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WO2001074398A1 - Composes pour therapie photodynamique - Google Patents

Composes pour therapie photodynamique Download PDF

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Publication number
WO2001074398A1
WO2001074398A1 PCT/GB2000/001215 GB0001215W WO0174398A1 WO 2001074398 A1 WO2001074398 A1 WO 2001074398A1 GB 0001215 W GB0001215 W GB 0001215W WO 0174398 A1 WO0174398 A1 WO 0174398A1
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mthpc
mab
conjugates
thpc
antibody
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Inventor
Martinus Bernardus Vrouenraets
Marijke Stigter
Gordon Brian Snow
Augustinus Antonius Maria Silverster Van Dongen
Pieter Edsge Postmus
Gerardus Wilhelmus Maria Visser
Fiona Anne Stewart
Hugo Oppelaar
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Priority to CA002376001A priority patent/CA2376001A1/fr
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Publication of WO2001074398A1 publication Critical patent/WO2001074398A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to compounds for photodynamic therapy (PDT) of cancerous and other diseased tissue.
  • PDT compounds those of USP 4,837,221 and USP 4,992,257 the disclosure of which is incorporated herein by reference.
  • n l to 3 and each substituent R in the phenyl rings, or other aryl groups replacing phenyl, is a hydroxy group. Particularly noted are those compounds where each substituent is o- hydroxyphenyl, m-hydroxyphenyl or p-hydroxyphenyl.
  • '257' includes di-hydro porphyrins (chlorins), and corresponding tetra- hydro porphyrins (bacteriochlorins) of the formulae:
  • each Ar is an aromatic group with one or more hydroxy substituent groups but as with '221' is desirably phenyl.
  • Preferred compounds are m-THPC, meta tetra(hydroxyphenyl) chlorin, currently in FDA trials, and the corresponding bacteriochlorin.
  • a porphyrin, chlorin or bacteriochlorin/isobacteriochlorin ring in any of its imino- nitrogen tautomeric forms carries four aromatic preferably phenyl substituents Ar each themselves carrying one or more hydroxy groups, one or more of which hydroxy groups is in turn linked to an antibody (in which are included antibody fragments) reactive to a cancer or other diseased -cell antigen, giving a conjugate valuable in PDT therapy of the disease.
  • the preferred aromatic substituent is m-hydroxy phenyl, as in m-THPC.
  • the antibodies can be linked direct to the hydroxy groups but generally the presence of a linking group is preferred.
  • Examples are ether-linked groups for example
  • n 1 to 4 and A is -OH or - ⁇ H 2 or, less preferred, ester-linked groups for example:-
  • n and A are as before and R 1 is hydrogen or a hydrocarbon or carboxylated amino-acid side chain, representing particularly glycine, alanine, lysine or glutamic acid.
  • Ester, amide or other links are then readily formed with the antibody according to the free reactive groups present on it.
  • the invention extends to compounds as in VIII but carrying such linking groups, as intermediates, as well as to the antibody conjugates themselves.
  • the invention further relates to the treatment of disease by PDT using the antibody conjugates and to the use of antibody conjugates in the preparation of medicaments for PDT.
  • the invention is not restricted to any mechanism, that in use of the conjugates they or at least the PDT active are internalized by the cells of diseased tissue after administration of the conjugate.
  • PDT agents destroy mitochondrial function by the generation of free radicals and/or reactive oxygen species.
  • free radicals or reactive oxygen species need to reach the mitochondria, which are within the cytoplasm, and it is supposed that for photodynamic therapy to be active, the PDT molecule has to penetrate the cell surface membrane and be energized in close proximity to the mitochondria. The free radicals and reactive oxygen species then do the damage.
  • the antibodies will normally be monoclonal antibodies of which mMAB 425 discussed in detail herein is an example. There are many such antibodies known, directed against cell surface antigens of cancer or other disease cells. Examples include
  • CD22 NHL CD33 Acute pro myelocytic leukemia CD45 Leukemia CD40 Leukemia
  • Target solid tumors .
