systemic toxicity in mice induced by localized...

[CANCER RESEARCH 50, 539-543. February 1, 1990]

Systemic Toxicity in Mice Induced by Localized Porphyrin Photodynamic Therapy1

Angela Ferrarlo and Charles J. Corner2

Clayton Ocular Oncology Center [A. F., C. J. G.Â¡,Children! Hospital of Los Angeles, and Departments of Pediatrics fC. J. GJ and Radiation Oncology [C. J. G.J,University of Southern California School of Medicine, Los Angeles, California 90027

ABSTRACT

An unexpected high level of acute lethality has been documentedfollowing Photofrin H-mediated photodynamic therapy (PDT) treatmentswhich were localized to the hind leg of normal and tumor-bearing mice.Doses of PDT which induced lethality (10 mg/kg Photofrin II, 200-500J/cm2) were in the range of doses required to obtain murine tumor cures.

The percentage of lethality was proportional to the total light dose butwas inversely proportional to the dose rate of delivered light. Comparablelevels of acute toxicity were observed in four pigmented mouse strains(C57BL/6J, C3H/HeJ, DBA/1, and DBA/2) and in two albino mousestrains (BALB/c and Swiss Webster). Decreased sensitivity to PDT-induced lethality was observed in two pigmented mouse strains (B,,,D,/OSN and Bi0D2/NSN). The administration of warfarin, aspirin, indo-methacin, or antihistamine had significant protective effects in terms ofdecreasing PDT-induced lethality. However, injection of cobra venomfactor (to deplete C3 and C5 of the complement system) did not alter thelethality mediated by PDT. Histological profiles obtained 24 h followingPDT demonstrated vascular congestion in the liver, kidney, lung, andspleen. Significant decreases in removable blood volume, core temperature, and spleen weight were also observed within 24 h of localized PDTtreatment. These results indicate that PDT-induced lethality is consistentwith a traumatic shock syndrome and suggest that endogenous vasoactivemediators of shock such as prostaglandins, thromboxanes, and histamineare associated with the lethality induced by localized PDT in mice.

INTRODUCTION

Photodynamic therapy is the generalized term for the treatment of solid malignancies by using tissue-penetrating visiblelight following the administration of a tumor localizing photo-sensitizer such as hematoporphyrin derivative or its purifiedcomponent Photofrin II (1, 2). The combination of drug uptakein malignant tissue and selective delivery of laser-generatedlight provides for an effective therapy with efficient tumorcytotoxicity and minimal normal tissue damage (3, 4). Thephotochemical generation of singlet oxygen and possibly otherreactive oxygen species is responsible for the cytotoxicity induced by PDT3 (5, 6). Information regarding the biochemical,

cellular, and preclinical parameters associated with PDT hasrecently been reviewed (6, 7). The clinical efficacy of PDT iscurrently being evaluated in Phase III trials for obstructive andpartially obstructive carcinoma of the bronchus and esophagusas well as for transitional cell carcinoma of the bladder (8). Inaddition, PDT is being used on a limited basis to treat malignancies of the head and neck, skin, cervix, eye, and brain (2, 8).

Recently, we encountered high levels of acute lethality inmice treated with Photofrin II-mediated PDT during experiments designed to evaluate effects of light dose rate on tumor

Received 8/21/89; revised 10/24/89; accepted 10/27/89The costs of publication of this article were defrayed in part by the payment

of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1This investigation was performed in conjunction with the Clayton Foundationfor Research and was supported in part by USPHS Grants R37-CA-31230 andR01-CA-44733 awarded by the National Cancer Institute, Department of Healthand Human Resources. Presented in part at the European Photobiology Meeting,Padova, Italy, September 6-10, 1987, and at the SPIE Conference on Photodynamic Therapy Mechanisms, January 19-20, 1989, Los Angeles, CA.

2To whom requests for reprints should be addressed, at Childrens Hospital of

Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027.3The abbreviation used is: PDT, photodynamic therapy.

response. This observation was unexpected in that: (a) the PDTdoses that were used (10 mg/kg Photofrin II, 200-500 J/cm2)

were comparatively low and were in the range of doses requiredto produce tumor cures in mice (9); and (b) the area of lighttreatment was specifically localized to the hind leg in order toeliminate light exposure to all vital organs and structures.Lethal toxicity induced by various photosensitizers has beendocumented as early as 1911 (reviewed in Ref. 10), and systemictoxicity has been reported following whole body and abdominallight exposure of porphyrin PDT in mice (11). In this report,we describe the clinical, hematological, and histopathologicalresponses of acute toxicity induced by Photofrin II-mediatedPDT as a function of various treatment parameters and mousestrains.

