Long circulating half-life and high tumor selectivity of the photosensitizer meta-tetrahydroxyphenylchlorin conjugated to polyethylene glycol in nude mice grafted with a human colon carcinoma

In a model of nude mice bearing a human colon carcinoma xenograft, the biodistribution and tumor localization of meta-tetrahydroxyphenylchlorin (m-THPC) coupled to polyethylene glycol (PEG) were compared with those of the free form of this photosensitizer used in photodynamic therapy (PDT). At different times after i.v. injection of both forms of ¹²⁵I-labeled photosensitizer, m-THPC-PEG gave on average a 2-fold higher tumor uptake than free m-THPC. In addition, at early times after injection, m-THPC-PEG showed a 2-fold longer blood circulating half-life and a 4-fold lower liver uptake than free m-THPC. The tumor to normal tissue ratios of radioactivity concentrations were always higher for m-THPC-PEG than for free m-THPC at any time point studied from 2 to 96 hr post-injection. Significant coefficients of correlation between direct fluorescence measurements and radioactivity counting were obtained within each organ tested. Fluorescence microscopy studies showed that m-THPC-PEG was preferentially localized near the tumor vessels, whereas m-THPC was more diffusely distributed inside the tumor tissue. To verify whether m-THPC-PEG conjugate remained phototoxic in vivo, PDT experiments were performed 72 hr after injection and showed that m-THPC-PEG was as potent as free m-THPC in the induction of tumor regression provided that the irradiation dose for m-THPC-PEG conjugate was adapted to a well-tolerated 2-fold higher level. The overall results demonstrate first the possibility of improving the in vivo tumor localization of a hydrophobic dye used for PDT by coupling it to PEG and second that a photosensitizer conjugated to a macromolecule can remain phototoxic in vivo. Int. J. Cancer 76:842–850, 1998.© 1998 Wiley-Liss, Inc.     

Fluorescence detection of chlorine E6 based photosensitizer in urinary bladder tumors

The authors present pilot experience with accumulation and distribution of chlorine E6 based photosensitizer in unaffected mucosa and tumor of human urinary bladder (UB). Local fluorescence spectroscopy in vivo has shown that 2-3 hours after intravenous injection of the photosensitizer in a dose 1 mg/kg its exogenic fluorescence is detected in the tumor but not in unaffected UB mucosa. This indicates selective accumulation of the sensitizer in UB tumors. Thus, chlorine E6 based photosensitizer can be used for fluorescence-based diagnosis of UB cancer and treatment of such patients with photodynamic therapy. Application of local fluorescence spectroscopy allows monitoring of photobleaching in the course of treatment session.     

Liposomal quercetin efficiently suppresses growth of solid tumors in murine models.

PURPOSE: Quercetin is a potent chemotherapeutic drug. Clinical trials exploring different schedules of administration of quercetin have been hampered by its extreme water insolubility. To overcome this limitation, this study is aimed to develop liposomal quercetin and investigate its distribution in vivo and antitumor efficacy in vivo and in vitro. EXPERIMENTAL DESIGN: Quercetin was encapsulated in polyethylene glycol 4000 liposomes. Biodistribution of liposomal quercetin i.v. at 50 mg/kg in tumor-bearing mice was detected by high-performance liquid chromatography. Induction of apoptosis by liposomal quercetin in vitro was tested. The antitumor activity of liposomal quercetin was evaluated in the immunocompetent C57BL/6N mice bearing LL/2 Lewis lung cancer and in BALB/c mice bearing CT26 colon adenocarcinoma and H22 hepatoma. Tumor volume and survival time were observed. The mechanisms underlying the antitumor effect of quercetin in vivo was investigated by detecting the microvessel density, apoptosis, and heat shock protein 70 expression in tumor tissues. RESULTS: Liposomal quercetin could be dissolved in i.v. injection and effectively accumulate in tumor tissues. The half-time of liposomal quercetin was 2 hours in plasma. The liposomal quercetin induced apoptosis in vitro and significantly inhibited tumor growth in vivo in a dose-dependent manner. The optimal dose of liposomal quercetin resulted in a 40-day survival rate of 40%. Quantitative real-time PCR showed that liposomal quercetin down-regulated the expression of heat shock protein 70 in tumor tissues. Immunohistochemistry analysis showed that liposomal quercetin inhibited tumor angiogenesis as assessed by CD31 and induced tumor cell apoptosis. CONCLUSIONS: Our data indicated that pegylated liposomal quercetin can significantly improve the solubility and bioavailability of quercetin and can be a potential application in the treatment of tumor.     