  • EGF-r Breast, renal, pancreatic, H&N, lung
  • chemistry of the conjugation of the actives and antibodies depends on their nature and on whether a linking group is used and is not central to the invention in its broad sense.
  • chemistry as described herein for m-THPC is suitable for other chlorins and also for porphyrins and bacteriochlorins/isobacteriochlorins, particularly the m-hydroxy phenyl derivatives corresponding to m-THPC.
  • mTHPC met -tetrahydroxyphenylchlorin
  • MAbs tumor selective monoclonal antibodies
  • HNSCC head and neck squamous cell carcinoma
  • cMAb selective chimeric MAb
  • Photodynamic therapy is a therapeutic modality for the treatment of superficially localized tumors.
  • a photosensitive dye photosensitizer
  • the sensitizer After exposure to laser light in the red or near-infrared region, the sensitizer is excited and is able to produce singlet oxygen, a cytotoxic form of oxygen.
  • Direct cell killing, occlusion of tumor blood vessels as well as a strong acute inflammatory reaction can occur. These combined effects result in tumor necrosis.
  • PDT has been applied for non-invasive treatment of many types of cancer, including colon, bladder, lung, and head and neck cancer.
  • mTHPC met ⁇ -tetrahydroxyphenylchlorin
  • a limitation is the lack of tumor selectivity, which can result in severe normal tissue damage after PDT of large surface areas.
  • An option to overcome this problem is to couple mTHPC to monoclonal antibodies (MAbs) directed against tumor-associated antigens. In this way the photosensitizer will be targeted selectively to the tumor.
  • MAbs monoclonal antibodies
  • These mTHPC-MAb conjugates are especially suitable for the treatment of multiple tumor foci in large areas, as is the case in minimal residual disease after surgical resection of thoracic and peritoneal tumors.
  • the problem of phototoxicity is also reduced since the accessibility of the skin is limited for MAbs.
  • MAbs for selective targeting of squamous cell carcinoma of the head and neck (HNSCC).
  • HNSCC head and neck
  • MAbs E48 and U36 have been developed (3,4). Radioimmunoscintigraphy/biodistribution studies in HNSCC patients showed that these MAbs are highly capable of selective tumor targeting (5,6,7). This observation justifies a study for the use of these MAbs as transport vehicle for selective delivery of mTHPC to HNSCC.
  • mTHPC eto-tetrahydroxyphenylchlorin
  • MAb U36 Monoclonal Antibodies. Selection and production of MAb U36 and its chimeric (mouse/human) IgGl derivative (cMAb U36) have been described previously (4, 8). MAb U36 recognizes the v6 domain of the 200 kDa CD44 splice variant epican (9), which is highly expressed in squamous cell carcinoma of the head and neck, lung, skin, oesophagus and cervix, adenomacarcinomas of breast and lung, as well as in normal stratified epithelium. A clinical RIS study with "Tc-labeled U36 revealed that U36 IgG accumulates selectively and to a high level in HNSCC (7), and therefore the MAb is currently evaluated in RIT studies.
  • Murine monoclonal antibody 425 (mMAb 425) is a IgG2a MAb developed and characterized by Murthy et al. (10).
  • the epitope recognized by mMAb 425 is localized on the external domain of the EGF receptor (EGFR), which has been shown to be highly expressed by various tumor types including HNSCC, renal cell cancer, gliomas and carcinoma of the oesophagus, bladder, cervix, stomach, lung and breast.
  • EGFR EGF receptor
  • anti- EGFR MAbs After binding to this antigen, anti- EGFR MAbs are internalized and catabolized by A431 cells (11).
  • Anti-EGFR MAbs, MAb 425 included, have been extensively studied in clinical trials (12,13).
  • HPLC analysis was performed by using a LKB 2150 HPLC-pump (Pharmacia Biotech, Roosendaal, The Netherlands), a LKB 2152 LC controller (Pharmacia Biotech) and a 25-cm Lichrosorb 10 RP 18 column (Chrompack, Middelburg, The Netherlands) at a flow-rate of 2 ml/min.
