Water-soluble derivatives of chlorophyll were first introduced as potential drugs by E.Snyder (USA) in 1942. The other step was that peroral and intravenous administration of chlorin mixtures mainly containing chlorin p₆ favoured low toxicity, hypotensive, antisclerotic, spasmolytic, anaesthetic, antirheumathoid action to result in their usage for prevention and treatment of cardiovascular diseases, rheumatoid poliarthritis and atherosclerosis.

The first PDT usage of chlorins relates to phaeophorbide a derivatives. Some of them were patented as prospective PSs for PDT in 1984 in Japan by I.Sakata.

  The application of chlorin-type derivatives in PDT was reported in 1986. A research team from the U.S., which included J. Bommer, Z. Sveida, and B. Burnhem, analyzed mono-L-aspartyl chlorin e6 (MACE) properties. This compound showed good tumor tropism and strong absorption in the far-red region. It thus met the most vital PDT requirements. This compound was put to tests in Japan, and now it passes the final stage of clinical trials. J. Bommer and B. Burnhem, working with the Nippon Petrochemicals Company (Japan), filed a U.S. patent for some functional derivatives of chlorin e6 and bacteriopheophorbid A.

In 1990s in Belorussia a group of scientists at first headed by G.Gurinovich reported about their search for a water-soluble chlorin type PS derived from nettle. As far as there was no clear chemical composition of the drug substance reported about, the investigators probably dealt with mixtures similar to chlorine mixtures described in the above-mentioned works by E.Snyder and E.AIIen.

  From 1994 to 2001, Russia carried out comprehensive investigations of tetrapyrrol chlorin-type macrocycles (chlorophyll A derivatives). It has to establish the structural and functional features of their accumulation in tumors. It also needed to increase PDT efficiency and to create chlorin-type drugs. At that time, scientists developed a technique for extracting biologically active chlorins from plants. Plant chlorins were found to mainly contain chlorin e6. As a result, photosensitizers of the second generation were created. They were named Photochlorin and Photodithazine. These photosensitizers come as an 0.35% solution for intravenous injections.

Radachlorin® is the registered trade mark of Photochlorin. This drug substance represents an aqueous solution of three chlorins, including sodium chlorin e₆ (90-95 %) (Figures 1-2), sodium chlorin p₆ (5-7 %) (Figure 3), and a third chlorin that it is not preferred to be disclosed (1-5 %). Chlorin constituents (generally called chlorins) of the drug substance are 98 % of its dry weight. It has been found by us that the most stable way to store this drug substance is in the form of 7 % aqueous solution.

There is a patented process at our disposal now for the preparation of Radachlorin®. The elaborated technological process for Radachlorin® includes 4 steps: (1) acetone extraction of chlorophyll a from the dry mass of micro-algae Spirulina Platensis, magnesium removal with diluted hydrochloric acid and purification of the resulting phaeophytin a; (2) acid hydrolysis of the latter in the organic solvent-aqueous medium to phaeophorbide a and its purification; (3) saponification of phaeophorbide о to chlorin e₆; (4) conversion of chlorin e₆ to Radachlorin®. This drug substance is used as well for the preparation of two drug formulations on its base, named Radachlorin® solution for intravenous administration 0.35 % 10 ml and Radachlorin® gel for exter­nal application 0.1 % 25 g (Figure 4) which have passed through the obligatory volume of labo­ratory (non-clinical) studies, satisfied the official (GLP) requirements and were applied for the registration in The Russian Federation as pharmaceutical means in June, 2001. Currently, the drugs are approaching phase lib studies which are to be done in the strict compliance with GCP requirements in Russia and Europe.

To activate chlorin e6 photosensitizers the "Crystal 2000" semiconductor laser device was created in Russia in 2000. It emits at 662 nm (Figures 5-6), and available in five modifications with output power from 1 to 4 W and the standard SMA-905 connector, aperture 0.38 in 250 /jm, weight of device 4 kg. It can be optionally equipped with additional chan­nel of 808 or 980 nm with output power of 3 or 30 W for laser thermal therapy or laser sur­gery.