Comparison of free and liposome encapsulated doxorubicin tumor drug uptake and antitumor efficacy in the SC115 murine mammary tumor

Tumor drug uptake and antitumor efficacy of free and liposomal doxorubicin (DOX) were determined in the SC115 Shionogi mouse mammary tumor. Liposomal DOX systems were prepared by pH gradient-driven drug encapsulation in 170 nm egg phosphatidylcholine/cholesterol (55:45, mol ratio) vesicles. Intravenous injection of free DOX at 6.5 mg/kg, the maximum tolerated dose for free drug in the multiple dose therapy regimen, resulted in tumor-associated drug levels of 2.0 micrograms/g tissue at 1 h which remained constant over 24 h. Liposomal DOX injected at 6.5 mg/kg led to an accumulation of drug in the tumor from 2.6 micrograms/g tissue to 5.5 micrograms/g tissue between 1 h and 24 h, respectively. Increasing the dose of liposomal DOX to 13.0 mg/kg increased tumor drug uptake levels to 5.7 micrograms/g and 10.2 micrograms/g tissue at 1 h and 24 h, respectively. Administration of free or liposome encapsulated DOX every 7 days for 3 weeks resulted in a dose-dependent decrease in tumor growth rate. However, liposomal DOX injected at 6.5 mg/kg exhibited enhanced tumor growth inhibition compared to an equivalent dose of free drug. Further, the ability to administer increased doses of the less toxic liposomal DOX not only resulted in a greater inhibition of tumor growth but also significantly reduced tumor weight. Tumors weighing as much as 5 g were diminished to less than 0.5 g upon treatment with liposomal DOX at a dose of 13 mg/kg. In addition, groups receiving the highest liposomal DOX dose exhibited 25% complete tumor regression which persisted over the 50-day study period. These results demonstrate the ability of appropriately designed liposomal DOX systems to significantly enhance the delivery and retention of drug at solid tumor sites, resulting in increased therapeutic activity.     

Basic study on hepatic artery chemoembolization and tumor selective drug targeting by temperature-sensitive liposome with local hyperthermia

Temperature-sensitive liposome entrapping adriamycin (L-ADM) was administered into the hepatic artery of hepatic tumor-bearing rats. The embolization of the hepatic artery with liposome and bio-distribution of ADM were examined. ADM concentration in blood showed a peak at 30 min after local heating on tumor (the heating had been performed for 6 min at 41-42 degrees C 2 hr. after injection). The value at the peak was about 3 times higher than that just before heating. ADM administered in liposomal form showed a high accumulative property to tumor with heating; ADM concentration in tumor 8 hr. after administration of ADM in liposomal form was about 5 times higher than that in liver and about 30 times higher than that in the heart, and about 20 times higher than that in tumor after administration in free form.     

Efficacy of antitumoral photodynamic therapy with hypericin: relationship between biodistribution and photodynamic effects in the RIF-1 mouse tumor model.

