Photodynamic Therapy with Porphyrin Derivatives - ACS Symposium

Chapter 18

Photodynamic Therapy with Porphyrin Derivatives

Downloaded by UNIV OF OKLAHOMA on March 30, 2015 | http://pubs.acs.org Publication Date: April 15, 1994 | doi: 10.1021/bk-1994-0559.ch018

Leonard I. Grossweiner Department of Physics, Illinois Institute of Technology, Chicago, I L 60616-3793 Wenske Laser Center, Ravenswood Hospital Medical Center, Chicago, I L 60640

Photodynamic therapy (PDT) is an experimental treatment for malignant tumors utilizing the combined action of visible light and a tumor-localizing photosensitizing agent. PDT drugs derived from the porphyrin mixture hematoporphyrin derivative are being employed for clinical t r i a l s . This paper reviews the current status of PDT, emphasizing clinical results, the mechanism of action, and recent developments.

Approximately 5000 patients have been treated with PDT on an experimental basis since 1978. The voluminous PDT l i t e r a t u r e includes the results of c l i n i c a l t r i a l s , photosensitization studies on biochemical and b i o l o g i c a l systems, l i g h t dosimetry modeling, PDT devices, and combination therapies. This paper reviews the current status of c l i n i c a l and p r e c l i n i c a l PDT research. History of Photodynandc Therapy Photodynamic treatment of tumors was f i r s t attempted i n 1903 by Tappenier and Jesionek ( I ) . An unsuccessful e f f o r t was made to treat skin cancer by t o p i c a l application of eosin dye followed by exposure of the lesions to d i r e c t sunlight. The early f a i l u r e probably resulted from an i n s u f f i c i e n t l o c a l i z e d dye concentration and an inadequate sunlight dose. These l i m i t a t i o n s were surmounted with the discovery of new PDT drugs and the a v a i l a b i l i t y of strong a r t i f i c i a l l i g h t sources. The f i r s t p r a c t i c a l PDT drug was synthesized by Lipson i n 1961 (2). The porphyrin mixture hematoporphyrin derivative (HPD) was obtained by treating commercial hematoporphyrin with a mixture of g l a c i a l acetic and s u l f u r i c acids, followed by n e u t r a l i z a t i o n and extensive washing of the resultant brown powder. A d i l u t e solution of HPD l o c a l i z e s i n neoplastic tissues after intravenous i n j e c t i o n . Tissue uptake of HPD i s i d e n t i f i e d by a c h a r a c t e r i s t i c red fluorescence. HPD fluorescence has been used for

0097-6156/94/0559-0255$08.00/0 © 1994 American Chemical Society

In Porphyric Pesticides; Duke, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

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tumor diagnosis and v i s u a l i z a t i o n since the 1960s. In 1975, Kelley and Snell used HPD for PDT on one patient with bladder cancer (3). Interest accelerated i n 1978 when the group of Dougherty at Roswell Park Cancer Institute reported preliminary PDT results for 25 patients with recurrent skin cancers (4). The procedure was f i r s t referred to as "photoradiation therapy" and more recently as "photodynamic therapy". Photofrin porfimer sodium (QLT Phototherapeutics, Vancouver, BC) i s the HPD drug currently approved for Phase II and Phase III c l i n i c a l t r i a l s i n the U.S.