Radachlorin®'s properties
     Radachlorin® and the drug forms on its base are chemically stable during 2 years at 0+8 °C in the dark, therefore their storing periods have been stated as 1.5 years at these conditions.
     Radachlorin®'s uniqueness is in the following photophysical characteristics. It possesses intensive absorption band in the middle-red part of the spectrum in the bio­logical medium, where biological tissues are transparent to a lager extent than in case of the first generation PSs (Figure 7). Radachlorin® also favours intensive fluorescence, which is helpful for photodynamic diagnostics (PDD) (Table 1).

Radachlorin® is shown to combine a high value of interconversion coefficient of 96 % (Table 2) and, consequently, a high quantum yield of singlet oxygen (75 %) with a high extinction, that is optimal for PDT, since much laser light is absorbed by PS molecules, with 96 % of it being used for electron transition to a higher energy state than needed for fluorescence only, and 4 % of the absorbed energy being used for fluorescence (useful for PDD). Upon relaxation of this state, 75 % of the initially absorbed energy is used for generation of singlet oxygen, which makes Radachlorin® a highly cytotoxic agent upon irradiation.

It is of very high importance for in vivo use of a PS that the interconversion coefficient be equal in various media. It is the evidence of low ability to aggregation and predictable spectral properties in various types of tumours.

Radachlorin® has been found to be characteristic of a low acute toxicity in vivo in the dark (white breedless mice). Radachlorin®'s acute toxicity is 119 mg/kg for LD₁₀, and 147 mg/kg for LD₅₀. It is non-pyrogenic and does not have histamine-like action in the test dose of 0.70 mg/kg corresponding to the recommended clinical dose (rabbits and cats).

For Radachlorin® and its intravenous drug form, experiments on the chronic toxicity, allergenity, immunogenity, local irritating action, CMS action, cardiovascular action, biochemistry of blood and histology were done, showing the absence of serious Radachlorin®'s side-effects on the organisms of mice, rats, rabbits, guinea-pigs.

As the model for tumour growth, metastasizing lymphogenically embryocarci-noma (MLEC T36) has been used inoculated either s.c. or i.m. in experiments on mice. Experiments were performed within 14 days, when the tumour diameter was 10 mm (1±0.1 g). Spontaneous tumour necrosis was minimal or absent for these tumour sizes. Maximum tumour accumulation of Radachlorin® (0.70 pM) was achieved by 5 h p.i. at i.p. administration at the dose of 40 mg/kg, and 0.32 ^M by 0.5 h p.i. at i.v. administra­tion of the dose twice as lower. We have shown that these values are enough for effi­cient PDT procedure with this drug. It is noteworthy, that tumour concentration was still high enough to perform PDT efficiently (0.48 jL/M) by 18 h p.i. at i.p. administration, being only 1.5 times lower than at its absolute maximum by 5 h p.i. (Figure 8).

Maximum contrast with Radachlorin® administered i.p. was observed 18 h p.i. with the maximum tumour-to-muscle ratio about 32, and tumour-to-skin ratio about 44. If the drug was administered i.v., maximum contrast with Radachlorin® was observed 3 h p.i. with the maximum tumour-to-muscle ratio about 3, and tumour-to-skin ratio about 14. The full clearance period has been found to be 48 h p.i. at any way of administration. Thus, optimally from selectivity point, light was to be delivered by 3 h p.i. at i.v. way of administration, and by 18 h p.i. at i.p. way of administration. Optimum time for light delivery from accumulation point is considered to be 0.5 h p.i. at i.v. way of administration, and 5 h p.i. at i.p. way of administration.

PC12 (pheochromocytoma) cell line and MTT-test were used for in vitro stu­dies. Dishes for light experiments were then irradiated with laser light: l_ex 662 nm (the Crystal 2000 laser device) for Radachlorin® and Photosense at the doses of 50 J/cm². For every PS two experiments were done: with photoirradiation («light») and without pho-toirradiation («dark»), and in each pair of the dishes there was found to be an equal amount of cells. Some of Radachlorin®'s characteristics significant for PDT are given in Table 3.