We investigated the hypericin-mediated PDT effects on the tumor and normal skin and in correlation with its biodistribution. These studies were carried out on C3H mice bearing RIF-1 tumors. The hypericin distribution and PDT effects were recorded at different intervals (0.5-24 hr) after intravenous injection of a 5-mg/kg dose of hypericin. After administration, rapid biphasic exponential decay was observed in the plasma drug concentration. It was found that hypericin was preferentially bound to the plasma lipoproteins. The tumor drug levels increased rapidly over the first few hours and reached a maximum around 6 hr after injection. In contrast, PDT efficacy was maximal when irradiation was performed at 0.5 hr after hypericin administration, which led to 100% cure. The PDT efficacy decreased rapidly as the administration-irradiation interval was prolonged. No tumor cure was obtained at the 6-hr interval, even though it was at this time that the tumor drug level peaked. Fluorescence microscopic studies showed that hypericin was mainly confined within the tumor vasculature at 0.5 hr after injection, whereupon it rapidly diffused to the surrounding tumor tissue. At 6 hr, a strong hypericin fluorescence was observed in the tumor tissue with only faint fluorescence within the vasculature, whereas at 24 hr the fluorescence in the tumor also decreased and became more diffused, and no fluorescence could be seen in the tumor vasculature. Like the tumor response, skin reactions were also found to be much more dramatic at short administration-irradiation intervals. Hypericin distribution and PDT response studies revealed a close correlation between the plasma drug level and the PDT effects, which suggests that vascular damage is the primary effect of hypericin-mediated PDT in this tumor model.     

Biodistribution and photodynamic therapy with hypericin in a human NPC murine tumor model

The use of photodynamic therapy (PDT) for the treatment of recurrent and residual nasopharyngeal carcinoma (NPC) has been encouraging. To determine the potential of hypericin as a PDT tool in the treatment of NPC, we investigated the effect of hypericin-mediated PDT on subcutaneously implanted NPC/HK1 tumor cells and the relationship between the biodistribution of hypercin and photodynamic effects. The plasma hypericin level increased rapidly and reached its peak concentration at 1 h after injection. The uptake of hypercin in tumor tissue was maximal 6 h after hypericin administration, at which time the drug concentration in the circulation was low. The efficacy of hypericin-mediated PDT was maximal when light irradiation was performed at 6 h after hypericin administration. Tumor relative regression percentage (RRP) induced by PDT at 1-h interval was comparable to that at 6-h interval, whereas light treatment performed at other time intervals induced less tumor RRP, albeit significant when compared to the control group. Hypericin appears to be an effective photosensitizer for the treatment of NPC. It is likely that hypericin-mediated PDT induces both vascular damage and direct tumor cell killing, thereby bringing about tumor necrosis and shrinkage.     

Postradiation high-grade myofibroblastic sarcoma of the prostate -- a rare entity of prostatic tumors -- responding to liposomal Doxorubicin

BACKGROUND: Prostatic postradiation sarcoma (PRS) is a very rare malignant disease with a dismal prognosis. Aggressive surgical resection is the most widely used therapy for PRS. Chemotherapy so far has been unsatisfactory, with doxorubicin being the only drug with established activity. Liposomal doxorubicin has been shown to have comparable activity and a more favorable toxicity profile compared with unpegylated doxorubicin. CASE REPORT: A 78-year-old man presented with high-grade myofibroblastic sarcoma 13 years after curatively intended pion irradiation of the prostate with 30 Gy. He was treated with liposomal doxorubicin 40 mg/m(2) every 4-6 weeks up to now with a total dose of 800 mg. Partial remission has been achieved after 17 months of treatment with liposomal doxorubicin. Toxicity is minimal with palmoplantar erythrodysesthesia WHO grade 1, resolving completely after extending treatment intervals to 6 weeks. RESULT: Liposomal doxorubicin led to a sustained tumor stabilization over 17 months in a patient with prostatic postradiation high-grade sarcoma. Postradiation sarcoma (PRS) usually has a dismal prognosis and only very limited therapeutic possibilities. As in sarcomas of different origin, anthracyclines including liposomal doxorubicin seem to have potential antitumor activity in postradiation sarcoma of the prostate.     