MATERIALS AND METHODS

Drugs. Photofrin II (dihematoporphrin-ether) was obtained fromPhotomedica, Inc., Raritan, NJ, as a sterile solution at a concentrationof 2.5 mg/ml. The drug was diluted with saline to obtain a workingconcentration of I mg/ml. A 10-mg/kg dose of Photofrin II wasadministered by i.p. injection 24 h prior to localized laser irradiationin PDT experiments. Sodium warfarin (Coumadin, DuPont Pharmaceuticals, Inc., Wilmington, DE), indomethacin (Indocin, Merck Sharp& Dohme, Inc., West Point, PA), and aspirin (acetylsalicyclic acid,Sigma Chemical Co., St. Louis, MO) were administered in the drinkingwater of test mice. The concentration of warfarin was 5 mg/liter andmice were administered the drug from day â€”¿�3to day â€”¿�1prior to PDT

light treatment (12, 13). Indomethacin was dissolved in 95% ethanolat a concentration of 10 mg/ml, and was then added to the drinkingwater for a final concentration of 20 mg/liter in 0.25% ethanol (14,15). Indomethacin was administered to test mice from day -4 to day+2. Aspirin was added to the drinking water at a concentration of 625mg/liter and was administered to mice from day â€”¿�4to day +2 (16).The antihistamine pyrilamine malÃ©ate(Histavet-P, Schering Corp.,Kenilworth, NJ) was delivered to test mice by i.m. injection. A 0.5-mg/kg dose of antihistamine was administered immediately following PDTto the hind leg not involved in the PDT treatment (17). Cobra venomfactor was obtained from Cordis Laboratory, Inc., Miami, FL, as alyophilized powder. The drug was dissolved in water and administeredby i.v. injection at a dose of 250 units/kg on day -2 (18).

Animals. Eight strains of female mice (8 to 12 weeks old) wereutilized in various experiments. Pigmented mice included: C57BL/6J,C3H/HeJ (endotoxin resistant), DBA/U (C5 proficient), DBA/2J (C5deficient), B10D2/OSN (C5 deficient) and B10D2/NSN (C5 proficient).Albino mouse strains used in this study included Swiss Webster andBALB/c. All mice were purchased from The Jackson Laboratory, BarHarbor, ME.

Tumor Models. Pigmented and nonpigmented B16 melanomas wereused during initial experiments in this study (9). The tumors wereoriginally obtained from the NIH Tumor Repository and they weremaintained by serial passage in the hind flank of C57BL/6J mice. A 1-mm3 piece of tumor was transplanted s.c. via trochar injection in the

shaved hind right leg of mice. Tumor volumes were determined 3 times/week and mice with tumors measuring 25-35 mm3 were entered into

PDT experiments.Photodynamic Therapy Protocols. An i.p. injection of Photofrin II

(10 mg/kg) was administered 24 h prior to light treatment (19). A 1-cm diameter spot localized to the hind right leg was used as thetreatment area for all light exposures. Red light at 630 nm was generated by an argon pumped dye laser (Spectra-Physics, Inc., Mountain-

539

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PDT-INDUCED SYSTEMIC TOXICITV

view, Ã‡A).A 400-Mtn diameter quartz fiber was interfaced to the outputof the dye laser and a microlens was attached to the distal tip of thefiber for uniform light delivery. The wavelength of delivered light wasdocumented with a spectroscope (Cooper Lasersonics, Inc., SantaClara, CA) and a power meter (Coherent Radiation, Palo Alto, CA)was used to measure light intensity. All mice undergoing PDT wererestrained in holders without anesthesia.

HistolÃ³gica!and Hematological Evaluation. Acute histological specimens were obtained for C57BL/6J mice by sacrificing the animals 24h following PDT (10 mg/kg Photofrin II, 150 mW/cm2, 500 J/cm2).

