Journal of Literature Pharmacy Sciences

Nanoantikorların Genel Özellikleri/ Tanı ve Tedavide Kullanımları: Geleneksel Derleme
General Properties of Nanobodies/Uses in Diagnosis and Treatment: Traditional Rewiew
Türker SALMANa,b, Sibel İLBASMIŞ TAMERa
aGazi Üniversitesi Eczacılık Fakültesi, Eczacılık Teknolojisi Bölümü, Farmasötik Teknoloji AD, Ankara, Türkiye
bFırat Üniversitesi Kovancılar Meslek Yüksekokulu, Eczane Hizmetleri Bölümü, Eczane Hizmetleri Programı, Elazığ, Türkiye
J Lit Pharm Sci. 2024;13(2):85-98
doi: 10.5336/pharmsci.2023-100206
Article Language: TR
Full Text
ÖZET
Hedefleme amacıyla tedavilerde kullanılan geleneksel antikorlar, kanser başta olmak çeşitli hastalıklarda önemli başarılar sağlamıştır. Ancak büyük boyutları ve buna bağlı olarak kısıtlı tümör penetrasyonları, düşük stabiliteleri ve immünojenisiteleri kullanımlarını sınırlandırır. Bu durum zamanla daha küçük antikor fragmanlarına olan ilgiyi artırmıştır. Hamers-Casterman ve ark. şans eseri Camelidae (devegiller) türlerinde ve bazı kıkırdaklı balıklarda (köpek balığı) yeni bir antikor türü keşfetmiştir. Nanoantikor (nanobody) adı verilen bu tam antijen bağlama kapasitesine sahip küçük antikor parçaları, hafif zincirlerden yoksundur. Monoklonal antikorlara nazaran daha küçük boyuta (12-14 kDa) sahip olmaları, yüksek kimyasal ve termal stabiliteleri, suda çözünürlüklerinin yüksek olması, düşük immünojeniklik, kısa kan dolaşım süresine bağlı kandan hızla temizlenme ve yüksek doku penetrasyonu gibi çeşitli avantajları mevcuttur. Ayrıca nanoantikorlar immün, saf ve sentetik kütüphanelerden çeşitli mikroorganizmalar vasıtasıyla, etkin bir şekilde düşük maliyetle ekonomik olarak üretilebilmektedir. Bunun yanında modifikasyona yatkın olmalarından dolayı istenen özelliklere sahip nanoantikorlar araştırmacılar tarafından kolaylıkla tasarlanmaktadır. Nanoantikorlar ilaçlara, toksinlere, radyonüklidlere ve ilaç taşıyıcı sistemlere basitçe konjuge edilebildiğinden bu moleküllerin uygun hedeflere spesifik olarak gönderilmesi için önemli terapötik potansiyel taşımaktadır. Ayrıca kararlı yapıları ve uygulamadan kısa bir süre sonra yüksek tümör-arka planı oluşturmaları nedeniyle tanı ve görüntüleme çalışmalarında sıklıkla kullanılmaktadır. Bu derleme makalesinde nanoantikorların bazı üstün özelliklerinin yanı sıra kanser ve diğer hastalıkların biyomedikal araştırmaları, tanı ve tedavisindeki güncel uygulamalar incelenmiştir.

Anahtar Kelimeler: Nanoantikor; antikor; antineoplastik ajan; moleküler hedefe yönelik tedavi; tanı
ABSTRACT
Conventional antibodies used in targeting therapies have achieved significant success in various diseases, especially cancer. However, their large size and therefore limited tumor penetration, low stability and immunogenicity limit their use. This has increased interest in smaller antibody fragments over time. By chance, Hamers-Casterman and his team discovered a new type of antibody in Camelidae species and some cartilaginous fish (sharks). These small antibody fragments with full antigen-binding capacity, called nanoantibodies (nanobody), lack light chains. They have various advantages compared to monoclonal antibodies, such as their smaller size (12-14 kDa), high chemical and thermal stability, high water solubility, low immunogenicity, rapid clearance from blood due to short blood circulation time, and high tissue penetration. In addition, nanoantibodies can be produced effectively and economically at low cost from immune, pure and synthetic libraries through various microorganisms. In addition, nanoantibodies with desired properties can be easily designed by researchers because they are prone to modification. Since nanoantibodies can be simply conjugated to drugs, toxins, radionuclides, and drug delivery systems, they have significant therapeutic potential for the specific delivery of these molecules to appropriate targets. In addition, they are frequently used in diagnostic and imaging studies due to their stable structure and high tumor-background formation shortly after application. In this review article, some of the superior properties of nanoantibodies as well as current applications in biomedical research, diagnosis and treatment of cancer and other diseases are examined.