Photodynamic therapy of locoregional breast cancer recurrences using a chlorin-type photosensitizer

Chest wall recurrences are a frequent problem in patients treated by mastectomy for breast cancer. Surgery and ionizing radiation are established treatment modalities in these cases. Photodynamic therapy (PDT) provides an alternative treatment modality using a photosensitizer and laser light to induce selective tumor necrosis. PDT was performed as compassionate use in 7 patients aged 57.6 years (+/-12.6 SD). A total of 89 metastatic skin nodes were treated in 11 PDT sessions. As photosensitizer meta-tetra(hydroxyphenyl)chlorin (m-THPC) was applied intravenously. Patients (n = 3) photosensitized with a drug dose of 0.10 mg/kg bodyweight were irradiated 48 hr after drug application at a lightdose of 5 J/cm(2). Patients (n = 4) were illuminated by an optical dose of 10 J/cm(2) 96 hr after photosensitization with 0.15 mg/kg. Laser light at a wavelength of 652 nm was generated by a diode laser and applied by a front lens light diffuser using a fluence rate of 20--25 mW/cm(2). PDT using m-THPC resulted in complete response in all patients. Response to treatment did not differ when using the 2 different drugdose protocols. Healing time depended mainly on the size of the illumination field but not on the lightdose. Pain score usually raised 1 day after PDT and lasted at higher levels for about 10 days. Healing time usually ranged between 8--10 weeks. Photodynamic technique offers a minimal-invasive, outpatient treatment modality for recurrent breast cancer on the chest wall with few side effects, high patient's satisfaction and with possible repetitive application.     

Phthalocyanine: a new photosensitizer in photodynamic therapy

Photodynamic therapy (PDT) with hematoporphyrin derivative (HpD) combined with laser irradiation has been introduced as a new promising clinical method for the treatment of various malignancies. Recently, sulphonated aluminum chloro phthalocyanine (A1PC) has attracted a great deal of attention as a new photosensitizer. Tissue concentrations and photodynamic effects of A1PC and HpD, that has been using clinically in PDT, were determined in nude mice transplanted bladder tumors. According to the tissue distribution of A1PC and HpD at various times after administration, the ratios of tumoral concentration to muscular concentration of A1PC were higher than those of HpD, and skin concentration of A1PC at 24 to 168 hrs. after administration was lower than that of HpD. These results suggest that more A1PC localizes in malignant tumor than HpD, and there is a possibility of reducing skin photosensitivity with A1PC as compared with HpD. The regression of tumor volume after PDT was higher with A1PC and laser light at 670 nm than with HpD and laser light at 630 nm.     

Therapy of murine liver metastases by administration of MDP encapsulated in liposomes

In a reproducible murine model of liver metastases, it was demonstrated that liposomal muramyl dipeptide (MDP) as an adjuvant therapy reduces and prevents the development of metastases. C26 colon adenocarcinoma cells were injected into the spleen (5 x 10(4) cells per mouse) of syngeneic BALB/c mice. On day 3, the spleen was removed to prevent a large tumor burden in the spleen. On day 17, 100% of the mice had developed tumor foci in the liver. Liposomal MDP treatment consisted of the i.v. or i.p. administration of 1 mumol of liposomal lipid containing 5 micrograms of MDP per mouse for ten consecutive days. When therapy was initiated two days after tumor cell inoculation, the number of metastases that had developed on day 17 was strongly reduced compared to control mice. Approximately 20% of the mice were free of liver metastases. Initiation of therapy two days prior to tumor cell inoculation enhanced the effect significantly: about 45% of the mice were free of metastases on day 17. The treatment protocol for survival studies was slightly different; liposomal MDP was administered on the first six consecutive days followed by administration twice weekly, through day 24. Control mice died between day 21 and 33 after tumor cell inoculation, whereas liposomal MDP treated mice died between day 26 and 46 with 1 out of 25 mice surviving for more than 120 days. The mortality of the liposomal MDP treated mice that were free of liver metastases was caused by a local tumor at the site of operation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tumor-associated antigens as immunotherapy targets