Samples from the liver, spleen, lung, kidney, and skin were obtainedand placed in 10% buffered formalin. The specimens were embeddedin paraffin, sectioned, and processed by using hematoxylin-eosin staining or periodic acid-Schiff staining.

An electronic blood cell counter (ELT-8/DS, Orthodiagnostics Systems, Inc.) was used to obtain quantitative values for hematocrits,platelets, and WBC from C57BL/6J mice treated with PDT (10 mg/kg, 500 J/cm2, 150 mW/cm2). Blood samples were collected by heart

puncture at the completion of the PDT light treatment (0 h) and at 1,2, and 4 h, and 1, 3, 7, and 14 days. Control mice received either salineor Photofrin II (without light).

Statistical Analysis. The x2 test was used to evaluate mouse lethalityresponses and the Student's t test was used to evaluate the mean values

for hematological determinations.

RESULTS

The percentage of acute lethality induced by localized PDTin C57BL/6J mice with either pigmented or nonpigmented B16melanomas is shown in Table 1. PDT-induced lethality isdocumented as a function of both total light dose (200-500 J/cm2) and dose rate of delivered light (150 or 600 mW/cm2). In

all cases, the site of light exposure covered the tumor and wasconfined to a 1-cm-diameter spot on the hind right leg. Anincrease in total light dose corresponded to a concomitantincrease in the percentage of PDT-induced deaths for bothmouse-tumor models. However, increasing the dose rate ofdelivered light produced a decrease in lethality for mice treatedat equal total light doses.

Acute lethality in normal C57BL/6J mice following localizedPDT directed to the hind leg is summarized in Table 2. Theseexperiments were performed to determine whether the highdegree of PDT-mediated lethality described in Table 1 was due

Table 1 Lethality in C57BL/6J mice following PDT localized to the hind legforthe treatment ofB16 melanoma"

% of lethality

Nonpigmented melanoma Pigmented melanomaPDT dose

(J/cm2) 150mW/cm2 600 mW/cm2 150 mW/cm2 600 mW/cm2

20030040050016.67(12)*52.38(21)54.54

(22)76.74(43)21.43(14)23.08(13)16.67(12)54.54(22)0(10)33.33(15)41.18(17)59.26(27)0(12)0(11)9.10(11)42.86(21)

" Photofrin II was administered as an i.p. injection (10 mg/kg) 24 h prior to

light treatment. Lethality was observed within 48 h of PDT treatment.* Numbers in parentheses, number of mice.

Table 2 Lethality induced by PDT in normal C5 7BL/6 mice as a function oflight dose rate'

PDT dose(J/cm2)300

400500

600600 (light alone)%

oflethality150mW/cm212.00(25)*

40.48 (42)64.00 (25)69.75 (32)

0(5)600

mW/cm20(12)

12.00(25)12.00(25)47.37(19)

0(5)

to the fact that the first group of treated mice had tumors. Thepercentage of lethality described in Table 2 is documented as afunction of both total light dose and light dose rate. Thepercentage of lethality was again observed to be directly proportional to the total light dose and inversely proportional tothe dose rate of delivered light. Light exposure without prioradministration of Photofrin II did not induce any lethality eventhough local temperature rises of 6Â°C(150 mW/cm2) and 21Â°C(600 mW/cm2) were produced at the site of light exposure.

The effects of localized PDT on different strains of mice aredocumented in Table 3. The PDT parameters (10 mg/kg, 150mW/cnr, 500 J/cm2) were comparable to dose parameters

required to achieve cures in most mouse tumor models. Similarlevels of PDT-induced lethality were observed in all mousestrains except for the B10D2/OSN and B,0D2/NSN strains,which exhibited significantly decreased lethality followingPDT.

