Skip to main content
SpringerLink
Log in

Bacteriochlorophyll Sensitizers in Photodynamic Therapy

  • Chapter
Chlorophylls and Bacteriochlorophylls

Part of the book series: Advances in Photosynthesis and Respiration ((AIPH,volume 25))

Abstract

Recent progress in the bioproduction and chemical manipulation of bacteriochlorophyll (BChl) a has opened the way for utilization of highly potent sensitizers in photodynamic therapy. Although less stable than their chlorin analogues in their native form, BChl derivatives provide a superior optical and biophysical profile for the generation of reactive oxygen species (ROS). In fact this pigment family probably represents the most ef- ficient light collectors and radical generators in nature. Here we describe a recent development of this exciting family of drugs, with particular emphasis on vascular targeted therapy (VTP).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Borle F, Radu A, Fontolliet C, van den Bergh H, Monnier P and Wagnieres G (2003) Selectivity of the photosensitizer Tookad® for photodynamic therapy evaluated in the Sirian golden hamster cheek pouch tumour model. Br J Cancer 89:2320–2326

    Article  PubMed  CAS  Google Scholar 

  • Chen L, Gross S, Rosenbach-Belkin V, Brandis A, Scherz A and Salomon Y (1998) Photoinactivation of microorganisms by chlorophyll-serine, bacteriochlorophyll-serine and by targeted bacteriochlorophyll-IgG. In: Patrice T (ed) IPA-98 Proceedings, RC-41. Ispen Biotech, Nantes (CD-ROM)

    Google Scholar 

  • Chen Q, Huang Z, Luck D, Beckers J, Brun P-H, Wilson BC, Scherz A, Salomon Y and Hetzel FW (2002a) Preclinical studies in normal canine prostate of a novel palladium-bac-teriopheophorbide (WST09) photosensitizer for photodynamic therapy of prostate cancer. Photochem Photobiol 76:438–45

    Article  CAS  Google Scholar 

  • Chen Q, Huang Z, Luck D, Beckers J, Brun P-H, Wilson BC, Scherz A, Salomon Y and Hetzel FW (2002b) WST09 (TOOKAD) mediated photodynamic therapy as an alternative modality in the treatment of prostate cancer. Proc SPIE 4612:29–39

    Article  CAS  Google Scholar 

  • Chen Y, Graham A, Potter W, Morgan J, Vaughan LA, Bellnier DA, Henderson BW, Oseroff A, Dougherty TJ and Pandey RK (2002c) Bacteriopurpurinimides: Highly stable and potent photosensitizers for photodynamic therapy. J Med Chem 45:255–258

    Article  CAS  Google Scholar 

  • Dagan A, Gatt S, Cerbu-Karabat S, Maziere J-C, Maziere C, Santus R, Engelhardt EL, Yeh KA, Stobbe CC, Penning MC and Chapman JD (1995) Uptake by cells and photosensitizing effectiveness of novel pheophorbide derivatives in vivo. Int J Cancer 63:831–839

    Article  PubMed  CAS  Google Scholar 

  • Damoiseau X, Schuitmaker HJ, Lagerberg JWM and Hoebeke M (2001) Increase of the photosensitizing efficiency of the bacteriochlorin a by liposome-incorporation. J Photochem Photobiol B-Biol 60:50–60

    Article  CAS  Google Scholar 

  • Doi M, Shioi Y, Gad'on N, Golecki JR and Drews G (1991) Spectroscopical studies on the light-harvesting pigment-protein complex II from dark-aerobic and light-anaerobic grown cells of Rhodobacter sulfidophilus. Biochim Biophys Acta 1058:235–241

    Article  CAS  Google Scholar 

  • Eichwurzel I, Stiel H, Teuchner K, Leupold D, Scheer H, Salomon Y and Scherz A (2000) Photophysical consequences of coupling bacteriochlorophyll a with serine and its resulting solubility in water. Photochem Photobiol 72:204–209

