation studies of VTP parameters such as WST-11 concentration or/and laser fluence should provide better efficacy of VTP for the combination with 90 Y-DOTA-AR. Preclinical large animal studies of VTP and multi-center phase 2 and 3 studies of localized prostate cancer have reported a dose dependent response rate that depends on the treatment conditions of WST-11 concentration and laser fluence (22–25). Further evaluation of these factors may be warranted.…”

Section: Discussionmentioning

confidence: 99%

“…Upon illumination, WST-11 generates reactive oxygen/nitrogen species such as superoxide, hydroxyl radicals and nitric oxide within the blood vessel, that mediate instantaneous arrest of the feeding arteries and draining veins producing an effect similar to profound, localized ischemia/reperfusion injury (6–8). Recent studies have demonstrated that permanent vascular arrest is limited to vessels smaller than 40 μm, which is well suited to the tumor microenvironment (9). We hypothesized that the ability of WST-11 VTP to permanently shut down the tumor circulation would reduce radiotracer washout from the tumor microenvironment and improve upon localized imaging and treatment effects.…”

Section: Introductionmentioning

confidence: 99%

Bombesin Antagonist-Based Radiotherapy of Prostate Cancer Combined with WST-11 Vascular Targeted Photodynamic Therapy

Kim

Zhang

Rosa

et al. 2017

Clinical Cancer Research

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Purpose DOTA-AR, a bombesin-antagonist peptide, has potential clinical application for targeted imaging and therapy in Gastrin Releasing Peptide receptor (GRPr) positive malignancies when conjugated with a radioisotope such as 90Y. This therapeutic potential is limited by the fast washout of the conjugates from the target tumors. WST-11 (Weizmann STeba-11 drug; a negatively charged water-soluble palladium-bacteriochlorophyll derivative, Tookad® Soluble) Vascular targeted photodynamic therapy (VTP) is a local ablation approach recently approved for use in early stage prostate cancer. It generates reactive oxygen/nitrogen species within tumor blood vessels, resulting in their instantaneous destruction followed by rapid tumor necrosis. We hypothesize that the instantaneous arrest of tumor vasculature may provide a means to trap radiopharmaceuticals within the tumor thereby improving the efficacy of targeted radiotherapy. Experimental design GRPr positive prostate cancer xenografts (PC-3 and VCaP) were treated with 90Y-DOTA-AR with or without VTP. The uptake of radioisotopes was monitored by Cherenkov luminescence Imaging (CLI). The therapeutic efficacy of the combined VTP and 90Y-DOTA-AR in PC-3 xenografts was assessed. Results CLI of 90Y-DOTA-AR demonstrated longer retention of radiotracer within the VTP treated PC-3 xenografts compared with the non-VTP treated ones (p < 0.05) at all time points (24–144 hours) post 90Y-DOTA-AR injection. A similar pattern of retention was observed in VCaP xenografts. When 90Y-DOTA-AR administration was combined with VTP, tumor growth delay was significantly longer than for the control or the mono-therapy groups. Conclusions Tumor vascular arrest by VTP improves 90Y-DOTA-AR retention in the tumor microenvironment thereby enhancing therapeutic efficacy.

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Nonthermal Ablation by Using Intravascular Oxygen Radical Generation with WST11: Dynamic Tissue Effects and Implications for Focal Therapy

Cited by 25 publications

References 41 publications

Detection of Treatment Success after Photodynamic Therapy Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Detection of Treatment Success after Photodynamic Therapy Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Treatment Effects of WST11 Vascular Targeted Photodynamic Therapy for Urothelial Cell Carcinoma in Swine

Bombesin Antagonist-Based Radiotherapy of Prostate Cancer Combined with WST-11 Vascular Targeted Photodynamic Therapy

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