Evaluation of the photosensitizer Tookad(R) for photodynamic therapy on the Syrian golden hamster cheek pouch model: Light dose, drug dose and drug-light interval effects[para]
We have evaluated the efficacy of the new photosensitizer (PS) Tookad(R) in photodynamic therapy (PDT) in vivo. This PS is a palladium-bacteriopheophorbide presenting absorption peaks at 762 and 538 nm. The light dose, drug dose and drug injection-light irradiation interval (DLI), ranging between 100 and 300 J/cm^sup 2^, 1 and 5 mg/kg and from 10 to 240 min, respectively, were varied, and the response to PDT was analyzed by staging the macroscopic response and by the histological examination of the sections of the irradiated cheek pouch. The level of PDT response, macroscopically and histologically, shows a strong dependence on the DLI, light dose and drug dose at the applied conditions in the normal hamster cheek pouch. A decay of the tissular response with increasing DLI is observed corresponding to a time of half-maximum response ranging from 10 to 120 min, depending on drug dose and light dose. The tissues affected at the lowest doses are predominantly the vascularized diffuse connective tissue situated between the inner and outer striated muscle (SM) layers as well as these muscle layers themselves. The highest response at the shortest DLI and the absence of a measurable response at DLI longer than 240 min at 300 J/cm^sup 2^ and drug dose of 5 mg/kg are characteristics of a predominantly vascular effect of this PS. This observation suggests that Tookad(R) could be effective in PDT of vascularized lesions or pathologies associated with the proliferation of neovessels.
Abbreviations: BPD-MA, benzoporphyrin derivative monoacid ring A; CT, diffuse connective tissue; DLI, drug injection-light irradiation time interval; LP, lamina propria; mTHPC, meta-(tetra-hydroxyphenyl)chlorin; Pd-Bpheid, palladium-bacteriopheophorbide; PDT, photodynamic therapy; PS, photosensitizet; SM, striated muscle.
Photodynamic therapy (PDT) is being developed as a treatment for cancer of the esophagus (1), bronchi (2,3) and bladder (4,5) as well as for other nononcological applications such as the treatment of age-related macular degeneration, with the recent approval of the benzoporphyrin derivative Visudyne(R) or Verteporfin(R) (6). PDT is also a successful noninvasive therapeutic modality for treating cutaneous neoplasm (7,8). Current photosensitizers (PS) (Photofrin(R) and Foscan(R)) accepted for the curative or palliative treatment of oncological indications still present strong drawbacks, such as prolonged cutaneous photosensitization, heterogeneous tissue response, scarring of healthy tissue and interpatient fluctuations (9,10). These drawbacks are partly due to the difficulties in predicting the response to the drug dose and to the lack of specificity for the targeted tissue. Therefore, applications of PDT are restricted to a limited number of clinical indications.
The further in vivo testing of new second-generation PS by preclinical assay remains an important goal in establishing the basis for clinical treatment. Because it is difficult to optimize many parameters in a clinical context for each new PS, using an animal model provides preclinical data of high interest for the clinical use of PDT.
This study describes the PDT properties of the PS Tookad(R), a palladium-metalated complex of bacteriopheophorbide (Pd-Bpheid) a (11,12), in terms of the response after treatment using different drug doses, drug-light intervals (DLI) and light doses. Tookad(R) has an absorption spectrum typical of the bacteriochlorin macrocycle, with a main absorption peak of the monomeric form in the near-infrared at a wavelength of 762 nm. The presence of an absorption band at this wavelength allows treatment with a longer-wavelength source, which results in a deeper penetration of the irradiation light (13). This feature enables a more efficient treatment of solid tumors or pigmented tissues, in particular if the interstitial approach is used. This advantage has been demonstrated by the deeper necrotic area obtained by a PS of the bacteriochlorin type (meta-(tetra-hydroxyphenyl)bacteriochlorin, [lambda]^sub abs^ = 740 nm) compared with the chlorin type (meta-(tetra-hydroxyphenyl)-chlorin [mTHPC], [lambda]^sub abs^ = 652 nm) (14). In vitro assays of bacteriochlorophyll derivatives demonstrate a higher phototoxic effect compared with hematoporphyrin derivatives (15,16). The PS Tookad(R) has an extremely low level of fluorescence, similar to the Pd-bacteriochlorophyll, which is characterized by a high intersystem crossing to the T^sub 1^ triplet state and a low fluorescence yield (17,18). Therefore, the monitoring of the PS concentration in vivo is not easily obtained by spectrofluorimetry. Only diffuse reflectance spectroscopy has been reported in the rabbit model, showing a peak concentration in the skin at DLI shorter than 30 min after injection (19). The difficulties in obtaining precise concentration measurements of Tookad(R) in vivo in the biological tissues have led to the more direct and informative-oriented approach of measuring the level of damage after PDT for various conditions.