    Article  PubMed  CAS  Google Scholar 

  • Elhilali M (2003) Palladium bacteriopheophorbide (WST09)—PDT in the treatment of prostate cancer: A phase I/II clinical study for recurrent prostate cancer after radiation therapy. In: Symposium-Steba-Biotech, the XVIII Congress of the European Association of Urology. Madrid, Spain

    Google Scholar 

  • Fiedor L, Rosenbach-Belkin V, Sai M and Scherz A (1996) Preparation of tetrapyrrole-amino acid covalent complexes. Plant Physiol Biochem 34:393–398

    CAS  Google Scholar 

  • Gatt S, Dagan A, Santus R, Maziere JC, Chapman JD and Engelhardt EL (1996) Phorbine derivatives and their use in the diagnosis and therapy of cancer. US Pat 5,492,924

    Google Scholar 

  • Gerasimov OV, Boomer JA, Quails MM and Thompson DH (1999) Cytosolic drug delivery using pH- and light-sensitive liposomes. Adv Drug Deliv Rev 38:317–338

    Article  PubMed  CAS  Google Scholar 

  • Geskes C, Hartwich G, Scheer H, Maentele W and Heize J (1995) Electrochemical and spectroelectrochemical investigation of metal-substituted bacteriochlorophyll a. J Am Chem Soc 117:7776–7783

    Article  CAS  Google Scholar 

  • Ghosh R (2003) New nucleic acid encoding geranylgeranyl-di-phosphate synthase, and related cells, useful for preparation of farnesyl-bacteriochlorophyll a, for photodynamic therapy. DE10134103

    Google Scholar 

  • Gross S, Brandis A, Chen L, Rosenbach-Belkin V, Roehrs S, Scherz A and Salomon Y (1997) Protein-A-mediated targeting of bacteriochlorophyll-IgG to Staphylococcus aureus: A model for enhanced site-specific phototoxicity. Photochem Photobiol 66:872–878

    PubMed  CAS  Google Scholar 

  • Gross S, Gilead A, Mazor O, Brandis A, Schreiber S, Machluf Y, Neeman M, Scherz A and Salomon Y (2003a) Selective vascular and tumor responses to photodynamic therapy (PDT) with Pd bacteriopheophorbide (Tookad®): Online and offline analyses. Proc AACR 44:27

    Google Scholar 

  • Gross S, Gilead A, Scherz A, Neeman M, and Salomon Y (2003bb) Monitoring photodynamic therapy of solid tumors online by BOLD-contrast MRI. Nature Med 9:1327–1331

    Article  CAS  Google Scholar 

  • Henderson B W and Dougherty TJ (1992) How does photodynamic therapy work? Photochem Photobiol 55:145–157

    PubMed  CAS  Google Scholar 

  • Henderson BW, Sumlin AB, Owcharczak BL and Dougherty TJ (1991) Bacteriochlorophyll-a as photosensitizer for photodynamic treatment of transplantable murine tumors. J Photochem Photobiol B-Biol 10:303–313

    Article  CAS  Google Scholar 

  • Hoebeke M and Damoiseau X (2002) Determination of the singlet oxygen quantum yield of bacteriochlorin a: A comparative study in phosphate buffer and aqueous dispersion of dimiristoyl-L-alpha-phosphatidylcholine liposomes. Photochem Photobiol Sci 1:283–287

    Article  PubMed  CAS  Google Scholar 

  • Hoebeke M, Schuitmaker HJ, Jannink LE, Dubbelman TMAR, Jakobs A and van de Vorst A (1997) Electron spin resonance evidence of the generation of superoxide anion, hydroxyl radical and singlet oxygen during the photohemolysis of human erythrocytes with bacteriochlorin a. Photochem Photobiol 66:502–508

    PubMed  CAS  Google Scholar 

  • Katz S, Vakrat Y, Brumfeld V, Weiner L, Brandis A, Gabelmann E, Paul A, Hild M, Lendt K, Leupold D, Norris JR, Scheer H, Moser J, Salomon Y and Scherz A (1998) Bacteriochlorophyll-serine generates only OH radicals under near-infra-red illumination (MR). In: Patrice T (ed) IPA-98 Proceedings, RC-208. Ispen Biotech, Nantes (CD-ROM)