Keywords: Nanobody; antibody; antineoplastic agents; molecular targeted therapy; diagnosis
REFERENCES:
  1. Bathula NV, Bommadevara H, Hayes JM. Nanobodies: The future of antibody-based immune therapeutics. Cancer Biother Radiopharm. 2021;36(2):109-22. [Crossref]  [PubMed] 
  2. Liu M, Li L, Jin D, Liu Y. Nanobody-A versatile tool for cancer diagnosis and therapeutics. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2021;13(4):e1697. [Crossref]  [PubMed] 
  3. Jovčevska I, Muyldermans S. The therapeutic potential of nanobodies. BioDrugs. 2020;34(1):11-26. [Crossref]  [PubMed]  [PMC] 
  4. Sun S, Ding Z, Yang X, Zhao X, Zhao M, Gao L, et al. Nanobody: a small antibody with big ımplications for tumor therapeutic strategy. Int J Nanomedicine. 2021;16:2337-56. [Crossref]  [PubMed]  [PMC] 
  5. Vincke C, Muyldermans S. Introduction to heavy chain antibodies and derived Nanobodies. Methods Mol Biol. 2012;911:15-26. [Crossref]  [PubMed] 
  6. Muyldermans S. Nanobodies: natural single-domain antibodies. Annu Rev Biochem. 2013;82:775-97. [Crossref]  [PubMed] 
  7. Oliveira S, Heukers R, Sornkom J, Kok RJ, van Bergen En Henegouwen PM. Targeting tumors with nanobodies for cancer imaging and therapy. J Control Release. 2013;172(3):607-17. [Crossref]  [PubMed] 
  8. Muyldermans S. A guide to: generation and design of nanobodies. FEBS J. 2021;288(7):2084-102. [Crossref]  [PubMed]  [PMC] 
  9. Karakaş N, Öztürk İ, Tosyalı S, Bay S. Nanokorlar: tanı ve tedaviye yönelik antikor fragmanları [Nanobodies: diagnostic and therapeutic antibody fragments]. Acta Oncol Turc. 2018;51(2):240-50. [Crossref] 
  10. De Meyer T, Muyldermans S, Depicker A. Nanobody-based products as research and diagnostic tools. Trends Biotechnol. 2014;32(5):263-70. [Crossref]  [PubMed] 
  11. Steeland S, Vandenbroucke RE, Libert C. Nanobodies as therapeutics: big opportunities for small antibodies. Drug Discov Today. 2016;21(7):1076-113. [Crossref]  [PubMed] 
  12. Rossotti MA, Bélanger K, Henry KA, Tanha J. Immunogenicity and humanization of single-domain antibodies. FEBS J. 2022;289(14):4304-27. [Crossref]  [PubMed] 
  13. Liu B, Yang D. Easily established and multifunctional synthetic nanobody libraries as research tools. Int J Mol Sci. 2022;23(3):1482. [Crossref]  [PubMed]  [PMC] 
  14. Kang W, Ding C, Zheng D, Ma X, Yi L, Tong X, et al. Nanobody conjugates for targeted cancer therapy and imaging. Technol Cancer Res Treat. 2021;20:15330338211010117. [Crossref]  [PubMed]  [PMC] 
  15. Yu S, Xiong G, Zhao S, Tang Y, Tang H, Wang K, et al. Nanobodies targeting immune checkpoint molecules for tumor immunotherapy and immunoimaging (Review). Int J Mol Med. 2021;47(2):444-54. [Crossref]  [PubMed]  [PMC] 
  16. Yong Joon Kim J, Sang Z, Xiang Y, Shen Z, Shi Y. Nanobodies: robust miniprotein binders in biomedicine. Adv Drug Deliv Rev. 2023;195:114726. [Crossref]  [PubMed] 
  17. Jin BK, Odongo S, Radwanska M, Magez S. NANOBODIES®: a Review of diagnostic and therapeutic applications. Int J Mol Sci. 2023;24(6):5994. [Crossref]  [PubMed]  [PMC] 