It is seen from Table 3 that Radachlorin® is more lipophilic, and, in fact, amphiphilic, and characterised of n-octanol/phosphate buffer, pH 7.4 partition coefficient of 1.4, so that it can go from blood plasma to cell membranes and attach to nuclear membranes, mitochondria, lisosomes and neoplastic tissue. It has been supposed that Radachlorin®'s high photodynamic efficacy is connected with its ability to easily pene­trate into biological membranes, and also with tumour blood vessel stasis and throm­bosis caused by photoirradiation of the tumour lesion while Radachlorin® is accumula­ted therein. Radachlorin® did not show any toxicity on PC12 cell culture without irradi­ation except the range of very high concentrations. Thus, in vitro Radachlorin® is less toxic and more efficient PS upon irradiation than the drug of comparison.

Radachlorin® showed an expressed specific PDT activity in a mice model in the experiments. The study of Radachlorin®'s photodynamic efficacy with experimental ani­mals was performed using male Balb/c mice with embryocarcinoma T36 inoculated in the muscle of hind leg. The 662 nm light was delivered from the 2.5 W “Crystal 2000” laser device (Technica-Pro Co, Moscow, Russia) in 2 weeks after tumour cell inoculation (tumour weight of 0.9-1 g) and 5-6 h after drug administration at the i.p.dose of 40 mg/kg or i.v. dose of 20 mg/kg. The optimum light dose was 300 J/crm.

The results have been obvious for the expressed photodynamic activity to be stated for the drug. PDT procedure resulted in complete tumour necroses in 2-4 weeks.The laser irradiation only did not produce any effect to the tumour. The result of Radachlorin® action could be seen already in the first hours after irradiation. During the first two days the tumour grew darker from its bulk to periphery, and by the 3^r« day tumour necrosis started, resulting in tumour contraction and upper crust formation, its peeling away with normal tissues beneath (Figure 9). Biopsy revealed no cancerous cells.

The proposed therapeutic doses for the humans basing on these experiments were recommended as between 0.7 and 1.2 mg/kg.

Phase II-a experimental data of Radachlorin®, 0.35 % solution for intravenous administration and Radachlorin®, 0.1 % gel for outer application clinical trials

Hospital 1
     The “Crystal 2000” laser device with 662 nm wavelength was used. PS Radachlorin® was given by intravenous diffusion in 100 ml of physiological solution during 20 min, or it was applied externally as gel 1-3 h prio to the treatment.
     Since May, 2000 to May, 2001 in the Clinic of general surgery of Chelyabinsk State Medical Academy (CSMA) PDT method was applied to treatment of 35 patients (15 male and 20 female) with malignant tumours of skin, breast, gastrointestinal tract, female genitals, thyroid gland, etc. by Prof. V.A. Privalov.There were 31 patients with 1 procedure, 3 patients with 2 procedures and 1 patient with 3 procedures (Table 4).

Eight patients were subjected to PDT because of centra-indications to the traditional methods of treatment: age-specific changes, serious concomitant diseases. Tumours were on the 1 and II stage in 58 % of patients, in 4 cases there was primary-plural lesion of one or several organs.

Some of the patients (5 persons, 137 tumours) were previously treated with the help of traditional methods (surgery, radio-, chemo-, cryotherapy), and the possibilities of the given methods at treatment of vestigial tumour, recurrence and metastases were exhausted. In such patients the PDT was applied not earlier than in 1 month after radio-or chemotherapy.

Effectiveness of PDT was estimated according to visual, endoscopic, X-ray, ultrasonic and cytomorphological methods.         
      There were used four techniques of laser irradiation:

• Distant surfacial irradiation
• Intracavernous
• Interstissual
• Combination of surfacial and interstissual

    Delivery of radiation was fulfilled with fibres, diffusers and micro-lenses. Treatment was performed under local and systemic anaesthesia. Effectiveness of PDT was estimated right after the procedure, in 1-2 days, on the 7% 15^th, 3O day and then monthly. In period from 1 to 7 days the photochemical reaction, expressed to different extent, was noticed in 100 % of cases. Oedema and hyperaemia in the radiated zone, failure of blood circulation with tumour necrosis proved that in tumour developed photo-cytotoxic reaction.