    Google Scholar 

  • Kelleher DK, Thews O, Rzeznik J, Scherz A, Salomon Y and Vaupel P (1999) Water-filtered infrared-A radiation: A novel technique for localized hyperthermia in combination with bacteriochlorophyll-based photodynamic therapy. Int J Hyperthermia 15:467–474

    Article  PubMed  CAS  Google Scholar 

  • Kelleher DK, Thews O, Scherz A, Salomon Y and Vaupel P (2003) Combined hyperthermia and chlorophyll-based photodynamic therapy: Tumour growth and metabolic microenvironment. Br J Cancer 89:2333–2339

    Article  PubMed  CAS  Google Scholar 

  • Koudinova NV, Pinthus JH, Brandis A, Brenner O, Bendel P, Ramon J, Eshhar Z, Scherz A and Salomon Y (2003) Photodynamic Therapy with Pd-bacteriopheophorbide (TOOKAD): Successful in vivo treatment of human prostatic small cell carcinoma xenografts. Int J Cancer 104:782–789

    Article  PubMed  CAS  Google Scholar 

  • Kozyrev AN, Zheng G, Zhu C, Dougherty TJ, Smith KM and Pandey RK (1996) Syntheses of stable bacteriochlorophyll-a derivatives as potential photosensitizers for photodynamic therapy. Tetrahedron Lett 37:6431–6434

    Article  CAS  Google Scholar 

  • Krasnovsky Jr AA, Neverov KV, Egorov SYu, Roder B and LewaldW (1990) Photophysical studies of pheophorbide a pheophytin a. Phosphorescence and photosensitized singlet oxygen luminescence. J Photochem Photobiol B-Biol 5:245–254

    Article  Google Scholar 

  • Lindsay-Smith JR and Calvin M (1966) Studies on the chemical and photochemical oxidation of bacteriochlorophyll. J Am Chem Soc 88:4500–4506

    Article  CAS  Google Scholar 

  • Macdonald IJ and Dougherty TJ (2001) Basic principles of photodynamic therapy. J Porphyr Phthalocya 5:105–129

    Article  CAS  Google Scholar 

  • Mazor O, Brandis A, Gross S, Hami R, Vakrat Y, Koudinova N, Gladysh E, Kostenich G, Orenstein A, Salomon Y and Scherz A (2002) Pd-Bacteriopheophorbide (TOOKAD), a novel antivascular agent for photodynamic therapy of tumors: In vitro and in vivo studies. In: The 3rd Congress of the Federation of Israeli Societies for Experimental Biology (FISEB), p. 231. Book of abstracts, Eilat, Israel

    Google Scholar 

  • Mironov AF, Kozyrev AN and Brandis AS (1993) Sensitizers of second generation for photodynamic therapy of cancer based on chlorophyll and bacteriochlorophyll derivatives. Proc SPIE 1922:204–208

    Article  CAS  Google Scholar 

  • Mironov AF, Efremov AV, Efremova OA, Bonnett R and Martinez G (1998) Chlorins with an exocyclic δ-lactone ring and their derivatives. J Chem Soc-Perkin Trans 1:3601–3608

    Article  Google Scholar 

  • Mironov AF, Grin M and Tsyprovskiy AG (2002) Synthesis of the first N-hydroxycycloimide in the bacteriochlorophyll a series. J Porphyr Phthalocya 6:358–361

    Article  CAS  Google Scholar 

  • Moser JG (1993) Attempts to treat malignant melanoma by photodynamic therapy using bacteriopheophorbide ester as the sensitizer. Proc SPIE 1881:116–125

    Article  CAS  Google Scholar 

  • Moser JG (1998) Bacteriochlorophyllides, bacteriochlorins and bacteriopheophorbides. In: Moser JG (ed) Photodynamic Tumor Therapy:2nd and 3rd Generation Photosensitizers, pp. 43–49. Harwood, London

    Google Scholar 

  • Moser JG, Ruk A, Schwarzmaier H-J and Westphal-Frosch C (1992) Photodynamic cancer therapy: Fluorescence localization and light absorption spectra of chlorophyll-derived photosen-sitizers inside cancer cells. Opt Eng 31:1441–1446