  18. Mir MA, Mehraj U, Sheikh BA, Hamdani SS. Nanobodies: The "Magic Bullets" in therapeutics, drug delivery and diagnostics. Hum Antibodies. 2020;28(1):29-51. [Crossref]  [PubMed] 
  19. Unciti-Broceta JD, Del Castillo T, Soriano M, Magez S, Garcia-Salcedo JA. Novel therapy based on camelid nanobodies. Ther Deliv. 2013;4(10):1321-36. [Crossref]  [PubMed] 
  20. Yang EY, Shah K. Nanobodies: next generation of cancer diagnostics and therapeutics. front oncol. 2020;10:1182. [Crossref]  [PubMed]  [PMC] 
  21. Panikar SS, Banu N, Haramati J, Del Toro-Arreola S, Riera Leal A, Salas P. Nanobodies as efficient drug-carriers: progress and trends in chemotherapy. J Control Release. 2021;334:389-412. [Crossref]  [PubMed] 
  22. Debie P, Devoogdt N, Hernot S. Targeted nanobody-based molecular tracers for nuclear imaging and image-guided surgery. Antibodies (Basel). 2019;8(1):12. [Crossref]  [PubMed]  [PMC] 
  23. Hu Y, Liu C, Muyldermans S. Nanobody-based delivery systems for diagnosis and targeted tumor therapy. Front Immunol. 2017;8:1442. [Crossref]  [PubMed]  [PMC] 
  24. Bannas P, Hambach J, Koch-Nolte F. Nanobodies and nanobody-based human heavy chain antibodies as antitumor therapeutics. Front Immunol. 2017;8:1603. [Crossref]  [PubMed]  [PMC] 
  25. Bao G, Tang M, Zhao J, Zhu X. Nanobody: a promising toolkit for molecular imaging and disease therapy. EJNMMI Res. 2021;11(1):6. [Crossref]  [PubMed]  [PMC] 
  26. Verhaar ER, Woodham AW, Ploegh HL. Nanobodies in cancer. semin immunol. 2021;52:101425. [Crossref]  [PubMed]  [PMC] 
  27. Zimmermann I, Egloff P, Hutter CAJ, Kuhn BT, Bräuer P, Newstead S, et al. Generation of synthetic nanobodies against delicate proteins. Nat Protoc. 2020;15(5):1707-41. [Crossref]  [PubMed] 
  28. Roovers RC, Vosjan MJ, Laeremans T, el Khoulati R, de Bruin RC, Ferguson KM, et al. A biparatopic anti-EGFR nanobody efficiently inhibits solid tumour growth. Int J Cancer. 2011;129(8):2013-24. [Crossref]  [PubMed]  [PMC] 
  29. Duggan S. Caplacizumab: first global approval. drugs. 2018;78(15):1639-42. Erratum in: Drugs. 2018;78(18):1955. [Crossref]  [PubMed]  [PMC] 
  30. Mullard A. FDA approves second BCMA-targeted CAR-T cell therapy. Nat Rev Drug Discov. 2022;21(4):249. [Crossref]  [PubMed] 
  31. Keam SJ. Ozoralizumab: First Approval. Drugs. 2023;83(1):87-92. [Crossref]  [PubMed] 
  32. Nel J, Elkhoury K, Velot É, Bianchi A, Acherar S, Francius G, et al. Functionalized liposomes for targeted breast cancer drug delivery. Bioact Mater. 2023;24:401-37. [Crossref]  [PubMed]  [PMC] 
  33. Sayed-Tabatabaei L, Varshosaz J, Haghjooy Javanmard S, Soghrati S. Camouflaged liposomes by 11A4-nanobody for co-delivery of cisplatin and nitroxoline in breast cancer tumors: An in vitro/in vivo study. J Drug Deliv Sci Technol. 2022;71:103273. [Crossref] 
  34. Oliveira S, Schiffelers RM, van der Veeken J, van der Meel R, Vongpromek R, van Bergen En Henegouwen PM, et al. Downregulation of EGFR by a novel multivalent nanobody-liposome platform. J Control Release. 2010;145(2):165-75. [Crossref]  [PubMed] 
  35. Ghosh B, Biswas S. Polymeric micelles in cancer therapy: State of the art. J Control Release. 2021;332:127-47. [Crossref]  [PubMed] 
