Nano-ilaç taşıma sistemleri ve toksikolojik değerlendirmeleri

Yıl 2020, Cilt: 77 Sayı: 4, 509 - 526, 01.12.2020

Özge Marangoz Oğuzhan Yavuz

Öz

Bilim ve teknoloji dünyasına 1960’lı yılların başından itibaren giren nanoteknoloji, nanometre boyutundaki parçacıkların Nanoteknoloji günümüzde organik kimya, moleküler biyoloji, endüstri, elektronik ve sağlık gibi birçok alanda kullanılmaktadır. Nanoteknolojinin özellikle sağlık alanında kullanılması ile hastalıkların erken teşhisi, önlenmesi ve daha iyi takibi mümkün olabilmektedir. Beşeri ve veteriner hekimlikte ilaç etkin maddelerinin çeşitli nedenlerle etki yerinde istenen yoğunluğa ulaşamaması veya toksik düzeyin üstüne çıkması sıklıkla karşılaşılan istenmeyen durumlardır. Bu nedenle bütün dünyada etkin maddeyi hedef bölgeye yüksek yoğunluklarda ulaştıran ve istenmeyen etkileri mümkün olduğunca azaltan ilaç taşıma sistemleri elde edilmesi için çalışmalar yürütülmektedir. Bu amaçla son yıllarda nanoteknoloji yardımıyla geliştirilen nano-ilaç salınım sistemleri ile birlikte ilaç aktif maddeleri etki yerinde yeterli yoğunluğa ulaştırılabilmekte, sadece hedeflenen organ, doku ve hücrelerde etkin olabilmekte ve kullanılan doz ve doz aralığı azaltılarak istenmeyen etkilerin önüne geçilebilmektedir. Bunun gibi birçok avantaja sahip olmasına rağmen nano-ilaç komplekslerinin boyutları ve bileşenlerinin çok küçük olması nedeniyle, insan ve evcil hayvanların bu yapılara maruziyet riski oldukça artmıştır ve toksik etkilerinin olup olmadığı tartışmalı hale gelmiştir. Bu nedenle nano-ilaç salınım sistemlerinin güvenliklerinin çalışmalar önem kazanmıştır. Yapılan araştırmalarda nanomateryallerin hücrelerde apoptoz, nekroz, otofaji, mitotik yıkımlanma gibi istenmeyen etkilere yol açtıkları rapor edilmiştir. Ancak bu tür sonuçların elde edildiği toksikolojik araştırmalar daha çok in vitro denemelerdir ve in vivo çalışmaların yetersizliğinden dolayı nanoilaç ve nano-ilaç taşıma sistemlerinin canlı vücudu üzerindeki etkileri tam olarak ortaya konamamıştır. Bu nedenle nano-ilaçların toksisitesi konusunda ayrıntılı, sistematik ve uzun soluklu in vivo çalışmalara ihtiyaç duyulmaktadır. Bu derlemede, önemli nano-ilaç ve nano-ilaç taşıma sistemleri ile ilaç taşıma sistemlerinde kullanılan nanomateryallerin toksisitesi ve güvenli kullanımları değerlendirilmiştir.tespitine yönelik toksikolojik