    Article  Google Scholar 

  • Moser JG, Dembeck U, Hubert M, Spengler B, Bayer R and Wagner B (1994aa) Subcellular storage compartments of bacteriopheophorbide sensitizers. Proc SPIE 2078:532–538

    Article  CAS  Google Scholar 

  • Moser JG, Ostrowsky A, Gumusgadli M and Kleiber B (1994bb) Bacteriopheophorbide esters: Photosensitizers without ‘threshold dose’? Proc SPIE 2078:193–204

    Article  CAS  Google Scholar 

  • Moser JG, Suchomski R, Danielowski T and Wagner B (1995) Significance of threshold doses for photodynamic therapy of melanotic and amelanotic tumors. Proc SPIE 2371:178–186

    CAS  Google Scholar 

  • Musewald C, Hartwich G, Pollinger-Dammer F, Lossau H, Scheer H and Michel-Beyerle ME (1998) Time-resolved spectral investigation of bacteriochlorophyll a and its transmetalated derivatives [Zn]-bacteriochlorophyll a and [Pd]-bacteriochlo-rophyll a. J Phys Chem B 102:8336–8342

    Article  CAS  Google Scholar 

  • Noy D, Fiedor L, Hartwich G, Scheer H and Scherz A (1998) Metal-substituted bacteriochlorophylls. 2. Changes in redox potentials and electronic transition energies are dominated by intramolecular electrostatic interactions. J Am Chem Soc 120:3684–3693

    Article  CAS  Google Scholar 

  • Pandey RK and Zheng G (2000) Porphyrins as photosensitizers in photodynamic therapy. In: Kadish KM, Smith KM and Guilard R (eds) The Porphyrin Handbook, Vol. 6, pp. 157–230. Academic Press, San Diego

    Google Scholar 

  • Post JG, Poele JAM, Schuitmaker JJ and Stewart FA (1996) A comparison of functional bladder damage after intravesical photodynamic therapy with three different photosensitizers. Photochem Photobiol 63:314–321

    PubMed  CAS  Google Scholar 

  • Roder B, Dressier C, Hagemann R, Fuchs B, Berlien H-P, Nowak C and Moser J (1994) The pharmacokinetics of 132-hydroxy-bacteriopheophorbide a methyl ester studied by fluorescence spectroscopy on Lewis lung carcinoma bearing mice. Proc SPIE 2078:427–37

    Article  Google Scholar 

  • Roehrs S, Ruebner A, Hartwich G, Scheer H and Moser JG (1995) Peripheral substitution of pheophorbides and bacteriopheophorbides to promote inclusion into inert carrier systems for PDT. Proc SPIE 2625:333–338

    Article  Google Scholar 

  • Rosenbach-Belkin V, Chen L, Fiedor L, Tregub I, Pavlotsky F, Brumfeld V, Salomon Y and Scherz A (1996) Serine conjugates of chlorophyll and bacteriochlorophyll: Photocytotoxicity in vitro and tissue distribution in mice bearing melanoma tumors. Photochem Photobiol 64:174–181

    PubMed  CAS  Google Scholar 

  • Rosenkranz AA, Lunin VG, Sergienko OV, Gilyazova DG, Voronina OL, Jans DE, Kofner AA, Shumiantseva MA, Mironov AF and Sobolev AS (2003) targeted intracellular site-specific drug delivery: Photosensitizer targeting to melanoma cell nuclei. Rus J Genet 39:259–268

    Article  Google Scholar 

  • Rovers JP, Schuitmaker JJ, Vahrmeijer AL, van Dierendonck JH and Terpstra OT (1998) Interstitial photodynamic therapy with the second-generation photosensitizer bacteriochlorin a in a rat model for liver metastases. Br J Cancer 77:2098–2103

    PubMed  CAS  Google Scholar 

  • Scheer H, Kammhuber N, Scherz A, Brandis A and Salomon Y (2001) Synthesis and photodynamic activity of chlorophyll and bacteriochlorophyll esters. PCT Appl. WO01/40232, 48 pp