Table 4 describes the effect of various pharmacological agentson the lethality induced by PDT in normal C57BL/6J mice.The combination of PDT and either warfarin, aspirin, indo-methacin, or antihistamine produced a protective effect in termsof decreased lethality and the protection was observed at alllight doses analyzed (300-500 J/cm2) and in each case the

reduction in lethality was approximately 50%. These drugs(which function by inhibiting cyclooxygenase, histamine, andcoagulation) were administered by using previously reportedprotocols (12-18). Cobra venom factor (which depletes C3 andC5 of the complement system) did not alter the lethality inducedby PDT. Experiments described in Tables 3 and 4 were performed approximately 3 months apart and therefore separategroups of positive controls (PDT, 500 J/cm2, 150 mW/cm2)

were used.Histological profiles obtained from PDT-treated C57BL/6J

Table 3 PDT-induced lethality as a function of mouse strain'

MousestrainC57BL/6C3H/HeJ*B,0D2/OSNCB.oDj/NSN''DBA/2JCDBA/U''BALB/cfSwiss

Webster'No.

of micetreated261020209101010%oflethality76.9270.0020.000.0077.7880.00100.0070.00

* The PDT treatment consisted of a 10 mg/kg i.p. injection of Photofrin II

administered 24 h prior to localized hind leg exposure to 630 nm light at a doseof 500 J/cm2 and delivered at a light dose rate of 150 mW/cm2. Lethality was

observed within 2 days of PDT treatment.* Endotoxin resistant.' C5 deficient.d C5 proficient.' Albino.

Table 4Lethality in C57BL/6J mice treated with exogenous pharmacological agents"

% of lethality

DrugtreatmentPDT

alonePDT + warfarinPDT + indomethacinPDT + aspirinPDT + antihistaminePDT + cobra venom factor300

J/cm244.44

(36)*

30.00 (20)5.00 (20)

20.00 (20)15.62(32)

NDC400

J/cm261.00(31)

50.00 (20)35.00 (20)30.00 (20)15.00(20)

ND500

J/cm288.89

(54)40.00 (20)40.00 (20)40.00 (20)35.00 (20)

100.00(10)

a Photofrin II was administered as a 10 mg/kg i.p. injection 24 h prior to light

treatment. Lethality was observed within 2 days of PDT treatment.* Numbers in parentheses, number of mice.

Â°The PDT treatment consisted of a 10 mg/kg i.p. injection of Photofrin IIadministered 24 h prior to localized hind leg exposure to 630 nm light (300-500J/cm2) delivered at a dose rate of 150 mW/cm2. Doses and administrationschedules of the various exogenous drugs are described in "Materials and Methods."

* Numbers in parentheses, number of mice.c ND, not determined.

540



PDT-INDUCED SYSTEMIC TOXICITY

mice were consistent with responses seen during a systemicshock reaction (20). Vascular congestion was present in theliver, kidney, lung, and spleen 24 h following PDT (data notshown). Hematological profiles (WBC, platelets, and hemato-crit) in C57BL/6J mice following PDT are shown in Figs. 1-3for time periods ranging from l h to 14 days following treatment. Fig. 1 shows that the WBC initially increased from abase-line level of 10,000/mm3 to over 40,000/mm3 during the

first 4 h following PDT. The WBC values were still over 30,000/mm3 at 24 h posttreatment. However, by 3 days posttreatmentthe WBC levels had decreased to 2,900/mm3 which was signif

icantly below control levels (P < 0.01). Animals surviving thePDT treatment had WBC levels which returned to controlvalues by 7 days posttreatment. Platelet levels in PDT-treatedmice were lower than control values for the initial 24 h followingtreatment as shown in Fig. 2. The platelet count increased tolevels significantly higher than control levels (P < 0.01) at 7and 14 days posttreatment. Hematocrit levels are shown in Fig.

50 -i

EE

oo.aÂ»â€¢¿�o

mM

O

om

012345

HOURS AFTER TREATMENT

10

1 O

DAYS AFTER TREATMENT

Fig. 1. WBC Â¡nC57BL/6J mice as a function of time after treatment withPDT (10 mg/kg Photofrin II, 500 J/cm2,150 mW/cm2) (ET),Photofrin II without

light (*), or normal saline (D). Points, mean for 10 mice; bars, SE.

EE3O

I

Mâ€¢¿�oCnim3O

Cfl

Ul

1600-,

1400 -

1200 -

1000

800

1600 -

1400 -

1200 -

1000 -

800-

600-

400012345


400


Fig. 2. Platelet values in C57BL/6J mice as a function of time after treatmentwith PDT (10 mg/kg Photofrin II, 500 J/cm2, 150 mW/cm2) (H), Photofrin II

without light (4), or normal saline (O). Points, mean for 10 mice; bars, SE.