Anahtar Kelimeler

Nano-ilaç, taşıma sistemleri, toksisite

Nano-drug delivery systems and their toxicological assessment

Öz

Nanotechnology, which involved in the science and technology from beginning of 1960s, defined as science of nano-sized particles. Nanotechnology is used in many fields, such as organic chemistry, molecular biology, industry, electronic and medicine. Thanks to usage of nanotechnology in the health sector, early diagnosis, prevention and better monitoring of diseases can be possible. Lower access of drug active ingredients than desired concentrations and their higher accumulations than the toxic levels in the action point are usual adverse effects in human and veterinary medicine. Therefore, studies are performed worldwide on drug delivery systems for transferring active ingredients in high concentrations to the target place and for reducing adverse effects as much as possible. Owing to nano-drug delivery systems, active ingredients can be transported to the effect point; they can be effective only in the target organ, tissue and cells; dose and dose intervals can be reduced and adverse effects can be decreased. But, because of small sizes of nano-drug complexes, exposure risk of humans and domestic animals to these materials increased and their toxic effects became conflictive. Thus, toxicity evcil hayvanların bu yapılara maruziyet riski oldukça artmıştır ve toksik etkilerinin olup olmadığı tartışmalı hale gelmiştir. Bu nedenle nano-ilaç salınım sistemlerinin güvenliklerinin çalışmalar önem kazanmıştır. Yapılan araştırmalarda nanomateryallerin hücrelerde apoptoz, nekroz, otofaji, mitotik yıkımlanma gibi istenmeyen etkilere yol açtıkları rapor edilmiştir. Ancak bu tür sonuçların elde edildiği toksikolojik araştırmalar daha çok in vitro denemelerdir ve in vivo çalışmaların yetersizliğinden dolayı nanoilaç ve nano-ilaç taşıma sistemlerinin canlı vücudu üzerindeki etkileri tam olarak ortaya konamamıştır. Bu nedenle nano-ilaçların toksisitesi konusunda ayrıntılı, sistematik ve uzun soluklu in vivo çalışmalara ihtiyaç duyulmaktadır. Bu derlemede, önemli nano-ilaç ve nano-ilaç taşıma sistemleri ile ilaç taşıma sistemlerinde kullanılan nanomateryallerin toksisitesi ve güvenli kullanımları değerlendirilmiştir.tespitine yönelik toksikolojik