PDT with Tookad(R) was used to test the elimination of prostatic tissue in a canine model (12) and on xenografted human prostatic small-cell carcinoma (20). Both studies showed the potential to strongly reduce the size of these tissues after PDT. These promising properties encouraged us to explore the effect of drug dose, light dose and DLI on the tissue response of the mucosae lining the ENT (ear, nose, throat) tract (upper aerodigestive tract). The hamster cheek pouch model has been previously used and mimics well the different tissue responses after PDT, both macroscopically and microscopically, of the human upper aerodigestive tract and esophagus (21-23). This model has been used to study the pharmacokinetics of PS such as mTHPC and benzoporphyrin derivative monoacid ring A (BPD-MA) (24). The measurement of the phototoxic effect of the tissue response in function of the DLI and of the threshold of response on real physiological systems is a decisive factor for the development of future protocols for PDT and is essential in the early phase of development of new PS. To optimize the therapeutic outcome of the PDT, three parameters (the drug dose [mg/kg], the DLI and the light dose [J/cm^sup 2^]) were varied in the healthy Syrian golden hamster cheek pouch model, and the resulting levels of response of the different tissues after treatment were measured.
The development of simple rule of thumb to predict a tissue response level for different values of the three clinical parameters (drug dose, DLI and light dose) is very interesting to predict the value of these parameters in future experiments and clinical trials. Therefore, the measured response after PDT was analyzed using two models: first, a simple elimination model with an exponential decay and second, a Gaussian model that matches more closely the observed data.
MATERIALS AND METHODS
One hundred and forty Syrian golden hamsters (male, average weight 135 + or – 50 g) were used for the photodynamic treatments on the normal cheek pouch. The study of the light doses, DLI and drug doses was conducted using four animals per condition. The animals were housed at room temperature, with a 12 h light and dark cycle. Food and drinking water were given ad libitum. All PDT experiments were performed under intraperitoneal anesthesia (ketalar 150 mg/kg and xylesine 15 mg/kg) and in accordance with protocols approved by the Experimental Animal Ethics Committee of the CHUV Hospital in Lausanne.
Photosensitizer. The WST09 (CA Reg. no. 274679-00-4), manufactured under the name Tookad(R) by Steba Biotech (The Hague, The Netherlands), is a Pd-Bpheid a (11,12). It is an amphiphilic anionic compound at neutral pH. The solution of Tookad(R) was used directly as the stabilized micellar solution in aqueous medium provided by Negma-Lerads (Magny-Les-Hameaux, France) at 5 mg/mL (Batch no. L565331).
Solutions at 2 and 1 mg/mL were obtained by dilution in a formulation buffer at pH 7.4 (Negma-Lerads).
The Tookad(R) solution was administered by intracardiac injection at 5, 2 or 1 mg/kg of body weight. Depending on animal weight, the injection volume remained between 90 and 200 [mu]L.
The animals were sacrificed 4 days after PDT, and the cheek pouch was excised for macrophotography and histological preparation.
Photometry. Irradiation at 762 nm was performed with a 4 W diode Laser Ceralas PDT 763 (CeramOptec GmbH, Bonn, Germany).