Fig.10. Before PDT. Basalioma in the area of right cheek
Fig.11. PDT, after 2 h - slight hyperemia
Fig.12. PDT, after 1 day-slight swelling, darkening and crust formation
Fig.13. PDT, after 7 days - slight swelling, scab in place of tumour
Fig.14. PDT, 4 weeks - dense scrub
Fig.15. PDT, 6 weeks - the scrub's peeling away with excellent cosmetic effect

Hospital 2
     The research workers of the Sector of Clinical and Experimental Research in Otorhinolaryngology of the Research Centre of I. M. Sechenov Moscow Medical Academy started on the basis of the Moscow Regional Research Clinical Institute approbation of Radachlorin® in 3 patients with oncology E.N.T. diseases. Radachlorin® was used as a PS during PDT course. It was administered intravenously 2 hours before the beginning of the PDT course. No side effects were noted before irradiation. After administration of the preparation all patients stayed in rooms without special sunlight protection. During the course the patients felt some pricking of the irradiated surface. After the PDT treatment the tissues showed some hyperaemia. Oedema of the surrounding tissues was insignificant.

- Patient N, age 62. DS: Laryngeal cancer, continuous growth.Tracheostoma.
     Treated with two PDT courses with one-month interval. Result of the treatment: partial tumour resorption with the subsequent rapid growth. Initially the tumour volume was not completely irradiated.

- Patient K, age 67. DS: Laryngeal cancer. Underwent two PDT courses.
     Result of the treatment: complete tumour resorption. Control biopsy was performed. Notably no tracheotomy was performed in this patient and after PDT treatment he developed no oedema-caused stenosis.

- Patient P, age 66. DS: Basalioma of the earflap (recurrence).
     One PDT course. Radachlorin® was administered intravenously and used locally by way of gel applications 30 minutes before the session. Result: Complete tumour absorption, epithelisation of the wounded surface.

Summary: PDT Radachlorin®-assisted treatment of oncology patients showed positive results in case of complete irradiation of the whole tumour volume. Radachlorin® gave no negative side effects, could be quickly accumulated inside tumour tissues and eliminated from the body. Radachlorin® could be recommended as more preferable in comparison with other PSs.
     At present the clinical trials phase lib in 5 more hospitals are in progress, and the results will be reported elsewhere.

Conclusive remarks

Since Radachlorin® is derived from pure phaeophorbide a, its chemical com­position is clear, it can be easily dissolved in water without forming aggregates, which is characteristic of haematoporphyrin-IX derivatives (Photofrin II, ets.).
     Radachlorin® is amphiphilic, so it can easily go over from serum to plasmatic membranes of cells and penetrate inside cells. In drug formulations it is complemented with N-methyl-D-glucamine often used in pharmaceutics as deaggregation agent that helps stabilise Radachlorin® in aqueous solutions and easily eliminates at slightly acidic pH values of neoplastic tissues allowing for the chlorins' retaining in the tissues. Therefore, for Radachlorin® a comparatively high tumour accumulation (therapeutic ratio) is observed.

Radachlorin® is stable in solutions for 1.5 years at 0+8 °C in the dark.
     Radachlorin® possesses good spectral and energy characteristics. It has an intensive absorption band in the medium red part of the spectrum, where biological tis­sues are transparent to considerable extent. It also favours intensive fluorescence at 668 nm, which is helpful for photodynamic diagnostics (PDD).
     Radachlorin® favours excellent pharmacokinetic and toxicological parameters. When introduced to tumour-bearing mice, it has maximal tumour uptake 3-5 hours post injection with high tumour-to-normal tissue ratios and clearance period about 24-48 hours.

Supplement
The main facts of Photodynamic tumour therapy history

Photodynamic tumour therapy (PDT) is a relatively new prospective therapeutic modality tor the treatment of definite types of malicious neoplastic formations [a]. The method is based on the combination of a photocytotoxic action of a drug (toxic effect produced on the cells upon the drug's interaction with light of the specific wavelength) with its predominant accumulation in neoplastic tissues.
     The curative features of light were depicted still long ago in Ancient Greece. Herodotos is fairly thought to be the father of heliotherapy [cyt. a]. However, the first successful attempts to find the key and strengthen this curative effect are dated from the end of 19» century.