(EOO

UJZI-zLUoocUlo.

85 -i

75 -

65 -

55 -

45

35

85 -

75 -

65 -

55 -

45 -'

35012345


1 5


Fig. 3. Hematocrit levels in C57BL/6J mice as a function of time aftertreatment with PDT (10 mg/kg Photofrin II. 500 J/cm2, 150 mW/cm2) (El),

Photofrin II without light (*), or normal saline (D). Points, mean for 10 mice;bars, SE.

Table 5 Removable blood volume, core body temperature, spleen weight, andliver weight in normal C57BL/6J mice determined 24 h following localized leg

PDTÂ°

TreatmentconditionControl*

Photofrin II*

PDTBlood

volume(ml)0.63

0.650.18Core

temperatureCO35.6

35.525.8Spleen

wt(mg)76.6

76.448.0Liver

wt(g)1.05

1.060.83

Â°The PDT treatment consisted of a 10 mg/kg i.p. injection of Photofrin IIadministered 24 h prior to a 500-J/cm2 dose of 630 nm light localized to the hind

leg. Data points are the average values for 5 mice.* Controls received an i.p. injection of saline and the Photofrin II group

received a 10-mg/kg i.p. injection of the drug (without light treatment).

3 and values were similar for control and PDT-treated mice atall time points analyzed.

The removable blood volume, spleen and liver weights, andcore body temperature in C57BL/6J mice at 24 h followingPDT (10 mg/kg, 150 mW/cm2, 500 J/cm2) are shown in Table

5. The removable blood volume (using heart puncture) was0.63-0.65 ml/mouse for controls and only 0.18 ml for PDT-treated mice. Spleen and liver weights were also decreased inPDT-treated mice. Spleen weights averaged 0.076 g for controlsand 0.048 g following PDT, while liver weights averaged 1.048-1.058 g for controls and 0.83 g for PDT-treated mice. A dropin core body temperature from a control average of 35Â°Cdownto 25.8Â°Cwas also observed 24 h following PDT.

DISCUSSION

Results from this study demonstrate that systemic toxicity inthe form of acute lethality is induced following Photofrin II-mediated PDT in both normal and tumor-bearing mice. Thephenomenon of acute toxicity (lethality) in experimental animals following photosensitizer-initiated photodynamic actionhas been reported previously (10, 11), but there have not beenany prior reports on lethality induced by porphyrin PDT associated with localized tumor treatments. The PDT dose responseexperiments (combining various pharmacological agents), together with the histopathological observations and hematolog-ical responses obtained in this study, strongly suggest that

541



PDT-INDUCED SYSTEMIC TOXICITY

localized PDT elicits systemic toxicity in the form of a traumatic shock syndrome (20). Traumatic shock can be producedby tissue injury which in turn leads to inadequate peripheralperfusion. Despite a wide variety of inducers of shock, the finalpathway appears to be circulatory collapse (20). The etiologyof irreversible shock includes induction of significant levels ofischemia or hypoxemia, the release of prostaglandins and kin-ins, as well as production of large amounts of cell necrosis.Indomethacin and aspirin are antiinflammatory agents whichcan inhibit cyclooxygenase and therefore decrease prostaglan-din and thromboxane synthesis. Warfarin acts as an anticoagulant and antihistamine actions are primarily related to antagonizing the effects of histamine. Each of these agents can reducethe action of endogenous mediators of microcirculatory disruption which is characteristic of traumatic shock. Our observations are therefore in agreement with previous reports describing the generation of eicosanoids and antihistamine followingporphyrin photosensitization (17, 21). A separate study hasalso shown that inhibitors of cyclooxygenase (indomethacinand aspirin) can significantly reduce the vasoconstriction andvascular stasis induced by PDT (22).

It is significant to note that the doses of PDT used in thecurrent study were comparable to those used previously intumor cure experiments (20). Equally important is the fact thatthe site of PDT treatment in the current set of experiments wasspecifically limited to the hind leg in order to avoid illuminationof all vital organs. Interestingly, the lethality observed in micefollowing PDT is not unique to Photofrin II. We have observedcomparable effects with chlorin photosensitizers4 and other

investigators have observed lethality following PDT by usingphthalocyanines.5 Fortunately, the type of acute systemic shock

reaction described in this study has not been observed in humansundergoing clinical PDT. In addition, larger animals (rats andrabbits) treated with the highest doses of Photofrin II-mediatedPDT used in the current study did not exhibit any systemictoxic reaction (data not shown). These observations wouldsuggest that the relationship of PDT treatment area to totalbody area may be an important parameter in the induction ofacute lethality.