Light delivery. PDT on the mucosae of the hamster cheek pouch was carried out using a light distributor with a 12 mm diameter cylindrical radial diffuser equipped with a circular side window of 1 cm^sup 2^, producing a homogeneous irradiation onto the inner cheek pouch in direct contact with the diffuser as described in former publications (25,26).
A light dose rate of 150 mW/cm^sup 2^ was used for all treatments. The cylindrical diffuser was calibrated using an integration sphere by comparison with a frontal light diffuser (FD-1, Medlight S.A., Ecublens, Switzerland), delivering 150 mW measured with a power-meter (Spectra Physics Power-meter 407A, Mountain View, CA).
The light doses used for PDT were 100, 200 and 300 J/cm^sup 2^. DLI of 10, 30, 120 and 240 min, defined as the duration between the end of injection and the beginning of the irradiation, were used.
The treated cheek pouches were resected, photographed and then fixed in 5% buffered formalin (pH 7.0). The fixed specimens were paraffin embedded, sectioned in 5 [mu]m thick slices and stained with hematoxylin and eosin for histological examination. For each animal, the necrotic area was examined in serial sections to evaluate the depth of the histological necrosis extending to the different mucosal layers.
Determination of the spectral properties of Tookad(R)
Absorption spectroscopy of Tookad(R) in visible-near-infrared was performed by dilution of the solution of Tookad(R) at 25[degrees]C to a concentration of 0.01 mg/mL in the formulation buffer. The spectra were recorded using a Cary-Varian 500 Scan spectrophotometer (Varian Australia Pty Ltd., Mulgrave, Victoria, Australia), with the formulation buffer as reference.
Evaluation of the photodynamic effect
The assessment of the necrosis was made 4 days after PDT. To evaluate the depth and extent of the PDT, we used a tissue damage scale graded from O to 4. This scale is based on the extension of the macroscopic necrosis, the formation of fibrin, and the extension of necrosis to the different mucosal layers after histological examination of the tissue sections, in a similar way to the previous studies with different PS (24,27,28,22).
Histologically, the tissue damage scale is related to the number of layers of tissues that are necrosed as well as the lateral extension of the necrosis. The grading of the response was expressed following the tissue damage scale summarized in Table 1.
Modeling of the response level
The DLI-dependent tissue response (A) to PDT was analyzed by following two models: an exponential decay and a Gaussian decay. If one considers a simple elimination model, the drug concentration follows, in a first approximation, an exponential decay. All the maximal responses are observed for the shortest DLI of 10 min, meaning that the duration of the accumulation of the PS in the tissue is not longer than 30 min. The dependence of the initial response at DLI = 10 min was better fitted, as shown below, by the square root of the light dose multiplied by the drug dose than by direct proportionality with the light dose or the drug dose.
light dose in J/cm^sup 2^, and the drug dose in mg/kg.
Modeling and least-square analysis were conducted using the software MathCAD 2000 from Mathsoft Engineering & Education, Inc. (Cambridge, MA).
Spectral properties of Tookad(R)
The absorption spectrum of the Tookad(R) diluted in a formulation buffer shows the two Q bands typical for the bacteriochlorin cycle, which can be used for PDT: a first one in the near-infrared at 762 nm (molar absorption coefficient [epsilon] = 88 500 L mol^sup -1^ cm^sup -1^) and a second one in the green at 538 nm ([epsilon] = 23 100 L mol^sup -1^ cm^sup -1^) as shown in Fig. 1. These two bands correspond to the absorption maxima of bacteriochlorophyll substituted with palladium in the presence of a coordinating solvent (29).
Macroscopic aspects of the tissue reaction
The animal model of the Syrian hamster cheek pouch allows PDT to be performed on a controlled surface with different layers of tissues, representative of the human aerodigestive tract. For the response levels 3 and 4, edema of the cheek pouch was observed 1 day after PDT, and the inflammatory reaction as well as necrosis developed during the following days. Four days after PDT, the analysis of the induced necrosis allowed the determination of the PDT parameters producing damage above a defined threshold. The treatment of tumors requires knowledge of the conditions generating limited tissue damage to the healthy mucosa and the threshold conditions for obtaining a response after PDT.