  36. Chaudhuri A, Ramesh K, Kumar DN, Dehari D, Singh S, Kumar D, et al. Polymeric micelles: a novel drug delivery system for the treatment of breast cancer. J Drug Deliv Sci Technol. 2022;77:103886. [Crossref] 
  37. Wang Y, Wang Y, Chen G, Li Y, Xu W, Gong S. Quantum-dot-based theranostic micelles conjugated with an anti-egfr nanobody for triple-negative breast cancer therapy. ACS Appl Mater Interfaces. 2017;9(36):30297-305. [Crossref]  [PubMed]  [PMC] 
  38. Talelli M, Oliveira S, Rijcken CJ, Pieters EH, Etrych T, Ulbrich K, et al. Intrinsically active nanobody-modified polymeric micelles for tumor-targeted combination therapy. Biomaterials. 2013;34(4):1255-60. [Crossref]  [PubMed] 
  39. Asadullah Khan M, Peng R, Liu CL, Chen Z. Synthesis, dynamics and applications (cytotoxicity and biocompatibility) of dendrimers: a mini-review. Eur Polym J. 2022;181(6):111708. [Crossref] 
  40. Wu T, Liu M, Huang H, Sheng Y, Xiao H, Liu Y. Clustered nanobody-drug conjugates for targeted cancer therapy. Chem Commun. 2020;56(65):9344-7. [Crossref]  [PubMed] 
  41. Kunde SS, Wairkar S. Targeted delivery of albumin nanoparticles for breast cancer: a review. Colloids Surf B Biointerfaces. 2022;213:112422. [Crossref]  [PubMed] 
  42. Altıntaş I, Heukers R, van der Meel R, Lacombe M, Amidi M, van Bergen En Henegouwen PM, et al. Nanobody-albumin nanoparticles (NANAPs) for the delivery of a multikinase inhibitor 17864 to EGFR overexpressing tumor cells. J Control Release. 2013;165(2):110-8. [Crossref]  [PubMed] 
  43. Hu B, Liu T, Li L, Shi L, Yao M, Li C, et al. IgG-Binding Nanobody Capable of Prolonging Nanobody-Based Radiotracer Plasma Half-Life and Enhancing the Efficacy of Tumor-Targeted Radionuclide Therapy. Bioconjug Chem. 2022;33(7):1328-39. [Crossref]  [PubMed] 
  44. Lemaire M, D'Huyvetter M, Lahoutte T, Van Valckenborgh E, Menu E, De Bruyne E, et al. Imaging and radioimmunotherapy of multiple myeloma with anti-idiotypic Nanobodies. Leukemia. 2014;28(2):444-7. [Crossref]  [PubMed] 
  45. Deken MM, Kijanka MM, Beltrán Hernández I, Slooter MD, de Bruijn HS, van Diest PJ, et al. Nanobody-targeted photodynamic therapy induces significant tumor regression of trastuzumab-resistant HER2-positive breast cancer, after a single treatment session. J Control Release. 2020;323:269-81. [Crossref]  [PubMed]  [PMC] 
  46. van Driel PBAA, Boonstra MC, Slooter MD, Heukers R, Stammes MA, Snoeks TJA, et al. EGFR targeted nanobody-photosensitizer conjugates for photodynamic therapy in a pre-clinical model of head and neck cancer. J Control Release. 2016;229:93-105. [Crossref]  [PubMed]  [PMC] 
  47. Behdani M, Zeinali S, Karimipour M, Khanahmad H, Schoonooghe S, Aslemarz A, et al. Development of VEGFR2-specific Nanobody Pseudomonas exotoxin A conjugated to provide efficient inhibition of tumor cell growth. N Biotechnol. 2013;30(2):205-9. [Crossref]  [PubMed] 
  48. Deng C, Xiong J, Gu X, Chen X, Wu S, Wang Z, et al. Novel recombinant immunotoxin of EGFR specific nanobody fused with cucurmosin, construction and antitumor efficiency in vitro. Oncotarget. 2017;8(24):38568-80. [Crossref]  [PubMed]  [PMC] 