The potential of liposomes to act as immunoadjuvant carriers of tumor-associated antigens (TAA) has been investigated. The incorporation of B16 melanoma TAA within liposomes resulted in immunological recognition by non-tumor-bearing mice, and subsequent inhibition of tumor growth upon tumor challenge. The immunogenicity and protective activity were enhanced by the concomitant incorporation of a lipophilic immunoadjuvant, MDP-GDP, in the liposome preparation. The ability of liposomal preparations to augment the immunogenicity of a human oncofetal antigen, CEA, was also studied. The incorporation of CEA within liposomal carriers resulted in immunological recognition in mice at doses (0.1 micrograms) significantly less than required in Freund's complete adjuvant (25 micrograms), maximal responsiveness being found with liposomal-CEA-MDP-GDP preparations. Liposomal TAA vaccines may therefore require the presence of immuno-adjuvant-active agents for the induction of effective immunological responses in individuals at risk from recurrent disease.     

Folate receptor targeted delivery of liposomal daunorubicin into tumor cells

BACKGROUND: The folate receptor (FR) is amplified in a wide variety of human tumors. Thus, targeting cytotoxic therapies to FR is a promising strategy for chemotherapy. MATERIALS AND METHODS: FR-targeted liposomal daunorubicin (f-L-DNR) was compared to non-targeted liposomal DNR (L-DNR) for cellular uptake and cytotoxicity in FR-expressing cells. Liposomal DNR retention was evaluated for liposomes loaded with either sodium citrate or ammonium sulfate as the trapping agent. The cellular uptake of liposomal DNR was determined by flow cytometry and fluorometry measurements while cytotoxicity was determined by the 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: Liposomal DNR retention was superior for liposomes prepared using ammonium sulfate. Cellular uptake of f-L-DNR in KB oral carcinoma cells, Chinese hamster ovary (CHO-FR-beta), and KG-1 human acute myelogenous leukemia cells were 9.4, 40, and 4,6-fold higher than non-targeted L-DNR, respectively. The cytotoxicity of f-L-DNR in KB and CHO-FR-beta cells was 18 times and 49 times higher than L-DNR, respectively. Both cellular uptake and cytotoxicity of f-L-DNR could be inhibited by 1 mM folic acid. CONCLUSION: FR-mediated delivery of liposomal DNR to FR-expressing cells increases DNR cellular uptake and cytotoxicity. Therefore, therapeutic evaluation in relevant animal models is warranted.     

Uptake and kinetics of 14C-labelled meta-tetrahydroxyphenylchlorin and 5-aminolaevulinic acid in the C6 rat glioma model.

Meta-tetrahydroxyphenylchlorin (m-THPC) and 5-aminolaevulinic acid (5-ALA) are two second-generation photosensitizers which are currently under investigation for photodynamic therapy (PDT) and photodynamic diagnosis (PDD). So far, the experience with these photosensitizers for use within brain tumours is limited. We examined the distribution and retention of 14C-labelled m-THPC and [14C]5-ALA in the rat C6 glioma brain tumour model. After intraperitoneal injection of m-THPC (71,909 d.p.m. microl(-1); 0.16 mg ml(-1) m-THPC; 0.3 mg kg(-1)), the following activities were found after 36 h: brain tumour 223,664 d.p.m. g(-1), brain contralateral to the tumour side 2567 d.p.m. g(-1), liver 369,959 d.p.m. g(-1) and skin 55,197 d.p.m. g(-1); 100,000 d.p.m. corresponding to 0.22 microg of m-THPC. After 7 days, the concentration of m-THPC decreased to 76,277 d.p.m. g(-1) in tumour and 635 d.p.m. g(-1) in brain. The radioactivity after intravenous administration of [14C]5-ALA (23,079 d.p.m. microl(-1); 40 mg ml(-1); 120 mg kg(-1)) increased within 15 min (59,634 d.p.m. g(-1) in tumour, 17,427 d.p.m. g(-1) in brain); after 8 h only a small amount (3653 d.p.m. g(-1) in tumour) remained. Brain adjacent to the tumour was also found to have a higher uptake of 5-ALA. This study provides basic information for the use of m-THPC and 5-ALA in brain tumours. Because of the different pharmacokinetic and toxicological profile, we recommend m-THPC for PDT and 5-ALA for PDD. Clinical trials now have to prove the superior phototoxic properties of these second-generation photosensitizers.     

