Antivascular Treatment of Solid Melanoma Tumors with Bacteriochlorophyll-serine-based Photodynamic Therapy¶

Zilberstein, Judith; Schreiber, Smadar; Bloemers, M.; Bendel, Peter; Neeman, Michal; Schechtman, Edna; Kohen, Förtüne; Scherz, Avigdor; Salomon, Yoram

doi:10.1562/0031-8655(2001)0730257atosmt2.0.co2

Cited by 21 publications

(17 citation statements)

References 48 publications

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“…The clearance of Tookad is very fast, with a plasma half-life in the mouse typically ,1 h (A. Scherz, personal communication). Consistent with this, in several other tissues (including tumor and skin) studied in preclinical in vivo models (32), it has been observed that the light must be applied within a short time after (or even during) drug administration. In this regard, Tookad is similar to benzoporphyrin derivative monoacid ring ''a'' (Verteporfin; QLT, Vancouver, Canada), used for age-related macular degeneration, which is also activated while in the vascular system (38).…”

Section: Discussionsupporting

confidence: 58%

“…Hence, the observations here are directly relevant to assessing the likely clinical utility of Tookadbased PDT of prostate cancer, assuming that the response of the malignant tissue will not be less than that of normal prostate. The high vascularity of tumor tissue makes it a good target for Tookad-PDT because the effects are believed to be primarily vascular (32). Furthermore, in locally recurrent cancer after radical radiation therapy, the normal prostate tissue becomes relatively avascular (33,34), which may confer some selective sensitivity of the neovascularized tumor.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical trials are currently being designed, initially for treatment of patients with localized recurrence of disease after radiation therapy failure. The initial drug and light doses and dose rates, and the drug-light time intervals, will be based on the findings reported above, together with other preclinical toxicology and PDT-response data (23,32,35). Although this study and the initial trials are not predicated on there being an intrinsic selectivity for prostate cancer compared with normal prostate tissue, it will be of great interest to investigate whether this is the case.…”

Section: Discussionmentioning

confidence: 99%

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Preclinical Studies in Normal Canine Prostate of a Novel Palladium-Bacteriopheophorbide (WST09) Photosensitizer for Photodynamic Therapy of Prostate Cancer¶

Chen

Huang

Luck

et al. 2007

Photochemistry and Photobiology

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Photodynamic therapy (PDT) uses light to activate a photosensitizer to achieve localized tumor control. In this study, PDT mediated by a second‐generation photosensitizer, palladium‐bacteriopheophorbide WST09 (Tookad) was investigated as an alternative therapy for prostate cancer. Normal canine prostate was used as the animal model. PDT was performed by irradiating the surgically exposed prostate superficially or interstitially at 763 nm to different total fluences (100 or 200 J/cm2; 50, 100 or 200 J/cm) at 5 or 15 min after intravenous administration of the drug (2 mg/kg). Areas on the bladder and colon were also irradiated. The local light fluence rate and temperature were monitored by interstitial probes in the prostate. All animals recovered well, without urethral complications. During the 1 week to 3 month posttreatment period, the prostates were harvested for histopathological examination. The PDT‐induced lesions showed uniform hemorrhagic necrosis and atrophy, were well delineated from the adjacent normal tissue and increased linearly in diameter with the logarithm of the delivered light fluence. A maximum PDT‐induced lesion size of over 3 cm diameter could be achieved with a single interstitial treatment. There was no damage to the bladder or rectum caused by scattered light from the prostate. The bladder and rectum were also directly irradiated with PDT. At 80 J/cm2, a full‐depth necrosis was observed but resulted in no perforation. At 40 J/cm2, PDT produced minimal damage to the bladder or rectum. On the basis of optical dosimetry, we have estimated that 20 J/cm2 is the fluence required to produce prostatic necrosis. Thus, the normal structure adjacent to the prostate can be safely preserved with careful dosimetry. At therapeutic PDT levels, there was no structural or functional urethral damage even when the urethra was within the treated region. Hence, Tookad‐PDT appears to be a promising candidate for prostate ablation in patients with recurrent, or possibly even primary, prostate cancer.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Preclinical Studies in Normal Canine Prostate of a Novel Palladium-Bacteriopheophorbide (WST09) Photosensitizer for Photodynamic Therapy of Prostate Cancer¶