  49. He R, Li L, Zhang T, Ding X, Xing Y, Zhu S, et al. Recent advances of nanotechnology application in autoimmune diseases-a bibliometric analysis. Nano Today. 2023;48:101694. [Crossref] 
  50. Papp KA, Weinberg MA, Morris A, Reich K. IL17A/F nanobody sonelokimab in patients with plaque psoriasis: a multicentre, randomised, placebo-controlled, phase 2b study. Lancet. 2021;397(10284):1564-75. Erratum in: Lancet. 2021;397(10290):2150. [Crossref]  [PubMed] 
  51. Ma L, Zhu M, Li G, Gai J, Li Y, Gu H, et al. Preclinical development of a long-acting trivalent bispecific nanobody targeting IL-5 for the treatment of eosinophilic asthma. Respir Res. 2022;23(1):316. [Crossref]  [PubMed]  [PMC] 
  52. Alirahimi E, Kazemi-Lomedasht F, Shahbazzadeh D, Habibi-Anbouhi M, Hosseininejad Chafi M, Sotoudeh N, et al. Nanobodies as novel therapeutic agents in envenomation. Biochim Biophys Acta Gen Subj. 2018;1862(12):2955-65. [Crossref]  [PubMed] 
  53. Ben Abderrazek R, Vincke C, Hmila I, Saerens D, Abidi N, El Ayeb M, et al. Development of Cys38 knock-out and humanized version of NbAahII10 nanobody with improved neutralization of AahII scorpion toxin. Protein Eng Des Sel. 2011;24(9):727-35. [Crossref]  [PubMed] 
  54. Hmila I, Saerens D, Abderrazek RB, Vincke C, Abidi N, Benlasfar Z, et al. A bispecific nanobody to provide full protection against lethal scorpion envenoming. FASEB J. 2010;24(9):3479-89. [Crossref]  [PubMed] 
  55. Bailon Calderon H, Yaniro Coronel VO, Cáceres Rey OA, Colque Alave EG, Leiva Duran WJ, Padilla Rojas C, et al. Development of Nanobodies Against Hemorrhagic and Myotoxic Components of Bothrops atrox Snake Venom. Front Immunol. 2020;11:655. [Crossref]  [PubMed]  [PMC] 
  56. Li T, Bourgeois JP, Celli S, Glacial F, Le Sourd AM, Mecheri S, et al. Cell-penetrating anti-GFAP VHH and corresponding fluorescent fusion protein VHH-GFP spontaneously cross the blood-brain barrier and specifically recognize astrocytes: application to brain imaging. FASEB J. 2012;26(10):3969-79. [Crossref]  [PubMed] 
  57. Custers ML, Wouters Y, Jaspers T, De Bundel D, Dewilde M, Van Eeckhaut A, et al. Applicability of cerebral open flow microperfusion and microdialysis to quantify a brain-penetrating nanobody in mice. Anal Chim Acta. 2021;1178:338803. [Crossref]  [PubMed] 
  58. Wouters Y, Jaspers T, De Strooper B, Dewilde M. Identification and in vivo characterization of a brain-penetrating nanobody. Fluids Barriers CNS. 2020;17(1):62. [Crossref]  [PubMed]  [PMC] 
  59. Barakat S, Berksöz M, Zahedimaram P, Piepoli S, Erman B. Nanobodies as molecular imaging probes. Free Radic Biol Med. 2022;182:260-75. [Crossref]  [PubMed] 
  60. Yang E, Liu Q, Huang G, Liu J, Wei W. Engineering nanobodies for next-generation molecular imaging. Drug Discov Today. 2022;27(6):1622-38. [Crossref]  [PubMed] 
  61. Kijanka MM, van Brussel AS, van der Wall E, Mali WP, van Diest PJ, van Bergen En Henegouwen PM, et al. Optical imaging of pre-invasive breast cancer with a combination of VHHs targeting CAIX and HER2 increases contrast and facilitates tumour characterization. EJNMMI Res. 2016;6(1):14. [Crossref]  [PubMed]  [PMC] 