Anahtar Kelimeler

Nano-drug, delivery systems, toxicity

Kaynakça

• Tüylek Z. İlaç taşıyıcı sistemler ve nanoteknolojik etkileşim. Bozok Tıp Derg, 2017; 7(3): 89-98.
• Lamprecht A. Nanotherapeutics: Drug Delivery Concepts in Nanoscience. Singapore: Pan Stanford, 2016.
• Yavuz O, Marangoz Ö. Farmakoloji ve toksikolojide in siliko yöntemlerin kullanımı. In: Güvenç D, ed. İlaç Araştırma, Geliştirme ve Toksikolojik Çalışmalarda Kullanılan Alternatif Yöntemler, 1. Baskı. Ankara. Türkiye Klinikleri, : 35-42.
• Marangoz Ö. Nano ilaç ve nano ilaç taşıma sistemleri. Doktora Semineri, Ondokuz Mayıs Üniversitesi Sağlık Bilimleri Enstitüsü, 2018.
• Vural GU, Özer AY. Nükleer tıpta ilaç taşıyıcı sistemler ve teranostik Kullanımları. Nükleer Tıp Seminerleri, 2015; (2): 109-19.
• Sayıner Ö, Çomoğlu T. Nanotaşıyıcı sistemlerde hedeflendirme. Ankara Ecz Fak Derg, 2016;
• Bhargav E, Madhuri N, Ramesh K, Anand M, Ravi V. Targeted drug delivery-A review. World J Pharm Pharm Sci, 2013; 3(1): 150-9.
• Roursgaard M, Knudsen KB, Northeved H, Persson M, Christensen T, Kumar PE et.al. In vitro toxicity of cationic micelles and liposomes in cultured human hepatocyte (HepG2) and lung epithelial (A549) cell lines. Toxicology in Vitro, ; 36: 164-71.
• Yin X, Luo L, Li W, Yang J, Zhu C, Jiang M et.al. A cabazitaxel liposome for increased solubility, enhanced antitumor effect and reduced systemic toxicity. Asian J Pharm Sci, 2019; 14(6): 658-67.
• Pippa N, Stangel C, Kastanas I, Triantafyllopoulou E, Naziris N, Stellas D et.al. Carbon nanohorn/ liposome systems: Preformulation, design and in vitro toxicity studies. Materials Sci Engin C, ; 105: 110114.
• Abud MB, Louzada RN, Isaac DLC, Souza LG, Dos Reis RG, Lima EM et.al. In vivo and in vitro toxicity evaluation of liposome-encapsulated sirolimus. Intern J Retina Vitreous, 2019; 5(1):
• Zhang Y, Li N, Suh H, Irvine DJ. Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity. Nature Commun, 2018; 9(1): 1-15.
• Knudsen KB, Northeved H, Kumar PE, Permin A, Gjetting T, Andresen TL et al. In vivo toxicity of cationic micelles and liposomes. Nanomed, ; 11(2): 467-77.
• Costamagna F, Hillaireau H, Vergnaud- Gauduchon J, Jamgotchian L, Loreau O, Denis S et.al. Nanotoxicology at the particle/micelle frontier: Influence of core-polymerization on the intracellular distribution, cytotoxicity and genotoxicity of polydiacetylene micelles. Nanoscale, 2020; 12: 2452-63.
• Soodvilai S, Tipparos W, Rangsimawong W, Patrojanasophon P, Soodvilai S, Sajomsang W et.al. Effects of silymarin-loaded amphiphilic chitosan polymeric micelles on the renal toxicity and anticancer activity of cisplatin. Pharm Develop Technol, 2019; 24(8): 927-34.
• Patil P, Harak K, Saudagar R. The solid lipid nanoparticles, a review. JDDT, 2019; 9(3): 525
• Patrick S, Eric DS, Anthony WC. A first approach to the study of calixarene solid lipid nanoparticle (SLN) toxicity. J Incl Phenom Macrocycl Chem, ; 46(3-4): 175-7.
• Silva AH, Filippin-Monteiro FB, Mattei B, Zanetti-Ramos BG, Creczynski-Pasa TB. In vitro biocompatibility of solid lipid nanoparticles. Sci Total Environ, 2012; 432: 382-8.
• Albuquerque J, Moura CC, Sarmento B, Reis S. Solid lipid nanoparticles: A potential multifunctional approach towards rheumatoid arthritis theranostics. Molecules, 2015; 20(6): 18.
• Mendonça MCP, Radaic A, Garcia-Fossa F, Da Cruz-Höfling MA, Vinolo MAR, De Jesus MB. The in vivo toxicological profile of cationic solid lipid nanoparticles. Drug Deliver Translation Res, 2020; (1): 34-42.
• Derman S, Kızılbey K, Akdeste ZM. Polymeric nanoparticles. Sigma, 2013; 31: 107-20.
• Ritter D, Knebel J, Niehof M, Loinaz I, Marradi M, Gracia R et.al. In vitro inhalation cytotoxicity testing of therapeutic nanosystems for pulmonary infection. Toxicol in Vitro, 2020; : 104714.
• Yıldırımer L, Thanh N, Loizidoua M, Seifalian MA. Toxicological considerations of clinically applicable nanoparticles. Nano Today, 2011;
• Hering I, Eilebrecht E, Parnham MJ, Günday- Türeli N, Türeli AE, Weiler M et.al. Evaluation of potential environmental toxicity of polymeric nanomaterials and surfactants. EnvironToxicol Pharmacol, 2020; 76: 103353.