Phototoxic effect of a row of natural dyes chemically represented by a series of conjugated macro-cycles (eosine, psoralene, cyclic tetrapyrroles, etc.) was discovered by Oscar Raab - a medical student from Munchen, Germany in 1898 when he did research under the guidance of Prof, fon Tappeiner. Oscar Raab exper­imented with a dye named acrydine, which revealed its preperty to kill a protist - paramecia - upon irradiation with light. There was no such effect observed in the absence of light. The method was at once tested to treat some skin diseases with certain success followed by reports in the literature in 1903-1907 [cyt. b].

In 1903 skin cancer was firstly successfully treated with dye eosine and light [a].
     Such natural dyes was named photosensitizers (PS) (fon Tappeiner, 1903), and the method itself -Photodynamic action on a cell (fon Tappeiner, 1904). At first the terms denoted all the processes where PS, liv­ing tissue (cell) and irradiation procedure were involved, and later on (Blum,1941) [cyt. b]] they began to use the notions of photosensitizer (PS) and photodynamic therapy (PDT) only at describing the processes involving molecules aroused with light, generating singlet oxygen, and destroying cells [cyt. b].
     In 1911 Hausmann started his first experiments with hematoporphyrin IX derived from blood, and since then this porphyrin had become the main the investigator's attention was paid to until 1980s [cyt. a].

For example, in the end of 1940s it was supposed that hematoporphyrin IX possessed increased affinity to cancer tissues. A hypothesis appeared that to kill the tumour, a highly doubtful factor of such affinity could be as well completed with another factor - that the processes of tissue degradation do not start until PS molecules are aroused with light having a strictly specific wavelength and delivered exactly locally - on the tumour volume. The most important condition is for the light to have the wavelength (or diapason) where natural biopolimers, water and natural aromatic systems do not strongly absorb (600 - 1200 nm). For hematopor­phyrin IX derivatives the weakest but most red-shifted peak of absorption is at 619 nm [cyt. c].
     A report about first successful application of the tumour-localised hematoporphyrin IX and light was done by Auler and Banzer in 1943 [cyt. c].

In the middle 1950s S.Swartz (Israel) supposed that the selective fluorescence of malignant tissues after the systemic administration of hematoporphyrin IX was connected not with hematoporphyrin IX but rather with some impurities contained in it, because it is quite difficult to obtain pure hematoporphyrin IX [cyt. d].
     R.Lipson et. al. (Mayo Clinic, USA) reported in 1961 that hematoporphyrin IX's ability to localise in tumours selectively can be increased by its chemical modification - a partial polymerisation [cyt. e, f]. The prepa­ration was named HpD (hematoporphyrin derivative) and became the first practically used PDT dye.
     R.Lipson and others in   1960-67s first applied this preparation to patients with tumours [cyt. c, f].
     Gregarie and others in 1968 showed that HpD at intravenous or intraabdominal administration could in marked amounts concentrate in squamose-celled carcinomae and adenocarcinomae, binding with structures present in excess in tumours comparatively to normal tissues [cyt. a, c].

In 1972 I.Diamond et.al. (Californian University, USA) studied the action of such oligomeric mixture on murine glioma, and showed that prolonged irradiation of the tunours sensitised with HpD let to their destruc­tion [cyt. d, g]). At the same time HpD studies of cancer diagnostics and treatment started at Roswell Park Memorial Institute (USA) leaded by T.Dougherty [f]. In the experiments there was used the drug prepared by the method of Swartz-Lipson (1961) with Dougherty's modification (1979) [cyt. h].
     Photochemical properties of HpD were studied by Weishaupt in 1978 [i].
     In 1983 Kessel and Chou [cyt. a] did much to increase HpD's ability to localise in tumours by applying purifica­tion to enreach the preparation in the olygomers of specific molecular mass range. Such drug was later on named Photofrin II. Photofrin I and and Photofrin II were patented by T.Dougherty, K.Weishaupt and U.Potter [i].
     There was a lot of experiments done involving HpD, including clinical ones thanks to T.Dougherty, ir I976-I983 when when HpD named Photofrin I was used to temporarily help at endobronchial and esophagus obstructions, as well as to treat skin, brain and bladder tumours. This preparation is not used in clinic now due to its low efficacy [cyt. a].