  62. Altunay B, Morgenroth A, Mottaghy FM. Use of radionuclide-based ımaging methods in breast cancer. Semin Nucl Med. 2022;52(5):561-73. [Crossref]  [PubMed] 
  63. Vosjan MJ, Perk LR, Roovers RC, Visser GW, Stigter-van Walsum M, van Bergen En Henegouwen PM, et al. Facile labelling of an anti-epidermal growth factor receptor Nanobody with 68Ga via a novel bifunctional desferal chelate for immuno-PET. Eur J Nucl Med Mol Imaging. 2011;38(4):753-63. [Crossref]  [PubMed]  [PMC] 
  64. Huang L, Gainkam LO, Caveliers V, Vanhove C, Keyaerts M, De Baetselier P, et al. SPECT imaging with 99mTc-labeled EGFR-specific nanobody for in vivo monitoring of EGFR expression. Mol Imaging Biol. 2008;10(3):167-75. [Crossref]  [PubMed] 
  65. Xavier C, Blykers A, Vaneycken I, D'Huyvetter M, Heemskerk J, Lahoutte T, et al. (18)F-nanobody for PET imaging of HER2 overexpressing tumors. Nucl Med Biol. 2016;43(4):247-52. [Crossref]  [PubMed] 
  66. Keyaerts M, Xavier C, Heemskerk J, Devoogdt N, Everaert H, Ackaert C, et al. Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma. J Nucl Med. 2016;57(1):27-33. [Crossref]  [PubMed] 
  67. Gainkam LO, Caveliers V, Devoogdt N, Vanhove C, Xavier C, Boerman O, et al. Localization, mechanism and reduction of renal retention of technetium-99m labeled epidermal growth factor receptor-specific nanobody in mice. Contrast Media Mol Imaging. 2011;6(2):85-92. [Crossref]  [PubMed] 
  68. Meng X, Yang F, Dong H, Dou L, Zhang X. Recent advances in optical imaging of biomarkers in vivo. Nano Today. 2021;38:101156. [Crossref] 
  69. Xu M, Chen Z, Zheng J, Zhao Q, Yuan Z. Artificial intelligence-aided optical imaging for cancer theranostics. Semin Cancer Biol. 2023;94:62-80. [Crossref]  [PubMed] 
  70. Oliveira S, van Dongen GA, Stigter-van Walsum M, Roovers RC, Stam JC, Mali W, et al. Rapid visualization of human tumor xenografts through optical imaging with a near-infrared fluorescent anti-epidermal growth factor receptor nanobody. Mol Imaging. 2012;11(1):33-46. [Crossref]  [PubMed] 
  71. Guo X, Li C, Jia X, Qu Y, Li M, Cao C, et al. NIR-II fluorescence imaging-guided colorectal cancer surgery targeting CEACAM5 by a nanobody. EBioMedicine. 2023;89:104476. [Crossref]  [PubMed]  [PMC] 
  72. Heiles B, Terwiel D, Maresca D. The advent of biomolecular ultrasound imaging. Neuroscience. 2021;474:122-33. [Crossref]  [PubMed] 
  73. Jiang Y, Hou X, Zhao X, Jing J, Sun L. Tracking adoptive natural killer cells via ultrasound imaging assisted with nanobubbles. Acta Biomater. 2023;169:542-55. [Crossref]  [PubMed] 
  74. Hernot S, Unnikrishnan S, Du Z, Shevchenko T, Cosyns B, Broisat A, et al. Nanobody-coupled microbubbles as novel molecular tracer. J Control Release. 2012;158(2):346-53. [Crossref]  [PubMed]  [PMC] 
  75. Fan X, Wang L, Guo Y, Tu Z, Li L, Tong H, et al. Ultrasonic nanobubbles carrying anti-psma nanobody: construction and application in prostate cancer-targeted imaging. PLoS One. 2015;10(6):e0127419. [Crossref]  [PubMed]  [PMC] 

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4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com