Mechanisms for optimising photodynamic therapy: second-generation photosensitisers in combination with mitomycin C.

Mechanisms for improving photodynamic therapy (PDT) were investigated in the murine RIF1 tumour using meso-tetrahydroxyphenylchlorin (m-THPC) or bacteriochlorin a (BCA) as photosensitisers and comparing these results with Photofrin-mediated PDT. The 86Rb extraction technique was used to measure changes in perfusion at various times after interstitial PDT. Non-curative combinations of light doses with m-THPC and BCA PDT markedly decreased vascular perfusion. This decrease was more pronounced for both new photosensitisers than for Photofrin. Comparison of tumour perfusion after PDT with tumour response revealed an inverse correlation for all three photosensitisers, but the relationship was less clear for m-THPC and BCA. In vivo/in vitro experiments were performed after Photofrin or m-THPC PDT in order to assess direct tumour kill (immediate plating) vs indirect vascular effects (delayed plating). For both photosensitisers, there was little direct cell killing but clonogenic survival decreased as the interval between treatment and excision increased. When m-THPC PDT was combined with mitomycin C (MMC), light doses could be decreased by a factor of 2 for equal tumour effects. Lower light and m-THPC doses could be used compared with Photofrin PDT in combination with MMC. BCA PDT with MMC did not result in a greater tumour response compared with BCA PDT alone. Reduction in both light and photosensitiser does for effective PDT regimes in combination with MMC offers substantial clinical advantages, since both treatment time and skin photosensitisation will be reduced.     

Evaluation of Hypocrellin B in a human bladder tumor model in experimental photodynamic therapy: biodistribution, light dose and drug-light interval effects

Hypocrellin B (HB), a monomeric perylenequinone pigment, is a promising second-generation photosensitizer for photodynamic therapy. We have evaluated the efficacy of HB mediated PDT by experimenting with various drug-light intervals, based on the biodistribution analysis in human bladder tumor (MGH cell line) models. Tumor growth rates were assessed at 10-day post treatment followed by morphometric analysis. Biodistribution of HB was evaluated using spectrofluorophotometry analysis (Ex: 480 nm, Em: 620-630 nm). The level of HB peaked at 6 h postinjection in tumor, peritumoral skin and normal muscle followed by a decline over the next 42 h. Concurrently, the ratio of drug in tumor versus skin was relatively low at all times in comparison to tumor to muscle ratio. In serum, concentration of HB peaked at 1 h. Almost 88% of its original uptake level was cleared at 48 h. The level of PDT response revealed a strong dependence on the drug-light intervals (DLI) and light dose. For both high and low fluence/fluence rate, comparable tumor response was observed at 1 h DLI; treated tumors exhibited significant tumor regression compared to 6 and 24 h DLI. The absence of tumor response was observed at 24 h DLI even at high light dose (100 J/cm(2); 100 mW/cm(2)). Tumor response detected at low light dose (12 J/cm(2); 12 mW/cm(2)) at short DLI suggests that the tumor vasculature is a more sensitive target compared to the cellular compartment of the tumor, correlating significantly with the bioavailability of the drug in serum. Therefore, HB mediated PDT effect is characteristics of a predominantly vascular mediated effect. This study confirms that for short drug-light intervals, PDT seems to target tumor vasculature, which contributes to tumor destruction.     