• Karabulut B, Kerimoğlu O, Uğurlu T. Dendrimerler-ilaç taşıyıcı sistemler. MÜSBED, ; 1(1): 31-40. Jain K, Kesharwani P, Gupta U, Jain NK. Dendrimer toxicity: Let’s meet the challenge. Int J Pharm, 2010; 394(1-2): 122-42.
• Wang Y, Li C, Du L, Liu Y. A reactive oxygen species-responsive dendrimer with low cytotoxicity for efficient and targeted gene delivery. Chine Chem Lett, 2020; 31(1): 275-80.
• Jain K, Mehra NK, Jain NK. Nanotechnology in drug delivery: Safety and toxicity issues. Curr Pharm Des, 2015; 21(29): 4252-61.
• Gorzkiewicz M, Konopka M, Janaszewska A, Tarasenko II, Sheveleva NN, Gajek A et.al. Application of new lysine-based peptide dendrimers D3K2 and D3G2 for gene delivery: Specific cytotoxicity to cancer cells and transfection in vitro. Bioorganic Chem, 2020; : 103-504.
• Monterio-Riviere NA, Tran CL. Nanotoxicology: Characterization, Dosing and Health Effects. New York: Informa Healthcare, 2007.
• Lee KC, Lo PY, Lee GY, Zheng JH, Cho EC. Carboxylated carbon nanomaterials in cell cycle and apoptotic cell death regulation. J Biotechnol, 2019; 296: 14-21.
• Nahle S, Safar R, Grandemange S, Foliguet B, Lovera-Leroux M, Doumandji Z et.al. Single wall and multiwall carbon nanotubes induce different toxicological responses in rat alveolar macrophages. J App Toxicol, 2019; 39(5): 764
• Siegrist KJ, Reynolds SH, Porter DW, Mercer RR, Bauer AK, Lowry D, Salisbury JL. Mitsui-7, heat-treated, and nitrogen-doped multi-walled carbon nanotubes elicit genotoxicity in human lung epithelial cells. Particle Fibre Toxicol, ; 16(1): 36.
• Zhao X, Chang S, Long J, Li J, Li X, Cao Y. The toxicity of multi-walled carbon nanotubes (MWCNTs) to human endothelial cells: The influence of diameters of MWCNTs. Food Chem Toxicol, 2019; 126: 169-77.
• Requardt H, Braun A, Steinberg P, Hampel S, Hansen T. Surface defects reduce carbon nanotube toxicity in vitro. Toxicol in Vitro, ; 60: 12-8.
• Liu Y, Jiang H, Liu C, Ge Y, Wang L, Zhang B et.al. Influence of functional groups on toxicity of carbon nanomaterials. Atmosph Chem Physics, 2019; 19(12): 8175-87.
• Mohammadian Y, Rezazadeh Azari M, Peirovi H, Khodagholi F, Pourahmad J, Omidi M et.al. Combined toxicity of multi-walled carbon nanotubes and benzo [a] pyrene in human epithelial lung cells. Toxin Rev, 2019; 38(3): 22.
• Tian R, Long X, Yang Z, Lu N, Peng YY. Formation of a bovine serum albumin diligand complex with rutin and single-walled carbon nanotubes for the reduction of cytotoxicity. Biophysic Chem, 2020; 256: 106268.
• Falinski MM, Garland MA, Hashmi SM, Tanguay RL, Zimmerman JB. Establishing structure- property-hazard relationships for multi-walled carbon nanotubes: The role of aggregation, surface charge, and oxidative stress on embryonic zebrafish mortality. Carbon, 2019; : 587-600.
• Chowdhry A, Kaur J, Khatri M, Puri V, Tuli R, Puri S. Characterization of functionalized multiwalled carbon nanotubes and comparison of their cellular toxicity between HEK 293 cells and zebra fish in vivo. Heliyon, 2019; 5(10):
• Pandey H, Saini S, Singh SP, Gautam NK, Singh S. Candle soot derived carbon nanoparticles: An assessment of cellular and progressive toxicity using Drosophila melanogaster model. Compar Biochem Physiol Part C: Toxicol Pharmacol, ; 228: 108646.
• Semak AE, Cherepanova NG, Komarchev AS, Ichkitidze LP, Sokolova DK. Toxicity Study of Solid Carbon Nanotube-Based Composites. In: 2019
• IEEE Conference of Russian Young Researchers in Electrical and Electronic Engineering, 2019; 4.
• Knudsen K. B, Berthing T, Jackson P, Poulsen SS, Mortensen A, Jacobsen NR et. al. Physicochemical predictors of multi- walled carbon nanotube–induced pulmonary histopathology and toxicity one year after pulmonary deposition of 11 different multi- walled carbon nanotubes in mice. Basic Clin Pharmacol Toxicol, 2019; 124(2): 211-27.
• Khalid P, Hussain MA, Suman VB, Arun AB. Toxicology of carbon nanotubes-A review. Int J Appl Eng Res, 2016; 11(1): 148-57.
• Kolosnjaj TJ, Baati T, Szwarc H, Moussa F. Toxicity studies of [60] fullerene and carbon nanotubes: State of the art. In: D’Souza F, Kadish KM, eds. Handbook of Carbon Nano Materials. Singapore. World Sci, 2012; 49-75.