The lethality induced in mice by localized PDT appears tobe a generalized phenomenon and not limited to tumor-bearingmice (which may have compromised immune systems) or toany one particular strain of mouse. In our study, similar levelsof PDT-induced lethality were observed for pigmented andalbino mice as well as for mice with transplanted melanomas.The only exception to the high level of PDT-induced lethality-

occurred in the two Bi0D2 mouse strains. It is currently unclearwhy these two mouse strains exhibited resistance to PDT-induced lethality. However, the resistance does not appear tobe related to complement activation since both C5-proficientand CS-deficient strains of B,0D2 mice were resistant to thetoxic effects of PDT. Interestingly, these two strains wereproduced by an initial cross between C57BL/10 mice and DBA/2 mice (23). The C57BL mouse is proficient for C5 while theDBA/2 mouse lacks C5 and yet both C57BL and DBA/2 miceexhibited high levels of PDT-induced lethality. In previousstudies, cutaneous phototoxicity was shown to be associatedwith a decrease in total complement activity and the phototoxicreaction was suppressed in complement-depleted animals (24,25). In the current study, the administration of cobra venomfactor (to deplete C3 and C5) had no effect on PDT lethality inC57BL mice. However, there may be differences in porphyrin

' Unpublished data.5J. van Lier, personal communication.

pharmacokinetics in the B,oD2 mouse strains which could influence the degree of systemic toxicity observed following PDTbut this has not yet been evaluated. It is also unknown whetherthe B,0D2 mouse strains are inherently more resistant to traumatic shock than the other mouse strains used in this study.

The inverse relationship between PDT-induced lethality andthe dose rate of delivered light was unexpected but may beassociated with physical and/or physiological properties of thetreatment. The highest light dose rate (600 mW/cnr) produceda 21Â°Clocalized temperature rise 1 mm below the surface at

the treatment site. This thermal condition could have induceda complete and localized vascular closure with a concomitantdecrease in the release to prostaglandins or other endogenoustoxic substances. In addition, the volume of blood flowingthrough the PDT treatment area would be 4 times lower forexposures performed at 600 mW/cm2 compared to those performed at 150 mW/cm2. Nevertheless, it is apparent that theaddition of local hyperthermia did not potentiate PDT-inducedlethality even though heat has been shown to enhance PDT-induced tumor destruction (6, 26).

Results from this study indicate that PDT-induced lethalityin mice will have to be taken into account when screening newtumor photosensitizers. Quantitative dose response experiments (using tumor cure as an end point) may be extremelydifficult to complete as a consequence of the high level oflethality which may accompany the treatment. In addition,possible systemic factors involved with tumor responses inPDT-treated mice (i.e., ecosonoid and/or cytokin release aswell as physiological factors involved with shock induction)may not be relevant in PDT treatment in larger animals or inhumans. The positive effects that indomethacin, aspirin, warfarin, and antihistamine had on reducing PDT-associated lethality strongly suggest that endogenously produced vasoactivemediators can influence generalized PDT responses. The dosesof PDT currently used in larger animals and humans (2) do notelicit any observable systemic toxicity, and therefore it is possible that systemic factors associated with PDT in mice will begreatly reduced or eliminated following treatment in largeranimals and humans.

In summary, the PDT-induced lethality documented in thecurrent study appears to be comparable to a traumatic shocksyndrome and is associated only with small animal models. Theacute lethality observed in mice does not appear to be clinicallyrelevant but the phenomenon should be taken into accountduring the in vivo screening of new tumor photosensitizersusing mouse models.

ACKNOWLEDGMENTS

We thank Dr. John Spikes for discussions regarding the history ofphotosensitizer-mediated toxicity.

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1990;50:539-543. Cancer Res Angela Ferrario and Charles J. Gomer Photodynamic TherapySystemic Toxicity in Mice Induced by Localized Porphyrin

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