Chen

Huang

Luck

et al. 2007

Photochemistry and Photobiology

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“…This effect is more pronounced in treatment protocols that involve short light/drug intervals and/or more hydrophilic sensitizers (1 3). Differences between the response of the tumor and the normal tissue vasculature may provide the key in selecting the best treatment (14)(15)(16)(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: synthesis, solubility, phototoxicity, and the effect of serum proteins

Brandis¹,

Mazor²,

Neumark³

et al. 2005

Photochem Photobiol

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New negatively charged water-soluble bacteriochlorophyll (Bchl) derivatives were developed in our laboratory for vascular-targeted photodynamic therapy (VTP). Here we focused on the synthesis, characterization and interaction of the new candidates with serum proteins and particularly on the effect of serum albumin on the photocytotoxicity of WST11, a representative compound of the new derivatives. Using several approaches, we found that aminolysis of the isocyclic ring with negatively charged residues markedly increases the hydrophilicity of the Bchl sensitizers, decreases their self-association constant and selectively increases their affinity to serum albumin, compared with other serum proteins. The photocytotoxicity of the new candidates in endothelial cell culture largely depends on the concentration of the serum albumin. Importantly, after incubation with physiological concentrations of serum albumin (500-600 microM), WST11 was found to be poorly photocytotoxic (>80% endothelial cell survival in cell cultures). However, in a recent publication (Mazor, O. et al. [2005] Photochem. Photobiol. 81, 342-351) we showed that VTP of M2R melanoma xenografts with a similar WST11 concentration resulted in approximately 100% tumor flattening and >70% cure rate. We therefore propose that the two studies collectively suggest that the antitumor activity of WST11 and probably of other similar candidates does not depend on direct photointoxication of individual endothelial cells but on the vascular tissue response to the VTP insult.

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“…For technical reasons, the microvessel density could only be determined for post-PDT tumor tissue because removing a portion of the tumor before PDT would cause bleeding, interfering with the blood flow measurements. As previously already demonstrated, an accurate measure for vasculature shutdown is the change in microvessel density [10,17,19,[54][55][56][57][58][59][60][61][62].…”

Section: Resultsmentioning

confidence: 90%

Blood flow dynamics during local photoreaction in a head and neck tumor model

et al. 2015

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We have applied continuous blood flow dynamics, quantified with diffuse correlation spectroscopy (DCS), in investigating photodynamic therapy (PDT) induced local photoreaction in a head and neck tumor model. Photoclor (0.47 µmol/kg) was intravenously administered 24 h before PDT. Two types of fluence rates were implemented: Low fluence rate (14 mW/cm 2 ) and high fluence rate (75 mW/cm 2 ). The total delivered fluence was 100 J/cm 2 for both types. We observed that PDT induced substantial vascular shut down in both types. While the shutdown was persistent in tumors exposed to low fluence rate PDT, the shutdown was transient in tumors exposed to high fluence PDT. Loss of microvascular structures was confirmed by the microscopic analyses of tumor section following immunostaining for CD31. Blood flow dynamics related metrics were also strongly correlated with crosslinking of STAT3, a molecular marker of photoreaction. STAT3 analysis indicated that low fluence rate yields a substantially higher photoreaction, and thus, a more effective PDT. Our results indicate that non-invasive blood flow measurements can monitor the efficacy of PDT in real-time and potentially provide a feedback for its optimization.

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Antivascular Treatment of Solid Melanoma Tumors with Bacteriochlorophyll-serine-based Photodynamic Therapy¶

Abstract: ABSTRACT

Cited by 21 publications

References 48 publications

Preclinical Studies in Normal Canine Prostate of a Novel Palladium-Bacteriopheophorbide (WST09) Photosensitizer for Photodynamic Therapy of Prostate Cancer¶

Preclinical Studies in Normal Canine Prostate of a Novel Palladium-Bacteriopheophorbide (WST09) Photosensitizer for Photodynamic Therapy of Prostate Cancer¶

Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: synthesis, solubility, phototoxicity, and the effect of serum proteins

Blood flow dynamics during local photoreaction in a head and neck tumor model

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