• Namadr F, Bahrami F, Bahari Z, Ghanbari B, Shahyad S, Mohammadi MT. Fullerene C60 nanoparticles decrease liver oxidative stress through ıncrement of liver antioxidant capacity in streptozotocin-ınduced diabetes in rats. Reactive Oxygen Species, 2020; 9(26): 70-80.
• Biby TE, Prajitha N, Ashtami J, Sakthikumar D, Maekawa T, Mohanan PV. Toxicity of dextran stabilized fullerene C60 against C6 Glial cells. Brain Res Bull, 2020; 155: 191-201.
• Fard JK, Jafari S, Eghbal MA. A review of molecular mechanisms involved in toxicity of nanoparticles. Adv Pharm Bull, 2015; 5(4): 447
• Bondarenko O, Juganson K, Ivask A, Kasemets K, Mortimer M, Kahru A. Toxicity of Ag, CuO and ZnO nanoparticles to selected environmentally relevant test organisms and mammalian cells in vitro: A critical review. Arch Toxicol, 2013; (7): 1181-200.
• Barkur S, Lukose J, Chidangil S. Probing nanoparticle–cell ınteraction using Micro-Raman Spectroscopy: Silver and gold nanoparticle- ınduced stress effects on optically trapped live red blood cells. ACS Omega, 2020; 5(3): 1439
• Selvaraj T, Thirunavukkarasu A, Rathnavelu SM, Kasivelu G. In Vivo non-toxicity of gold nanoparticles on wistar rats. J Cluster Sci, 2019; (2): 513-19.
• Hernandez-Adame L, Angulo C, Delgado K, Schiavone M, Castex M, Palestino G et.al. Biosynthesis of β-d-glucan-gold nanoparticles, cytotoxicity and oxidative stress in mouse splenocytes. Intern J Biol Macromol, 2019; 13:, 89.
• Bailly AL, Correard F, Popov A, Tselikov G, Chaspoul F, Appay R et.al. In vivo evaluation of safety, biodistribution and pharmacokinetics of laser-synthesized gold nanoparticles. Sci Reports, 2019; 9(1): 1-12.
• Elbehiry A, Al-Dubaib M, Marzouk E, Moussa I. Antibacterial effects and resistance induction of silver and gold nanoparticles against Staphylococcus aureus-induced mastitis and the potential toxicity in rats. Microbiol Open, 2019; (4): e00698.
• Wang L, Zhang C, Zhi X, Hou W, Li T, Pan S, Cui D. Impact of short-term exposure of AuNCs on the gut microbiota of BALB/c mice. J Biomed Nanotec, 2019; 15(4): 779-89.
• Sukumaran P, Eldho KP. Silver nanoparticles: Mechanism of antimicrobial action, synthesis, medical applications, and toxicity effects. Int Nano Lett, 2012; 2(1): 32.
• Mozafari M, Khoradmehr A, Danafar A, Miresmaeili M, Kalantar SM. Toxic effects of maternal exposure to silver nanoparticles on mice fetal development during pregnancy. Birth Defects Res, 2020; 112(1): 81-92.
• Giovanni L, Emilia G, Annarita F, Rosa C, Elisabetta A, Marco G. Toxicity effects of functionalized quantum dots, gold and polystyrene nanoparticles on target aquatic biological models: A review. Molecules, 2017; (9): 1439.
• Rzigalinski BA, Strobl JS. Cadmium-containing nanoparticles: Perspectives on pharmacology and toxicology of quantum dots. Toxicol Appl Pharmacol, 2009; 238(3): 280-8.
• Matos B, Martins M, Samamed AC, Sousa D, Ferreira I, Diniz MS. Toxicity evaluation of quantum dots (ZnS and CdS) singly and combined in zebrafish (Danio rerio). Intern J Environ Res Public Health, 2020; 17(1): 232.
• Yang Y, Lv S, Wang F, An Y, Fang N, Zhang W et.al. Toxicity and serum metabolomics investigation of Mn-doped ZnS quantum dots in mice. Intern J Nanomed, 2019; 14: 6297.
• Chen T, Li L, Lin X, Yang Z, Zou W, Chen Y et.al. In vitro and in vivo immunotoxicity of PEGylated Cd-free CuInS2/ZnS quantum dots. Nanotoxicol, 2020; 1-16.
• Singh V, Kashyap S, Yadav U, Srivastava A, Singh AV, Singh RK et.al. Nitrogen doped carbon quantum dots demonstrate no toxicity under in vitro conditions in a cervical cell line and in vivo in Swiss albino mice. Toxicol Res, 2019; (3): 395-406.
• Bai C, Tang M. Toxicological study of metal and metal oxide nanoparticles in zebrafish. J App Toxicol, 2020; 40(1): 37-63.
• Hou J, Wang L, Wang C, Zhang S, Liu H, Li S, Wang X. Toxicity and mechanisms of action of titanium dioxide nanoparticles in living organisms. J Environ Sci, 2019; 75: 40-53.
• Yousef MI, Mutar TF, Kamel MAE. Hepato- renal toxicity of oral sub-chronic exposure to aluminum oxide and/or zinc oxide nanoparticles in rats. Toxicol Reports, 2019; 6: 336-46.
• Hassan I, Husain FM, Khan RA, Ebaid H, Al- Tamimi J, Alhazza IM et.al. Ameliorative effect of zinc oxide nanoparticles against potassium bromate-mediated toxicity in Swiss albino rats. Environ Sci Pollut Res, 2019; 26(10): 9966-80.