    Google Scholar 

  • Scherz A, Salomon Y and Fiedor L (1994) Chlorophyll and bacteriochlorophyll derivatives, their preparation and pharmacological compositions comprising them as photosensitizers for photodynamic therapy. EP Appl. 584552, 32 pp

    Google Scholar 

  • Scherz A, Salomon Y, Scheer H, Hartwich G and Brandis A (1997) Synthesis and bactericidal activity ofmetal-substituted bacteriochlorophyll derivatives for use in photodynamic therapy and as bactericides and virucides. PCT Appl. WO97/19081, 36 pp

    Google Scholar 

  • Scherz A, Salomon Y, Brandis A and Scheer H (2000) Palladium-substituted bacteriochlorophyll derivatives and use thereof. PCT Appl. WO00/33833, 59 pp

    Google Scholar 

  • Scherz A, Brandis A, Greenwald M, Rosenbach-Belkin V, Mazor O, Gross S, Hammi R, Vakrat Y, Simonneaux G, Scheer H and Salomon Y (2001) TOOKAD — a novel palladium-bacterio-chlorophyll sensitizer for photodynamic therapy: Synthesis and characterization. In: Clinical and Basic Applications of Photodynamic Medicine, p. 79, IPA 8th World Congress of Photodynamic Medicine-Book of Abstracts, Vancouver, Canada

    Google Scholar 

  • Scherz A, Brandis A, Mazor O, Salomon Y and Scheer H (2004) Water-soluble anionic bacteriochlorophyll derivatives and their uses. PCT Appl WO04/045492, 56 pp

    Google Scholar 

  • Schreiber S, Gross S, Brandis A, Harmelin A, Rosenbach-Belkin V, Scherz A and Salomon Y (2002) Local photodynamic therapy (PDT) of rat C6 glioma xenografts with Pd-bacteriopheophorbide leads to decreased metastases and increase of animal cure compared with surgery. Int J Cancer 99:279–285

    Article  PubMed  CAS  Google Scholar 

  • Schuitmaker JJ, Vrensen GF JM, van Delft JL, de Wolff-Rouendaal D, Dubbelman TMAR and De Wolf A (1991) Morphological effects of bacteriochlorin a and light in vivo on intraocular melanoma. Invest Ophthalmol Vis Sci 32:2683–2688

    PubMed  CAS  Google Scholar 

  • Schuitmaker JJ, Jannik JE and Dubbelman T (1995) Influence of cell-culture medium on the photosensitizing effectiveness of bacteriochlorin-alpha. J Photochem Photobiol B-Biol 28:143–148

    Article  CAS  Google Scholar 

  • Smith KM, Lee S-J, Shiau F-Y, Pandey RK and Jagerovic N (1992) Syntheses of chlorin and bacteriochlorin-type photosensitizers for photodynamic therapy. In: Spinelli P, Dal Fante M and Marchesini R (eds) Photodynamic Therapy and Biomedical Lasers, pp. 769–773. Elsevier Science Publishers B.V, Amsterdam

    Google Scholar 

  • Struck A, Cmiel E, Katheder I, Schäfer W and Scheer H (1992) Bacteriochlorophylls modified at position C3: Long range intramolecular interaction with position C132. Biochim Biophys Acta 1101:321–328

    Article  CAS  Google Scholar 

  • Tsygankov AA, Laurinavichene TV and Gogotov IN (1994) Laboratory-scale photobioreactor. Biotechnol Tech 8:575–578

    Article  CAS  Google Scholar 

  • Tsygankov AA, Laurinavichene TV, Bukatin VE, Gogotov IN and Hall DO (1997) Biomass production by continuous cultures of Rhodobacter capsulatus grown in various bioreactors. Appl Biochem Microbiol 33:485–490

    Google Scholar 

  • Vakrat-Haglili Y (2002) Photophysical and photochemical processes in photodynamic therapy (PDT) Initiated by bacterio-chlorophyll derivatives (Bchl-Der): Novel second generation sensitizers, PhD Thesis. The Weizmann Institute of Science, Rehovot, Israel