  • the eluant consisted of a 9: 1 (v/v) mixture of MeCN and 0.1 % trifluoroacetic acid.
  • Absorption was measured at 230 nm and 415 nm by a Pharmacia LKB VWM 2141 UV detector. Radioactivity was measured by an Ortec 406 A single-channel analyzer connected to a Drew 3040 Data collector (Betron Scientific, Rotterdam, The Netherlands).
  • the absorption spectra of mTHPC and mTHPC-MAb conjugates were measured using a Ultrospec III spectrophotometer (Pharmacia Biochrom).
  • the mTHPC concentration in the conjugate preparations was assessed with the same apparatus at a wavelength of 415 nm.
  • the absorption of a range of dilutions (1-9 ⁇ g/ml) of mTHPC in MeCN was measured and graphically depicted using the least square method.
  • the mTHPC concentration in the conjugate preparations was determined using this calibration curve.
  • the integrity of the mTHPC-MAb conjugates was analyzed by electrophoresis on a Phastgel System (Pharmacia Biotech) using preformed 7.5 % SDS-PAGE gels under non- reducing conditions. After running, gels were stained with 0.2% Coomassie Brilliant Blue (CBB, Sigma) and exposed to a Phosphor plate for 1-3 h and analyzed with a Phosphor Imager (B&L-Isogen Service Laboratory, Amsterdam) for localization of the protein bands. Quantitative information was obtained by cutting the lanes into pieces and dual label counting in a gamma counter (LKB-Wallac 1282 CompuGamma, Pharmacia, Woerden, The Netherlands).
  • CBB Coomassie Brilliant Blue
  • reaction mixture was filtered through a 0.22 ⁇ M Acrodisc filter (German Sciences Inc., Ann Arbor, MI) and unbound 125 I was removed using a PD-10 column (Pharmacia Biotech, Woerden) with 0.9% ⁇ aCl as eluant. After removal of unbound 125 I, the radiochemical purity always exceeded 98 % .
  • 131 I-Labeling of mTHPC was trace-labeled with 131 I. This labeling and subsequent reaction steps with mTHPC were carried out in the dark and under a ⁇ 2 atmosphere to prevent unwanted photochemical reactions during the synthesis of the mTHPC-MAb conjugates.
  • 131 I-Labeling of mTHPC was performed using lodo-beads (Brunschwig Chemie) as follows: the appropriate amount of I31 I was added to 50 ⁇ l of 1 mM NaOH containing 10 ⁇ g Na- ⁇ SO 3 .
  • This 131 I-solution was added to 4 lodo-beads covered with 450 ⁇ l of a MeCN/H 2 O mixture (10: 1; v/v) followed by 100 ⁇ l (734 nmol) of a mTHPC-solution (5 mg/ml in MeCN). After labeling during 30 min the reaction mixture was diluted with 400 ⁇ l H2O, loaded on a conditioned Sep-pak Cis cartridge (Waters, Millipore, MA) and washed with 50 ml H 2 O. The 131 I-labeled mTHPC (actually consisting of a small proportion of 131 I-mTHPC and an excess of unlabeled mTHPC) was eluted with 3 ml MeCN. The solvent was evaporated under a stream
  • the radiochemical purity of 131 I-mTHPC was determined by HPLC analysis.
  • the HPLC retention times were: 9.8 min for 131 I-mTHPC, between 5-9 min for 131 I-labeled minor impurities and 9.6 min for mTHPC (For the ⁇ -NMR data of mTHPC see Table 1).
  • the conjugation efficiency was determined from the 125 I: 131 I ratio before and after PD-10 purification using dual label counting in a gamma counter.
  • the 131 I-mTHPC: 125 I-MAb molar ratio was determined by measuring the absorbance at 415 nm to calculate mTHPC concentration and 125 I measurement for MAb quantitation.
  • the integrity of the conjugate was checked by gel electrophoresis.