To exclude all thermal effects due to irradiation at 762 nm and any effect due to the possible interaction between the formulation buffer and irradiation, two blank series of four animals each were carried out: (1) irradiation at 762 nm with a light dose of 300 J/cm^sup 2^ and a light dose rate of 150 mW/cm^sup 2^ without PS and without injection of the formulation buffer and (2) irradiation at 762 nm with a light dose of 300 J/cm^sup 2^ and a light dose rate of 150 mW/cm^sup 2^ after injection of the formulation buffer without PS. In both blank series, no induced responses were observed (level 0), ensuring that all necroses were effectively due to the photodynamic effect of Tookad(R).
The response level measured according to the tissue damage scale is shown in the form of a histogram in function of the DLI and drug doses of 1, 2 and 5 mg/kg in Figs. 2a, 3a, 4a and for irradiation at light doses of 300, 200 and 100 J/cm^sup 2^, respectively. The typical standard deviation of results is + or -0.6 on the tissue damage scale. The analysis of the graphs (Figs. 2-4) shows that, for each drug dose, a sharp decrease in response is observed in function of the DLI: for DLI > 120 min at 5 mg/kg and for DLI > 30 min at 2 mg/kg. This means that a significant threshold level of drug is necessary to produce a measurable tissue response. The result in terms of the light dose (J/cm^sup 2^) presents a major shift between 100 and 200 J/cm^sup 2^. At 100 J/cm^sup 2^, the only condition that results in a damage of level > or =2 is the shortest DLI of 10 min with a drug dose of 5 mg/kg. The global difference between the response at 200 and 300 J/cm^sup 2^ is smaller than that between 100 and 200 J/cm^sup 2^: six conditions give a damage level of > or =2 in both light doses. Moreover, the conditions separating a tissular effect from an absence of measurable response arc identical for both light doses of 200 and 300 J/cm^sup 2^.
The typical time constant k^sub decay^ of Tookad(R) fitted by an exponential decay following an elimination model (Eq. 1) is k^sub decay^ = 0.011 min^sup -1^, corresponding to a time of half-elimination of 63 min. This represents a short clearance of the Tookad(R) from all the tissues in the cheek pouch, with a half-life comparable with the longest irradiation time (33 min for a light dose of 300 J/cm^sup 2^). Nevertheless, examination of the graphs (Figs. 2-4) shows clearly that an exponential decay cannot describe the dependence of the level of response in function of the DLI. The analysis of the response (Figs. 2-4) shows that a lower drug dose or a lower light dose induces a faster decay. An increase in drug dose can be compensated by a decrease in light dose, expressing a reciprocity between light dose and drug dose in the limit measured. Empirically, the level of response A in all the irradiation conditions can be better fitted for visual support by the Eq. 2, representing a Gaussian function of the DLI. It should be noted that the constant, [gamma], is not a time constant, and therefore it cannot be compared with k^sub decay^. The constant, [gamma], expresses the dependence of the level of response in function of the DLI, drug dose and light dose in the present system. A value of [gamma] = 7 + or – 1 was used for a better fit of the data. Different organs or tissues would have different values of [gamma], the larger the constant the faster the decay of the response of the tissue. A plot of the measured responses after PDT versus the calculated response following Eqs. 1 and 2 presents a linear correspondence with a correlation coefficient of r = 0.85 and 0.93, respectively, as shown in Fig. 5. The Gaussian model presents a belter correlation and less bias with the observed response than the exponential model.