Overview of a PDT Procedure Photofrin (PF) i s administered by intravenous i n j e c t i o n 24-48 hours p r i o r to the l i g h t treatment. Cutaneous photosensitization develops within a few hours and the patient must avoid d i r e c t sunlight for a variable period which averages about 6 weeks. The fluorescence of the l o c a l i z e d drug varies for different tumor s i t e s from barely perceptible to b r i g h t . PDT l i g h t i s provided by an argon-ion pumped tunable dye laser at 630 nm or another source of strong red l i g h t . S u p e r f i c i a l tumors are i r r a d i a t e d v i a an external o p t i c a l f i b e r , usually terminated with a "microlens" to provide a more uniform irradiance. Deep lesions can be treated by i n s e r t i n g the unclad t i p of an o p t i c a l f i b e r i n the tumor mass. Endoscopic techniques are employed for PDT of i n t e r s t i t i a l tumors, e . g . , a c y l i n d r i c a l diffuser i n the esophagus and a spherical diffuser i n the urinary bladder. PDT treatment times range from several minutes to more than an hour, depending on the tumor coloration and s i z e , drug dose, laser power, and mode of l i g h t d e l i v e r y . Blanching of tumor tissue and diffuse hemorrhage may be evident during or immediately after the l i g h t treatment. Tissue necrosis and eschar formation progress over a 2-3 week period, followed by a healing after about 6-8 weeks. The necrosed areas become almost natural appearing i n time, probably because PDT does not damage collagen. Survey of PDT C l i n i c a l T r i a l s PDT has been employed for patients who have f a i l e d or refused conventional therapies. The objective for many patients was p a l l i a t i o n of advanced disease. Phase I and Phase II c l i n i c a l t r i a l s are i n progress for the evaluation of PF and several "second generation" PDT photosensitizers. Randomized Phase III studies are being coordinated by Lederle Laboratories of American Cyanamid Company (Pearl River, NY). The PDT response of a tumor s i t e i s evaluated by h i s t o l o g i c a l diagnosis at 3 months after treatment as : "complete response" (CR), p a r t i a l response (PR), "no response" (NR), and "progressive disease" (PD). The duration of long-term follow-up has been highly v a r i a b l e , ranging from a few months to many years. Skin Cancer. More than 700,000 case of skin cancer are reported annually i n the U . S . , mostly basal c e l l carcinoma (BCC) and squamous c e l l carcinoma (SCC) on skin areas exposed to sunlight. Excisional surgery, curettage and electrodessication, cryosurgery, and r a d i a t i o n therapy are effective conventional therapies. PDT i s useful for patients who are not candidates for surgery and cancer s i t e s which are d i f f i c u l t to access. PDT of small, multiple lesions i s a


18.

GROSSWEINER


257

potential PDT a p p l i c a t i o n , including recurrent breast cancer on the chest wall after mastectomy, Bowen's disease, and basal c e l l nevus syndrome. A 1987 review indicates CR rates of 70-80% for BCC, 20% for SCC, and 60-70% for metastatic breast cancer (5). Typical l i g h t dose l e v e l s varied from 20-40 J/cm with PF administered at 2 mg/kg of body weight. The good results for BCC are supported by a 1990 report i n which a CR was achieved for 133 of 157 s i t e s (37 patients) with a minimum follow-up of 12 months (6). PF was administered at 1 mg/kg, which necessitated a l i g h t dose of 200 J/cm . This "nonreciprocity" between drug dose and l i g h t dose i s attributed to PF photobleaching (7).


2

Bladder Cancer. S u p e r f i c i a l bladder cancer has been diagnosed i n 50,000 patients per year i n the U.S r e s u l t i n g i n 10,000 annual cancer deaths. Over 90% of these are noninvasive t r a n s i t i o n a l c e l l carcinoma. The disease can occur as carcinoma-in-situ (CIS) or small p a p i l l a r y tumors. Surgical excision i s the standard therapy for s u p e r f i c i a l p a p i l l a r y tumors. CIS i s resistant to chemotherapy and immunotherapy with a recurrence rate of 40-70%. PDT offers an alternative to cystectomy, which i s the standard treatment for refractory bladder CIS. A review of PDT results from 1983-1991 indicates that 216 patients were treated for a l l stages of bladder cancer with a 47% CR rate (5). Uniform l i g h t exposure of the f l u i d distended bladder wall i s required. An o p t i c a l f i b e r with a spherical diffuser may be centered by sounding and ultrasound techniques. Whole bladder l i g h t doses ranged from 10-70 J/cm at 2 mg/kg PF. An ongoing Phase III study specifies a whole bladder l i g h t dose of 15 J / c m . In addition to skin photosensitivity, many patients experienced i r r i t a t i v e bladder symptoms for a few days to several weeks. 2