Photodynamic eradication of amelanotic melanoma of the hamster with fast acting photosensitizers

Three porphycenes with fast pharmacokinetics were tested for their ability to photosensitize amelanotic hamster melanoma A-Mel-3 at short time intervals after injection. Laser light irradiation was performed at the time of maximal photosensitizer level in tumor tissue. Photodynamic therapy as short as 5 min after injection led to complete local tumor remission at a dosage of 1.4 μmol/kg for the porphycene CBPn. In comparison, Photofrin required 8.4 μmol/kg for local tumor remission in 5 of 6 animals with 24 hr accumulation time after injection. We propose a swift photodynamic protocol which can compete favorably with conventional techniques of tumor treatment. © 1996 Wiley-Liss, Inc.     

In vivo fluorescence kinetics of mono-l-aspartyl chlorin e6 (NPe6) and influence of angiogenesis in fibrosarcoma-bearing mice

Background The photosensitizer, NPe6, was injected into mice previously transplanted with fibrosarcoma to study changes in ultrasmall lesions at an early stage of neoplasm. Methods Meth-A fibrosarcoma cells (1×10⁶) were transplanted subcutaneously at the hind legs of 5-week-old BALB/c-nu/nu Slc female mice. The fluorescence images of the tumor area obtained after intravenous administration of 5 mg/kg of NPe6 were analyzed in mice which were transplanted with fibrosarcoma 1, 2, 3, 4, 5, 6 or 7 days prior to the day of experiment. The fluorescence images were captured before and 30 seconds, 1, 3, 4, and 24 hours after NPe6 injection. Image analysis showed the concentration distribution map of NPe6 in the tumor. Pathologic studies were done to investigate the cause for the nonhomogeneous accumulation of the dye in the tumor. Results The tumor area was detectable on the day of transplantation. The concentration of NPe6 in the tumor began to increase rapidly 2 days after transplantation. The retention of NPe6 in the tumor was longer than that in the surrounding normal tissue area, and the intensity of fluorescence in the tumor was stronger than the surrounding normal area. Pathologic examination showed that angiogenesis became recognizable on the second day after the transplantation of tumor cells. The concentration of NPe6 in the tumor increased with the degree of angiogenesis. Conclusion Our results suggest that the retention of NPe6 in the tumor was involved with the angiogenesis in the tumor area.     

Foscan-based photodynamic treatment in vivo: correlation between efficacy and Foscan accumulation in tumor, plasma and leukocytes

The tumoricidal effect of Foscan-mediated photodynamic therapy may involve both vessel and tumor cell destruction. The relevant importance of each mechanism seems to be defined by the time interval between photosensitizer administration and illumination (drug-light interval, DLI). Short drug-light intervals favor vascular damage due to the preferential photosensitizer accumulation in the tumor vasculature, whereas long drug-light intervals trigger direct tumor cell damage due to the dye localization in the tumor. The purpose of this study was to investigate the influence of tumor, plasma and leukocyte concentrations of Foscan at different times after photosensitizer delivery on PDT response. Both pharmacokinetic and tumor-response studies were carried out in nude mice bearing s.c. Colo26 tumors. One to 96 h after i.v. injection of 0.5 mg/kg Foscan, animals were exposed to 10 J/cm(2) 652-nm light delivered at 30 mW/cm(2). Mean tumor regrowth time was determined for each schedule of treatment and correlated to Foscan distribution in the compartments of interest at the time of illumination. PDT efficacy was greatest for irradiations performed at 6 and 12 h post Foscan injection and limited at 96 h. Unlike tumor and plasma Foscan concentrations, photosensitizer accumulation in leukocytes exhibited a good correlation with PDT efficacy. The results suggest that leukocytes could play an important role in the mechanism of PDT-induced vascular damage either by being one of the main effector compartments or by better reflecting Foscan accumulation in endothelial cells compared to plasma. The prevalence of indirect damage was highlighted by the fact that PDT efficacy was not modified by the use of a higher fluence rate of irradiation (160 mW/cm(2)), which depleted intratumor oxygen and did not restrain PDT-induced cell toxicity.