In 1983 Kessel and Chou [cyt. a] did much to increase HpD's ability to localise in tumours by apply­ing purification to enreach the preparation in the olygomers of specific molecular mass range. Such drug was later on named Photofrin II. Photofrin I and and Photofrin II were patented by T.Dougherty, K.Weishaup' and U.Potter [i].
     There was a lot of experiments done involving HpD, including clinical ones thanks to T.Dougherty, ir I976-I983 when when HpD named Photofrin I was used to temporarily help at endobronchial and esophagus obstructions, as well as to treat skin, brain and bladder tumours. This preparation is not used in clinic now due to its low efficacy [cyt. a].
     Water-soluble derivatives of chlorophyll were first introduced as potential drugs by E.Snyder (USA' in 1942 [j]. Peroral and intravenous administration of chlorin mix tures mainly containing chlorin p_e a:(R,=Vi R₂=COOH, R₃=COOH, R₄=COOH) (Fig.16a) revealed their low toxicity, hypotensive, antisclerotic, spasmolytic anaesthetic, antirheumathoid action to result in their usage to prevent and treat cardiovascular diseases rheumathoid arthritis and atherosclerosis [k].

First PDT usage of chlorins relates to pheophorbide a derivatives b:(R,=Vi, R₂=COOH, R₃=COOMe; (Fig.16, b). Some of them were patented as prospective PS for PDT in 1984 in Japan by I.Sakata et.al. [I].
     In scientific literature there was first announced about good PDT properties of chlorins in 1986 [m] when a group of US authors (J.Bommer, Z.Sveida and B.Burnham) going out of a high potential of chlorin e, a:(R,=Vi, R₂=COOH, R₃=CH₂COOH, R₄=COOH), reported about the results of their search for a PS, possess­ing the most crucial PDT requirements, namely, good tumour affinity and intensive absorption in the middle-rec part of the spectrum. Their choice was mono-L-aspartyl-chlorin e, (MACE) a:(R,=Vi, R₂=COAsp, R₃=CH₂COOH R₄=COOH), which at present is at stage III clinical studies in Japan.
     Soon more functionalised chlorin and bacteriopheophorbide a c:(R=COOH) (Fig. 16, c) derivatives were patent pending in USA for Nippon Petrochemicals Company as PS for PDT [n].
     The first water-soluble chlorin e₆ drug agent was developed in 1994-2001 in Russia, and applied as PDT drug in 2000-2001.

In the present time a structure-activity relation-based search is going on among chlorins, bacteri-ochlorins, purpurins, benzoporphyrins, texaphyrins, etiopurpurins, naphthalo- and pthalocyanines [s]. PSs able not only to quickly and selectively accumulate in tumours and possessing good spectral properties but also having a high metabolic (catabolic) processing in the organism are of the spe cial interest now. With time, as chemotherapy history shows, there will be a bank of PDT drugs created contain ing a wide range of medicines of targetted action adopted to specific nozological forms of cancer.

Among second generation photosensitizers, mono- and diaspartyl chlorin e_s (MACE, NPe, and DACE) and lysyl-chlorin p_e (LCP) (Nippon Petrochemicals Co., Japan) are in clinical studies and the latter two proved to be less stable on storage and more expensive. Other drugs, such as benzoporphyrin derivative monoacid ring A (BPD, Verteporfin, Visudyne, QLT/CIBA Vision/Corxia Corp., Canada), Lu-texaphyrin (Lutrin, Pharmacyclics/NycoMed, USA), ethyl Sn-etiopurpurin (SnET2, Miravant/Pharmacia, USA) and tetra-meso-[m-hydroxyphenyl]chlorin (TMPC, Foscan, Great Britain and The Netherlands) are hydrophobic which brings additional application difficulties - solubility, shelf life and normal tissue photosensitivity problems.