Endobronchial Lung Cancer. Lung cancer i s the leading cause of cancer death i n the U. S. Non-small c e l l lung cancer occurs i n approximately 120,000 patients i n the U.S. annually, frequently accompanied by endobronchial obstruction. P a r t i a l removal of tumor by laser i s a standard treatment. PDT results were reported from 1985-1990 for 260 patients with various lung malignancies, including small c e l l and large c e l l cancers, adenocarcinomas, and SCC ranging from stage 1 to advanced disease (8). The o v e r a l l response rate was 22% CR, 48% PR, and 30% NR plus PD. Surface l i g h t doses ranged from 20-500 J/cm . Debridement of necrotic tumor v i a bronchoscopy after PDT was required. An additional 154 patients were treated with PDT for p a l l i a t i o n or improved o p e r a b i l i t y . C l i n i c a l improvement was reported for 132 patients including 17 CR. The advantages of PDT over conventional laser surgery include decreased l i k e l i h o o d of bronchial perforation, selective tumor c e l l destruction, f a c i l i t y of treating s u p e r f i c i a l wall l e s i o n s , minimal bleeding, and absence of an i r r i t a t i v e l a s e r plume. Head and Neck Cancer. More than 40,000 cases of head and neck cancers are diagnosed i n the U.S. each year. Radiation therapy and surgery are the standard treatments for SCC of the l i p , oral cavity, pharynx, and larynx. Many PDT patients had already received the maximum i o n i z i n g r a d i a t i o n . Results were reported for 164 patients with primary, recurrent, and metastatic head and neck cancers from


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1984-1990 with an o v e r a l l CR rate of 28% (9). Small, early stage tumors showed the best response. The CR rate was 73% i n a study on 41 patients treated for epidermoid carcinoma of the g l o t t i s for periods up to 5 years for 8 patients (9). A n a l y t i c a l l i g h t dosimetry modeling was used as a guide to treatment planning i n a Phase II study on head and neck SCC (20). The tumor dimensions were diagnosed by magnetic resonance imaging scans. Tumors less than 7 mm i n depth were treated by surface delivery at 125 J / c m ; deeper lesions were treated f i r s t by surface delivery followed by f i b e r insertions spaced 7-8 mm apart at 75 J/cm. A CR was achieved for 20 of 26 patients of which 16 patients remained free of tumor for up to 51 months.


2

Gynecological Malignancies. Approximately 50,000 women per year are diagnosed for cancer of the cervix. Vulvar and vaginal cancer account for 5% of female malignancies. Conventional and laser surgery are the standard treatments for CIS and s u p e r f i c i a l malignancies. The PDT l i t e r a t u r e for gynecological cancers includes lesions of a l l stages i n the cervix, perineum, cervix, vulva, vagina, p e r i a n a l , and endometrium (8). The results for 73 women indicate an overall CR rate of 48%. A recent Phase II study for 17 patients was l i m i t e d to CIS of the vulva, vagina, perineum, and perianal (11). Most patients were treated for multiple lesions with an o v e r a l l CR rate of 71%. Ten patients remained free of recurrences for 2 to 7 years. Venereal warts associated with vulvar CIS recurred soon after PDT. The results to date do not demonstrate that PDT has any clear advantages over conventional modalities for treatment of CIS. The l i m i t e d results for invasive gynecological cancers are not encouraging. Other Malignancies. Approximately 10,000 cases of esophageal cancer are diagnosed annually i n the U.S. P a l l i a t i o n of malignant dysphagia has been achieved by r a d i a t i o n therapy, Nd:YAG laser a b l a t i o n , and intraluminal placement of a tubular prosthesis. Regardless of the therapy, fewer than 4% of patients achieve five-year s u r v i v a l . PDT results reported for 71 patients with s u p e r f i c i a l lesions led to 62% CR with some long-term remissions (8). Removal of obstructing tumor with PDT can prolong and increase the q u a l i t y of l i f e for patients who are not candidates for surgery. R e l i e f of malignant dysphagia was reported for 95% of 55 treated patients. A study on PDT of early gastric cancer was carried out i n Japan where screening i s normally practiced (12). A CR rate of 82% was achieved for 32 patients with cancers described as ulcerative and circumscribed. PDT of brain tumors has been used as an adjunct to surgery. In a recent study on 50 patients with malignant supratentorial tumors, the median s u r v i v a l was 17.1 months for 12 patients evaluated as CR, with 1 and 2 year survivals of 62% and 38%, respectively (13).