  • the chemistry is summarised in Figure 1. Repeating the chemistry but starting with the porphyrins of USP 4,837,221, particularly o-, p- or m-THPP corresponding to o-, p- or m- THPC, or with the bacteriochlorins or isobacteriochlorins of USP 4,992,257, particularly o-, p- or m-THPB or THPiB corresponding to o-, p- or m-THPC, gives the mMAB 425 conjugates of those compounds.
  • mice were anesthetized, bled, killed and dissected. The urine was collected and the organs were removed. After weighing, the amount of gamma-emitting radioactivity in organs, blood and urine was measured in a gamma counter.
  • the blood, urine and organs were treated as follows: after complete decay of 123 I, tissue samples were placed in counting vials and 1 ml of Soluene-350 (Packard Instrument Company, Groningen, The Netherlands) was added to dissolve the organs. The vials were subsequently heated at 50°C for 24 h, after which 250 ⁇ l of a 1: 1 (v/v) mixture of 30% H 2 O2 and acetic acid was added for decolorization of the solutions. After 1 h Ultima Gold liquid scintillation cocktail (15 ml, Packard Instrument Company) was added to the samples prior to counting in a LKB-Wallac 1410 Liquid Scintillation Counter (Pharmacia, Woerden). Radioactivity uptake in the tissues was expressed as the percentage of the injected dose per gram of tissue (%ID/g).
  • Photoimmunotherapy in vitro Phototoxicity of the mTHPC-cMAb U36 conjugates and the unconjugated mTHPC was assessed in UM-SCC-22A cells using the sulforhodamine B (SRB, Sigma) assay, which measures the cellular protein content.
  • Cells were plated in 96-well plates (2500 per well) and grown for 3 days before incubating with mTHPC or mTHPC-cMAb U36 conjugates (0.1 nM to 1.0 ⁇ M mTHPC equivalent) in DMEM supplemented with 2 mM L- glutamine, 5% FCS and 25 mM HEPES at 37 °C.
  • mTHPC-cMAb U36 and mTHPC were removed by washing twice with medium. Fresh medium was added and cells were illuminated at 652 nm with a 6 W Diode Laser (AOC Medical Systems) at a dose of 25 J/cm 2 . Three days after illumination, growth was assessed by staining the cellular proteins with SRB and spectrophotometric measurement of the absorption at 540 nm with a microplate reader. ICso values were estimated based on the absorption values and defined as the concentration that corresponded to a reduction in growth of 50% compared with values for control cells (no mTHPC-MAb conjugates or mTHPC added but illuminated in the same way).
  • Phototoxicity of the mTHPC-mMAb 425 conjugates was assessed in A431 cells (2000 cells/well) in a similar way.
  • the purity of the fractions (0.5 ml) that were recovered from the LiChroprep column was analyzed using HPLC analysis at 415 nm for detection of mTHPC-(CH 2 CO-TFP)4 and at 230 nm for detection of ICH2CO-TFP, formed as a side-product. On the LiChroprep column this latter ester had a retention time slightly longer than mTHPC-(CH2CO-TFP) 4 .
  • the fractions that only contained mTHPC-(CH 2 CO-TFP)4 (under our conditions fractions 20-23) were, after collection, evaporated under a stream of N2 and stored in the dark at 4 °C until use.
  • the LiChroprep purification also removed unbound 131 1, and any unreacted TFP, EDC or ICH2COOH. As a result, the mTHPC-ester was obtained in an overall yield of 60% with a purity > 95 % .
  • the mixture was added to a solution of 125 I-MAb in 0.9% NaCl at pH 9.5. After 30 min at room temperature the 131 I-mTHPC-(CH 2 COOH) 3 CH 2 CONH- 125 I-MAb conjugate (5, Fig. 1) was purified on a PD 10 column.
  • the 13I I-mTHPC- 125 I-MAb molar ratio was about 2.0-2.5.
  • the conjugation efficiency was 60% + 10% (corrected for completely hydrolyzed ester, which is unable to couple), while the recovery of the MAb always exceeded 95% (measured by 125 I activity).