The different tissue layers are stacked in the mucosae in the following order from the irradiation side: epithelium (e), lamina propria (LP), inner striated muscle (SM), diffuse connective tissue (CT), outer SM and skin (S). The histological analysis of the tissue section has shown that necrosis at the lowest doses appears at the level of the vascularized CT situated between the inner and outer SM layers and only with larger therapeutic doses at the level of the inner epithelial layer. Necrosis of response levels 1 and 2 occurs therefore in the submucosal layer first, preserving the epithelial tissue of the mucosa, which is in direct contact with the light diffuser. In these conditions of response (levels 1 and 2), the epithelium of the mucosa exposed to the highest fluence presents no damage in contrast to the cellular part of vascularized CT and SM as shown on the histological section (Fig. 6). The epithelial tissue of the mucosae, which is in direct contact with the light diffuser, was preserved at the level of responses 1 and 2 and presented no damage as shown on the histological section (Fig. 5). This observation can be explained by a lower vascularization of the epithelial layer compared with the CT layer and therefore a lower local concentration of the PS at these short DLI. At a response level 2, the histological sections show an edema of the connective tissue and often show vascular occlusions and stasis as well as the beginning of an invasion by polymorphonuclear cells. At a response level 3, the necrolytic damage reaches the epithelial tissues, all layers of muscle and the connective tissue, and extensive edema is observed. At a response level 4 (Fig. 7), the necrosis extends across all the tissues, reaching the external epithelium (outside skin), corresponding to a transmural necrosis. At both levels 3 and 4, the extensive necrosis is associated with extensive cell death as shown by the disappearance of cell nuclei, the disappearance of the muscle microstructure, strong invasion by polymorphonuclear cells (strong inflammatory response) and extensive edema.
From these observations at damage levels 1 and 2, a contrast of damages for the vascularized CT and SM is induced by Tookad(R) after the PDT as seen in Fig. 6. The infiltration of neutrophils and the vascular occlusions in the CT are the consequence of a primary effect on microvasculature.
In this study, we measured the photodynamic activity of the new PS Tookad(R) in function of three critical parameters used in clinical PDT: the drug dose, the DLI and the light dose. In clinical applications, it is essential to obtain a complete tumor response while minimizing the risk of complications. Thus, adjustment of these parameters to get a particular level of response and to improve the therapeutic results is mandatory. The hamster cheek pouch model is very helpful in this context because it ensures to apply a controlled dosimetry of the light delivered on a super-position of histologically different layers of tissue, which allows the study of the level of necrosis after PDT.
The currently approved PS for oncological indications (Foscan(R) and Photofrin(R)) present a pharmacodynamic profile with phototoxic effects well over 100 h after injection (30,31). Such pharmacodynamics with potentially harmful PS in the presence of light in the skin or blood remains a drawback. Therefore, the interest in PS with much shorter clearance times has increased. Tookad(R) presents a rapid decay of the response in terms of the DLI, with all responses limited to DLI
Similar types of pharmacodynamics have been recorded for BPD-MA (Verteporfin(R) and Visudyne(R)), which exhibit rapid blood clearance, with a predominantly vascular localization (32).
In vivo models of the PDT response in function of the drug dose, the light dose and the DLI have been reported to study other PS such as Photofrin(R), aluminum sulfonated phthalocyanine in the rat (33,34), and confirm the concept of a threshold of absorbed photons by the PS in the tissue responsible to induce a defined level of response. In the case of Tookad(R), the threshold levels of drug that generate no tissue damage are obtained at DLI longer than 120 min at 5 mg/kg, DLI longer than 30 min at 2 mg/kg and DLI longer than 10 min at 1 mg/kg with a light dose of 200 J/cm^sup 2^. The fast decay of the response and the absence of response for DLI of 240 min at a light dose of 300 J/cm^sup 2^ and a drug dose of 5 mg/kg are characteristics of a PS with a rapid elimination from the tissues of the cheek pouch.
A contrast in damage is observed in favor of the vascularized CT and the SM as shown on the resected specimens presenting a level 2 response. At higher levels of damage, the epithelium is necrosed essentially due to the necrosis of the submucosal layer. This tissue response is in contrast to other PS such as mTHPC, which accumulates preferentially at longer DLI (>50 h) in the epithelial tissue and in the smooth muscle and has a much lower clearance (24). The observed stases and vascular occlusions combined with the rapid decay and absence of response at DLI longer than 120 min indicate a predominantly vascular effect of Tookad(R). These results are in agreement with the study on prostate canine model, in which the connective tissue and fibromuscular tissue were damaged as was glandular tissue, depending on microanatomical regions (12). In the canine model, the severe necrotic regions were correlated with destruction of vascular structure, in agreement with the observation on the hamster cheek pouch.