1. H.I.Pass, Photodynamic therapy in oncology: mechanisms and clinical use. // J.Nat.Cancer Inst. 1993. - V. 85. - N 6. - p. 443-456.
2. J.D.Spikes, The origin and the meaning of the term photodynamic (as used in photodynamic therapy, for example) //J. Photochem. Photobiol. - 1991. - V. 9. - p. 369-374.
3. J.Moan and K.Berg, Photochemotherapy of cancer: experimental research //Photochem. Photobiol. 1992.- V. 55. - p. 931-948.
4. R.W.Boyle, D.Dolphin // Photochem. Photobiol. - 1996. - V. 64. - N 3.   - p. 469-485.
5. J.Moan, Porphyrin photosensitisation and phototherapy // Photochem.   Photobiol. - 1986. - V. 43. - p. 681.
6. DoughertyT.J. Photodynamic Therapy. //Photochemistry and Photobiology. -1993. - V. 58. - N 6.- p. 895-900.
7. Valles  M.A.  HpD  and  second  generation  photosensitisers for the  photodynamic therapy of cancer. //Afinidad.1993. - V. 50. - N. 448. - p. 469-479.
8. Pandey R.K., Dougherty T.J., and Smith K.M. Synthesis of Hematoporphyrin Dimers and Trimers With Ether Linkages. // Tetrahedron Letters. -   1988. - V. 29. - N 37. - p. 4657-4660.
9. Pat. 5,028,621 (07/1991) USA/ Dougherty T.J., Potter W.R., Weishaupt K.R. Drugs comprising porphyrins. // {as a continuation of   Pat. 4,866,168 of 09/1989 and Pat. 4,649,151 of 05/1984} //C.A. - 1984. - V. 101.-N 14. - 116725y.
10. Pat. 2,274,101 (02/1942) USA// E.G.Snyder. Preparation of chlorin e.
11. Pat. 3,102,891 (09/1963) USA// E.A.Alien. New porphyrinic and chlorophyllic compositions and process therfor.
12. Pat. 4,709,022 (11/1987) USA// Sakata I., Nakajima S., et.al. Pheophorbide Derivatives and Alkaline Salts Thereof. // C.A. - 1985. - V. 103. - N 15. - 123271s.
13. Bommer J.C., Sveida Z.J., Burnham B.F. Further studies on the relationship between tetrapyrrole structure and usefulness as photosensitizers. // Proc. 1 st Int. Conf. Clinical Applications of Photosensitization for Diagnosis and Treatment. - 1986. - p. 129.
14. Pat. 4,656,186 (04/1987) USA // Bommer J.C., Burnham B.F. Tetrapyrrol Therapeutic Agents. // C.A. - 1987. - V. 106. - N 11. - 85048b.
15. A.V.Reshetnickov, G.V.Ponomarev, A.V.Ivanov, O.Yu. Abakumova, Т.Д. Tsvetkova, A.V. Karmenyan, A.G. Rebeko, R.Ph.Baum. Novel drug form of chlorin e₆ // In Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy IX. -T.J.Dougherty, ed., V. 3909, 124-129 (2000).
16. A.V.Ivanov, A.V.Reshetnickov, G.V.Ponomarev. One more PDT application of chlorin e6 // In Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy IX. - T.J.Dougherty, ed., V. 3909, 131-137(2000).
17. E.Ph.Stranadko, G.V.Ponomarev, V.M.Mechkov, U.M.Koraboyev, A.V.Ivanov, A.V.Reshetnickov, M.V.Ryabov The first experience of Photodithazine clinical application for PDT of malignant tumours // In Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy IX. - T.J.Dougherty, ed., V. 3909, 138-144 (2000)
18. Photosensitizer, and process therefor. Inventors: Andrei V. Reshetnickov, Igor D. Zalevsky, Yuri V. Kemov, et. al. patent appl. No.   2001108397 (filed 30.03.2001), RF. Assignee: RADA-PHARMA Co. Ltd.
19. A.V.Reshetnickov, V.I.Shvets, G.V.Ponomarev // in Advances of porphyrin chemistry - O.Golubchikov, ed. - StPetersbourg: Research Institute for Chemistry of St.Petersbourg State University. -1999. - V. 2. - Chapter 4. -  p. 70-114.