  • Biodistribution of 131 I-mTHPC- 125 I-cMAb U36 conjugates were performed to determine whether coupling of 131 I-mTHPC-(CH 2 COOH)4 to 125 I-cMAb U36 resulted in improved targeting of the sensitizer to the tumor. To this end the biodistribution of unconjugated 125 I-cMAb U36 and 131 I-mTHPC-(CH 2 COOH)4 were first determined. For evaluation of 1 5 I-cMAb U36, 5 ⁇ Ci 125 I-cMAb U36 (100 ⁇ g) were injected in 5 HNX-OE xenograft bearing nude mice.
  • mice were sacrificed 48 h after injection and the biodistribution was determined.
  • the mean uptake in tumor tissue was 19.5 %ID/g, while the mean blood level was 13.9 %ID/g. Uptake in all other organs was less than 4 %ID/g (Fig. 4A).
  • PDT-immunoconjugates can be parenterally administered in pharmaceutical compositions.
  • Such compositions comprising of PDT-immunoconjugate e.g.(m-THPC-MAb or m-THPBC-MAb) and a parenterally administrable medium are formulated by methods commonly used in pharmaceutical chemistry.
  • the effective concentration of immunoconjugates of the present invention is dictated by the PDT agent used in the conjugate.
  • One skilled in the art of preparing such compositions will be able to consider optimal ratio of composition of pharmaceutical components and PDT immunoconjugate.
  • an injectable solution 20% EtOH, 30% ethylene glycol 400, and 50% water (v/v) with NaCl to give an 0.9% solution (w/v) is made up with m-THPC-MAb to give a dose of 15 mg for an adult (70kg body weight) related to the m- THPC.
  • suitable dose ranges of the m-THPC and the other PDT actives discussed herein are for example 0.1 to 5 mg/kg related to the active.
  • mTHPC-MAb conjugates prepared according to the method described herein showed a minimal impairment of the integrity on SDS-PAGE ( ⁇ 10% aggregate formation), full stability in serum in vitro and an optimal immunoreactivity, provided that not more than 4 mTHPC molecules were coupled to the MAb. Nevertheless, the pharmacokinetics of mTHPC-MAb conjugates in xenograft bearing nude mice differed from that of unconjugated MAb. For conjugates with a mean ratio of 0.9 and 1.8, the 125 I-levels of the 131 I-mTHPC- 125 I-MAb in the blood at 48 h p.i. were 69% and 52% , respectively, of that of an unconjugated I25 I-MAb.
  • the 131 I-mTHPC-(CH 2 COOH)4 was cleared more rapidly from the circulation than the unmodified mTHPC.
  • the tumor selectivity of MAb-conjugated mTHPC was increased in comparison with both of these, despite the more rapid elimination of the conjugates with a higher ratio.
  • the tumor levels of I31 I-mTHPC were 5.7 and 4.4 %I.DJg, respectively. In absolute amounts this corresponds with 23 and 36 ng/g tumor, respectively. Given the fact that increasing the MAb dose to 400 ⁇ g per mouse does not result in antigen saturation, this implies that about 150 ng mTHPC per g tumor can be delivered.
  • Another aspect of evaluation is the uptake in the skin, in view of the problem of skin photosensitization.
  • the levels of the MAb-conjugated mTHPC in the skin were much lower than in the tumor (tumor: skin ratio's were 3.5; Fig. 4D).
  • the levels in the skin and tumor were almost the same, 24 h after injection (tumor: skin ratio's were 0.8 and 0.9, respectively; Fig. 5). This is in agreement with data of Whelpton et al.