Because of the limited number of experimental DLI tested, only a model with a single independent variable ([gamma]) was selected to Ht the experimental data. The response level in function of the [Delta]t can be modeled, as a practical rule of thumb for Tookad(R), by a Gaussian decay in function of the DLI, drug dose and light dose. This model closely describes the observation of a well-delimited region of necrosis produced by Tookad(R), corresponding to the tissues above the threshold level of reaction. This response type is confirmed by the sharply defined boundary of PDT-induced lesion reported in the canine prostate model (12). In the present study, the modeling of the response level equally suggests a drug dose-light dose reciprocity in the ranges studied, at least for DLI shorter than 120 min, meaning that a decrease in the light dose can be compensated by an increase in the drug dose. The study of Photofrin, mTHPC and bacteriochlorin in mouse also suggested a reciprocity drug-light dose in a defined range (35).
The vascular effect of Tookad(R) is an advantage for several clinical applications in which neovascularization plays a significant role (36), and its rapid elimination ensures the reduction of side effect such as skin photosensitization. Therefore, Tookad(R) might be well suited for the treatment of lesions sensitive to neoangiogenesis or vascularized tumors, restenosis after angioplasty (37) or chronic inflammatory reactions such as in rheumatoid arthritis (38).
Tookad(R) can be activated at relatively longer wavelengths than other PS, which permits a deeper light penetration into the tissues, particularly in a range in which most tissue pigments do not absorb, extending the action to interstitial PDT as shown on the canine prostate model (12).
Therefore, Tookad(R) might be well suited for the treatment of lesions sensitive to the neoangiogenesis or neovascularized tumor as well as already vascularized tumor (39). The treatment of atherosclerotic plaques (40) with other vascular PS has shown promising results on animal models, as well as on chronic inflammatory reaction in rheumatoid arthritis (41,43). These pathologies are potential targets for PS with a fast clearance such as Tookad(R).
Tookad(R) presents also an absorption peak in the green (538 nm), allowing the use of irradiation at wavelength presenting a lower tissue penetration (42) and opening the field of applications to superficial cancers in hollow organs, with a major reduction of the risk of fistulae or stenoses (43). Indeed, PDT at a shorter wavelength is already used to selectively treat a certain thickness of tissue in the cases of superficial bladder tumors (44) and for early cancers of the esophagus (43).
Finally, it should be noted that the presence of a free functional group in the molecular structure of Tookad(R) may enable the development of derivatives by coupling with other molecules for targeting (45).
In conclusion, the Tookad(R) presents the profile of a predominantly vascular PS with a fast decay of the response to PDT in function of the DLL The PDT response presents an on-off character in this animal model, making the drug dose, the light dose and the DLI critical parameters.
Acknowledgements-This work was supported by Steba Biotech (The Netherlands) and the Swiss National Science Foundation Grant 20-63716.00. The authors are grateful to Charlotte Fontolliet from the Institute of Pathology, University of Lausanne, Lausanne, Switzerland, for help with the histological interpretation and to Steba Biotech, The Hague, The Netherlands, and Negma-Lerads, Magny-Les-Hameaux, France, for kindly providing Tookad(R).[para] Posted on the website on 30 July 2003
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Francois Borle*1, Alexandre Radu2, Philippe Monnier2, Hubert van den Bergh1 and Georges Wagnieres1
1 Institute of Environmental Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland and Department of Otolaryngology, Head and Neck Surgery, CHUV Hospital, Lausanne, Switzerland
Received 6 May 2003; accepted 18 July 2003
* To whom correspondence should be addressed at: Institute of Environmental Engineering, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland. Fax: 41-0-(21)-693-36-26; e-mail: francois. firstname.lastname@example.org
Copyright American Society of Photobiology Oct 2003
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