How Does HPD Plus Light Eradicate Tuaors? The current theories of PDT action mechanism have been developed by extrapolating information derived from in vitro photosensitization studies and animal tumor models. Comparative results for HPD drugs and "second generation" PDT s e n s i t i z e r s provide some clues about the role of molecular structure.


18. GROSSWEINER


259


Composition of HPD Drugs. HPD contains monomeric porphyrins, including hematoporphyrin, protoporphyrin, and hydroxyethylvinyldeuteroporphyrin, and a higher molecular constituent that i s responsible for e s s e n t i a l l y a l l of the antineoplastic a c t i v i t y . The chemical structure of the active constituent was tentatively i d e n t i f i e d as "dihematoporphyrin ether" (DHE) (14). This material comprises approximately 35% of HPD and 85% of PF. Subsequent work

DHE:

Bis-l-[8-(1-hydroxyethyl)deuteroporphyrin-3-yl]ethyl

ether

has shown DHE has a variable structure, depending on the method of preparation and h i s t o r y (15). Ether and ester linkages have been i d e n t i f i e d i n covalent dimers and small oligomers. The s t r u c t u r a l analysis i s further complicated by p o s i t i o n a l and stereo isomers. The active material w i l l be referred to as "DHE", although the compound depicted above i s only one of many possible structures. PF absorption i s t y p i c a l of metal-free porphyrins, with a strong Soret band near 370 nm and four progressively weaker bands near 510, 540, 575, and 630 nm. The fluorescence emission bands are located near 630 and 680 nm. The band maxima and i n t e n s i t i e s are highly dependent on the medium owing to aggregation. Photophysical properties of HPDderived drugs are reported i n the l i t e r a t u r e . The relevance of t h i s data for the PDT action mechanism in vivo i s questionable owing to the variable pharmacokinetics and metabolic reactions of the constituents. Pharmacokinetics and B i o d i s t r i b u t i o n . The porphyrins i n PF are photosensitizing compounds with d i f f e r e n t degrees of hydrophobicity. Monomeric porphyrins are eliminated from tissue more r a p i d l y than DHE. It i s not known why c e r t a i n porphyrins tend to l o c a l i z e i n tumors. Suggested contributing factors include hydrophobicity, aggregate formation, selective binding to c e l l a r components, molecular charge, low tumor p#, poor lymphatic drainage, vascular permeability, and hypervascularity. PDT drugs are transported by plasma proteins. The pattern of drug d i s t r i b u t i o n i n tissues shows a rough c o r r e l a t i o n with the presence of receptors for low density l i p o p r o t e i n (LDL). Hydrophilic PDT drugs are more strongly bound to albumin and less to LDL (16). A recent report for seven human patients showed that the plasma h a l f - l i f e of PF i s highly variable with a mean of 19 days (17). The highest tissue concentrations of PF i n mice are found i n tissues high i n reticuloendothelial components: l i v e r , adrenal gland, urinary bladder > pancreas, kidney, spleen >