    Google Scholar 

  • van Geel IPJ, Oppelaar H, Oussoren YG, Schuitmaker JJ and Stewart FA (1995) Mechanisms for optimizing photodynamic therapy — 2nd-generation photosensitizers in combination with mitomycin-C. Br J Cancer 72:344–350

    PubMed  Google Scholar 

  • van Leengoed HLLM, Schuitmaker JJ, van der Veen N, Dubbelman TMAR and Star WM (1993) Fluorescence and photodynamic effects of bacteriochlorin a observed in vivo in ‘sandwich’ observation chambers. Br J Cancer 67:898–903

    PubMed  Google Scholar 

  • van Tenten Y, Schuitmaker HJ, De Wolf A, Willekens B, Vrensen GFJM and Tassignon MJ (2001) The effect of photodynamic therapy with bacteriochlorin a on lens epithelial cells in a capsular bag model. Exp Eye Res 72:41–48

    Article  PubMed  CAS  Google Scholar 

  • van Tenten Y, Schuitmaker HJ, De Groot V Willekens B, Vrensen GFJM and Tassignon M-J (2002) A Preliminary study on the prevention of posterior capsule opacification by photodynamic therapy with bacteriochlorin a in rabbits. Ophthalmic Res 34:113–118

    Article  PubMed  Google Scholar 

  • Watanabe T and Kobayashi M (1991) Electrochemistry of chlorophylls. In: Scheer H (ed) Chlorophylls, pp. 287–315. CRC Press, Boca Raton

    Google Scholar 

  • Wymer N, Gerasimov OV and Thompson DH (1998) Cascade liposomal triggering: Light-induced Ca2+ release from diplas-menylcholine liposomes triggers PLA2-catalyzed hydrolysis and contents leakage from DPPC liposomes. Bioconjugate Chem 9:305–308

    Article  CAS  Google Scholar 

  • Zilberstein J, Scherz A, Bromberg A, Bendel P, Neeman M and Salomon Y (1995) Mechanisms involved in chlorophyll based photoinduced cell damage: Photodynamic therapy of melanoma. Proc Soc Magn Res 3:1681–1682

    Google Scholar 

  • Zilberstein J, Bromberg A, Frantz A, Rosenbach-Belkin V, Kritzmann A, Pfefermann R, Salomon Y and Scherz A (1997) Light-dependent oxygen consumption in bacteriochlorophyll-serine-treated melanoma tumors: On-line determination using a tissue-inserted oxygen microsensor. Photochem Photobiol 65:1012–1019

    PubMed  CAS  Google Scholar 

  • Zilberstein J, Schreiber S, Bloemers MCWM, Bendel P, Neeman M, Schechtman E, Kohen F, Scherz A and SalomonY (2001) Antivascular treatment of solid melanoma tumors with bacte-riochlorophyll-serine-based photodynamic therapy. Photochem Photobiol 73:257–266

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Plant Sciences, Lomonsov Institute of Fine Chemical Technology, Moscow

    Alexander S. Brandis, Yoram Salomon & Avigdor Scherz

Authors
  1. Alexander S. Brandis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoram Salomon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Avigdor Scherz
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Humboldt University, Berlin, Germany

    Bernhard Grimm

  2. CSIRO Plant Industry, Canberra, Australia

    Robert J. Porra

  3. Ludwig-Maximilians-Universität München, Germany

    Wolfhart Rüdiger

  4. Ludwig-Maximilians-Universität München, Germany

    Hugo Scheer

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer

About this chapter

Cite this chapter

Brandis, A.S., Salomon, Y., Scherz, A. (2006). Bacteriochlorophyll Sensitizers in Photodynamic Therapy. In: Grimm, B., Porra, R.J., Rüdiger, W., Scheer, H. (eds) Chlorophylls and Bacteriochlorophylls. Advances in Photosynthesis and Respiration, vol 25. Springer, Dordrecht. https://doi.org/10.1007/1-4020-4516-6_33

Download citation

Publish with us

Policies and ethics

Search

Navigation