  • PDT photodynamic therapy
  • mTHPC meta- tetrahydroxyphenylchlorin
  • mMAb/cMAb murine/chimeric monoclonal antibody
  • CEA carcinoembyryonic antigen
  • HNSCC head and neck squamous cell carcinoma
  • RIS radioimmunotherapy
  • EGFR epidermal growth factor receptor
  • 'H-NMR proton nuclear magnetic resonance
  • HPLC high-performance liquid chromatography
  • SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis
  • TFP 2,3,5,6-tetrafluorophenol
  • EDC l-ethyl-3-(3-dimemylammopropyl)-carbodiimide
  • BSA bovine serum albumin
  • %ID/g percentage of injected dose/g of tissue
  • FCS fetal calf serum
  • SCS fetal calf
  • mTHPC-(CH2COOH) 3 CH2CONH-MAb conjugates are designated as mTHPC-MAb conjugates if the modification of mTHPC is not relevant for understanding
  • FIG. 1 Schematic representation of the synthesis of 13I I-mTHPC-(CH2COOHk its esterification, partial hydrolysis and conjugation to a 125 I-labeled MAb. It is of note that 131 I can occupy 12 positions (both ortho-positions and the para-position relative to the OH, in each of the 4 phenyl rings). In the mono-TFP ester 4, 1 of the 4 possible mono-TFP esters is depicted.
  • FIG. 3 Example of an SDS-PAGE and Phosphor Imager analysis of a I31 I-mTHPC- 125 I- cMAb U36 conjugate with ratio 1.8. Quantitative assessment of the radioactivity was obtained by cutting the lane and dual label counting.
  • FIG. 4 Biodistribution of I 5 I-cMAb U36 and 131 I-mTHPC-(CH2COOH)4 before and after conjugation. Each preparation was intravenously injected in 6 HNX-OE bearing nude mice.
  • mice were bled, sacrificed, dissected and the radioactivity levels (%ID/g + SE) of blood, tumor and several organs were assessed.
  • Tu tumor
  • Bl blood
  • He heart
  • Ki kidney
  • Sto stomach
  • II ileum
  • Co colon
  • Ste sternum
  • Lu lung
  • Mu muscle
  • Sk skin
  • Li liver
  • Sp spleen.
  • FIG. 6 The SRB assay was used to assess the antiproliferative effect of mTHPC and mTHPC-MAb conjugates upon illumination.
  • FIG. 7 Illustration of the phototoxicity of mTHPC to the integrity of 125 I-cMAb U36.
  • 50 ⁇ g 125 I-cMAb U36 was incubated in 500 ⁇ l MeCN/0.9% NaCl (1/4 v/v) at pH 9.5: with 25 ⁇ g mTHPC in dark (lane A), with 25 ⁇ g mTHPC in light under a N2 atmosphere (lane B), with 25 ⁇ g mTHPC in light (lane C), without mTHPC in light as a control (lane D). After 1 h incubation SDS-PAGE and Phosphor Imager analysis was performed.

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Abstract

L'invention concerne des composés pour thérapie photodynamique, qui renferment des tétra(hydroxyaryl)porphyrines, des chlorines et des bactériochlorines conjuguées à des anticorps sensibles à des antigènes de cellules cancéreuses ou d'autres cellules pathologiques.
PCT/GB2000/001215 2000-03-30 2000-03-30 Composes pour therapie photodynamique Ceased WO2001074398A1 (fr)

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AU35675/00A AU3567500A (en) 2000-03-30 2000-03-30 Photodynamic therapy compounds
CA002376001A CA2376001A1 (fr) 2000-03-30 2000-03-30 Composes pour therapie photodynamique
PCT/GB2000/001215 WO2001074398A1 (fr) 2000-03-30 2000-03-30 Composes pour therapie photodynamique

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WO2004002476A3 (fr) * 2002-06-27 2004-05-13 Health Research Inc Photosensibilisants fluores associes a des chlores et des bacteriochlores pour la therapie photodynamique
US7018395B2 (en) 1999-01-15 2006-03-28 Light Sciences Corporation Photodynamic treatment of targeted cells
US7053210B2 (en) 2002-07-02 2006-05-30 Health Research, Inc. Efficient synthesis of pyropheophorbide a and its derivatives
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CN105343878A (zh) * 2015-11-30 2016-02-24 中国人民解放军第三军医大学第三附属医院 还原敏感型水溶性分子靶向光敏剂及其制备方法和应用

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