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stomach, bone, lung, heart > skin > muscle > brain (29). PF accumulates p r e f e r e n t i a l l y i n stroma compared to tumor parenchyma, and especially i n endothelial c e l l s . Tissue binding s i t e s include free and fixed macrophages of connective t i s s u e , fibrous tissue matrix, mast c e l l s , and Kupffer c e l l s of the l i v e r . At the subcellular l e v e l , PF l o c a l i z e s f i r s t i n the plasma membrane, followed by r e d i s t r i b u t i o n to other l i p o p h i l i c s i t e s , including the mitochondrial, endoplasmic reticulum, and nuclear membranes. Effects of L i g h t . Indirect evidence indicates that tumor eradication i s i n i t i a t e d by a Type II photosensitization pathway, i n which singlet molecular oxygen i s generated by energy transfer from the DHE t r i p l e t state. A s i n g l e t oxygen molecule can diffuse about 0.1 μπι during i t s short l i f e t i m e i n t i s s u e , which confines the primary reactions close to the s i t e s of DHE l o c a l i z a t i o n . The acute effects of PDT on c e l l s and tissues are summarized i n a recent review (18). Photosensitization of c e l l cultures by PF requires about 5% oxygen for the maximum e f f e c t . Direct evidence for the oxygen requirement i n animals was shown by clamping (29). Vascular damage i s evident i n the i n i t i a l stages of PDT. Hypoxia develops within minutes after the s t a r t of i r r a d i a t i o n . The contribution of d i r e c t tumor c e l l k i l l has been estimated as 20-30% for PF i n animal models. The early c e l l u l a r responses to PDT include leakage of lactate dehydrogenase and release of eicosanoids (prostaglandins, thromboxanes) and histamine. These fast acting vasoactive agents are implicated i n the vascular damage component. This action i s accompanied by the induction of heat stress proteins (20). "Second Generation" PDT Drugs Hundreds of new PDT drugs have been proposed and the l i s t continues to grow. A useful PDT s e n s i t i z e r must be non-toxic, tumorl o c a l i z i n g , and tumor-photosensitizing. Emphasis has been given to drugs with less skin photosensitization than PF and stronger red or near-infrared absorptions. Chemical structure i s the key determinant of the pharmacokinetics and tissue d i s t r i b u t i o n . In general, a higher f r a c t i o n of a hydrophilic agent l o c a l i z e s i n cancer c e l l s compared to PF. The properties of some "second generation" PDT drugs are summarized i n Table I, with the abbreviations used i n the current l i t e r a t u r e for the class of compounds or a s p e c i f i c d e r i v a t i v e . Chlorins are characterized by a strong enhancement of the f a r - r e d absorption band compared to metal-free porphyrins. Mono-L-aspartyl c h l o r i n e6 (NPe6, MACE) was one of the f i r s t PDT s e n s i t i z e r s proposed as an alternative to PF (21). Tissue uptake and clearance of NPe6 are much faster then PF. This property enables PDT shortly after administration of the drug, but complicates treatment planning for lengthy procedures. The increased double-bond conjugation i n phthalocyanines (Pc) compared to porphyrins leads to stronger and red-shifted absorptions. The Pc structure accepts many types of metal ions. Diamagnetic ions (aluminum, z i n c , gallium) are better photosensitizers than paramagnetic ions (cobalt, copper, i r o n , n i c k e l , chromium) which quench the t r i p l e t state. Unsubstituted Pc are insoluble i n water, but they can be rendered soluble by sulfonation. Tetrasulfonated AlSPc has a low tendency to aggregate i n water and a high singlet oxygen y i e l d (22). Related compounds are


18. GROSSWEINER Table I .

Some Proposed "Second Generation" PDT Photosensitizers

Photosensitizer


261


Hydrophobicity

Ref.

a

λ"max

Mono-L-aspartyl c h l o r i n e6 (NPe6, MAGE)

water soluble

660 (9)

21

Sulfonated aluminum phthalocyanine (AlSPc)

water soluble

670 (40)

22

Benzoporphyrin derivative monoacid ring A (BPD-MA)

hydrophobic

690 (5)

23

Oc tae thylpurpurin (NT2)

hydrophobic

700 (15)

24

Pheophorbides (HEDP)

hydrophobic

660 (20)

25

5-Aminolevulinic acid (ALA)

hydrophilic

640 ( 2 )

26

Cationic dyes (GPS)

hydrophilic

c

b

27

a

The approximate l o c a t i o n of the longest wavelength absorption band i s indicated with the absorption intensity r e l a t i v e to PF at 630 nm i n parenthesis. Topical ALA i s converted to protoporphyrin IX within tumors. Many different types of CPS have been suggested for PDT with absorptions from 600-900 nm. c

sulfonated zinc phthalocyanine (ZnSPc) and c h l o r ο - a l u m i n u m sulfonated phthalocyanine (ClAlSPc). Benzoporphyrin derivatives (BPD) are benzo-derivatives of protoporphyrin IX (23). BPD are insoluble i n water and must be administered i n a vehicle such as liposomes or an o i l emulsion. The p o t e n t i a l l y useful features are fast uptake, s e l e c t i v i t y for neoplastic tissues and s i g n i f i c a n t clearance after about 24 hours. Purpurins are benzochlorins with additional conjugation through substitution. Octaethylpurpurin (NT2) and t i n etiopurpurin d i c h l o r i d e (SnET2.2C1) are proposed PDT s e n s i t i z e r s (24). The metal atom induces a b l u e - s h i f t to about 650 nm. Animal studies are indicative of high photodynamic efficacy and low skin photosensitization. Pheophorbides are metal-free derivatives of chlorophyll without the a l i p h a t i c phytol side chain. Animal tumor model studies indicate that 2 ( l - 0 - a l k y l ) ethyl-desvinyl-methyl pheophorbide-a (HEDP) i s an effective PDT s e n s i t i z e r with a low skin reaction after 3 days (25). 5-Aminolevulinic acid (ALA) i s the common metabolic precursor of porphyrins i n microorganisms, plants, and animals. The use of ALA as a PDT photosensitizer exploits the enhanced rate of protoporphyrin IX (PP) formation i n tumors compared to normal tissues (26). This innovative approach minimizes the protracted skin photosensitization induced by intravenous porphyrins. Most PDT drugs have anionic structures. Cationic photosensitizing dyes (CPS) have been proposed


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for PDT under anoxie conditions and i n combination with hyperthermia (27). CPS are s e l e c t i v e l y l o c a l i z e d i n mitochondria of tumor c e l l s . Representative classes of CPS include cyanines, triarylmethanes, oxazines, and chalcogenapyryliums. Very high l i g h t doses are required for tumor necrosis compared to porphyrins. The anionic cyanine dye merocyanine 540 (MC 540) i s being tested as an photosensitizing a n t i v i r a l agent (28). In the presence of serum components, MC 540 binds p r e f e r e n t i a l l y to e l e c t r i c a l l y excitable c e l l s , leukemia c e l l s , and c e r t a i n classes of immature normal blood cells. Exposure to white l i g h t leads to rupture of the plasma membrane and c e l l death.


PDT as an Adjuvant Therapy and Modified Procedures Intraoperative PDT may be effective f o r procedures i n which s u r g i c a l excision cannot remove the entire tumor. The combination of l o c a l i z e d hyperthermia (HT) and PDT has received attention. Animal tumor results indicate that a sub-curative PDT dose can i n i t i a t e tumor necrosis when combined with simultaneous HT (29). HT may be provided by a microwave generator or a Nd:YAG laser coupled into the PDT laser (30). The response of normal tissues exposed to PDT l i g h t sets a p r a c t i c a l l i m i t on PDT l i g h t dose. The PDT efficacy may be improved by s e l e c t i v e l y increasing tumor response and protecting normal tissues. Experimental techniques directed to t h i s objective include protection of normal tissue with radioprotective agents, increasing the l o c a l i z e d drug concentration by coupling to monoclonal antibodies, and increasing tumor oxygenation by fractionating the l i g h t dose. The combination of porphyrin photosensitization with ultrasound i s an interesting concept that has been found to increase l e t h a l i t y i n c e l l cultures (31). A possible mechanism involves the generation of c a v i t a t i o n energy at the interface between the c e l l surface and the medium. Administration of glucose to mice p r i o r to PDT potentiated the tumor response (32). The effect of hyperglycemia was attributed to lowering of intratumoral p/J. PDT Photophysics and Phototechnology A high f r a c t i o n of a l l tumors treated with PDT have shown at l e a s t a p a r t i a l response. However, the s t a t i s t i c s for long-term tumor eradication are widely v a r i a b l e . Many factors can lead to a p a r t i a l response including l o c a l heterogeneities i n the l i g h t dose, drug concentration, and the i n t r i n s i c tumor photosensitivity. The treatment parameters are controlled i n c l i n i c a l t r i a l s to allow f o r s t a t i s t i c a l evaluation of the r e s u l t s . Individualized treatment planning for each tumor s i t e w i l l be required when PDT i s f u l l y approved. Light dosimetry modeling based on tissue optics has been employed for t h i s purpose (33-35). The "threshold hypothesis" assumes that tumor eradication requires a minimum absorbed energy density by the l o c a l i z e d photosensitizer. The modeling objective i s to relate the incident fluence to the effective intratumoral l i g h t dose f o r given treatment conditions. According to the photon d i f f u s i o n approximation, the absorbed energy density equals the product of the l o c a l fluence rate and the photosensitizer absorption coefficient integrated over time. This quantity must exceed the absorbed energy threshold i n tissue regions most distant from l i g h t



18.

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263

entry. Monte Carlo simulation provides an independent test of the calculations (36). Recent advances i n tissue optic theory motivated by PDT have been extended to other biomedical applications, including modeling of l o c a l i z e d hyperthermia, l a s e r ablation of t i s s u e s , and non-invasive methods of o p t i c a l diagnosis and imaging. PDT phototechnology i s a c o l l a t e r a l research area. Noninvasive measurements of l o c a l i z e d drug dose based on fluorescence and diffuse r e f l e c t i o n should improve the r e l i a b i l i t y of modeling c a l c u l a t i o n s . Much effort has been directed to the development of improved PDT lasers. Argon-ion pumped dye lasers are bulky, require frequent adjustments, and do not provide adequate power output i n the f a r - r e d and near-infrared regions for "second generation" photosensitizers. Other dye pumping lasers employed for PDT include the pulsed Nd:YAG l a s e r doubled to 532 nm with a potassium t i t a n y l phosphate (KTP) c r y s t a l , the copper vapor laser (511 nm, 578 nm), and the XeCl excimer laser (308 nm). PDT has been c a r r i e d out with the gold vapor laser (628 nm), the titanium-sapphire l a s e r pumped by an argon-ion or doubled Nd:YAG l a s e r (670-1100 nm), and the Alexandrite laser (720790 nm). Semiconductor diode lasers are very compact, emit stable CW or pulsed l i g h t , have very long l i f e t i m e s , and may be temperature tuned. However, the applications have been l i m i t e d by low power output, less than 1 W i n the 660-690 nm region, and low irradiance that l i m i t s e f f i c i e n t coupling into an o p t i c a l f i b e r .

The Future of PDT? PDT remains an experimental therapy after almost two decades of c l i n i c a l t r i a l s . Encouraging short-term responses are reported for some malignancies. The lack of evidence for superior long-term efficacy compared to conventional treatments has contributed to the slow acceptance of PDT. Cutaneous photosensitization has been c i t e d as a negative f a c t o r . However, only a small f r a c t i o n of noncompliant PDT patients have experienced adverse reactions that required medical attention. Many c l i n i c i a n s are unfamiliar with phototherapy procedures and instrumentation. Active c l i n i c a l groups generally include a p h y s i c i s t for t h i s expertise. PDT has been the subject of a major p r e c l i n i c a l research e f f o r t . A recent review c i t e s 900 publications through 1989 (37). This number may have since doubled. Much of t h i s work i s reported i n journals that are not usually read by c l i n i c i a n s . unnecessary redundancy i n reporting appears to be a c h a r a c t e r i s t i c of t h i s f i e l d . The present impasse may be broken when PDT i s f u l l y approved for at l e a s t one condition. Recently, Canada's Health Protection Branch cleared Photofrin for PDT of bladder cancer (39). This step should accelerate the a c q u i s i t i o n of c l i n i c a l data and provide the information required for a more d e f i n i t i v e evaluation of the therapy.

Acknowledgments The author i s pleased to acknowledge the helpful comments of Rocco V. Lobraico, M.D. of Ravenswood Hospital Medical Center and James B. Grossweiner, M.D. During the preparation of t h i s paper the author received p a r t i a l support from the National Institutes of Health on Grant No. GM 20117 to I l l i n o i s Institute of Technology.


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