J Neurooncol (2009) 93:285–286 DOI 10.1007/s11060-008-9759-2

LETTER TO THE EDITOR

Future prospects of nanoparticles on brain targeted drug delivery C. Chakraborty Æ B. Sarkar Æ C. H. Hsu Æ Z. H. Wen Æ C. S. Lin Æ P. C. Shieh

Received: 27 July 2007 / Accepted: 3 November 2008 / Published online: 2 December 2008 Ó Springer Science+Business Media, LLC. 2008

To the editor Human brain is restricted and separated from circulatory network by a highly efficient blood brain barrier. This is constituted by relatively impermeable endothelial cells with tight junctions, enzymatic activity and active efflux transport systems. Physiologically, blood-brain barrier is designed in such a manner that it can only permit the transport of molecules essential for functional activity of brain. It efficiently prevents flow of water-soluble molecules from blood circulation into central nervous system, and can also decrease concentration of lipid-soluble molecules by the action of enzymes or efflux pumps [1]. Presently, drug delivery to central nervous system is a major menace as multiple cerebral diseases like Alzheimer’s, brain tumors, prion diseases are cropping up. The blood brain barrier (BBB) represents an insurmountable obstacle for a large number of drugs including antibiotics, antineoplastic agents and a variety of central nervous C. Chakraborty Department of Biotechnology, College of Engineering and Technology, IILM Academy of Higher Learning, Knowledge Park-II, Greater Noida, India C. Chakraborty
C. H. Hsu
Z. H. Wen
C. S. Lin Department of Marine Biotechnology and Resources, College of Marine Science and Division of Marine Biotechnology, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC B. Sarkar Amity Institute of Biotechnology, Amity University, Sector-125, Noida, India P. C. Shieh (&) Department of Pharmacy, Tajen University, Yanpu, Pingtung 907, Taiwan, ROC e-mail: [email protected]

system (CNS)-active drugs like neuropeptides [1, 2]. This creates a considerable threat for the therapy of cerebral diseases. Currently, nanoparticles are utilized as a drug delivery vehicle. The use of nanoparticles to deliver drugs to the brain by infiltrating blood brain barrier (BBB) may provide a significant strategy to break this impasse. The primary advantage of nanoparticle carrier technology is that it can cross blood brain barrier entrapping the original characteristics of the therapeutic drug molecule. Furthermore, this system may reduce drug leaching in the brain and decrease peripheral toxicity [3]. Drugs that have successfully been transported into the brain using nanoparticle carrier include the hexapeptide dalargin, the dipeptide kytorphin, loperamide, tubocurarine, the NMDA receptor antagonist MRZ 2/ 576, doxorubicin, etc. The nanoparticles may be special vehicle for the treatment of the brain tumors [2] especially for primary and metastatic brain tumors [4]. Currently, nanoparticle iron chelators have been used to treat Alzheimer disease and other neurologic disorders associated with trace metal imbalance [5]. It has been reported that PEGylated polymeric nanoparticles are efficient drug carrier for the delivery of active therapeutic molecules in prion diseases [6]. Strategies for nanoparticle targeting to the brain rely on the presence of its interaction with specific receptor-mediated transport systems in the BBB. For example, polysorbate 80/LDL, transferrin receptor binding antibody (such as OX26), lactoferrin, cellpenetrating peptides and melanotransferrin have been shown its efficacy of delivering a self non-transportable drug into the brain via chimeric construct that can undergo receptor-mediated transcytosis [7–11]. It has been reported that poly (butylcyanoacrylate) nanoparticles is able to deliver hexapeptide dalargin, doxorubicin and other agents into the brain which

123

286

is significantly obstructed by BBB [7]. Polysorbate 80 [12] and OX26 Mabs (anti-transferrin receptor MAbs) are the most studied BBB targeting molecule, which have been used to amplify the BBB penetration of lipsosomes [13]. Studies have shown that delivery to the brain of compounds normally excluded by the BBB could be significantly enhanced by prior binding of a drug or centrally active agent to poly (butylcyanoacrylate) (PBCA) nanoparticles, that are then over-coated with surfactant such as polysorbate 80 (Tween 80) [14]. Adsorption of drugs to polysorbate 80-coated nanoparticles has been shown to increase the transport of a number of substances across the BBB including the polar hexapeptide dalargin [15], tubocurarine [16] and the lipid-soluble P-glycoprotein substrates loperamide [17] and doxorubicin [2]. However, toxicity induced by the nanoparticles has also been repeatedly reported [18]. And for example, TiO2 nanoparticles could damage brain-cells [19]. On the other hand, if a nanoparticle is biodegradable (eg. lipidic nanoparticle), it will become less toxic when compared to polymeric nanoparticles [20]. The blood-brain barrier (BBB) is the most important limiting factor for the development of new drugs for the central nervous system. It may possible that most of the future therapeutics against brain diseases can be delivered through nano vehicles. But this functional drug delivery mechanism to the brain is a potential area of research. Nanoparticle based drug delivery technology which presently exist should be improved further, so that it can be safe, effective, target oriented and also cost effective . More participation and research grants from governmental as well as corporate sector should come up to make this essential technology feasible. However, a long way of optimization, standardization and randomization is needed before actual clinical application takes into effect.

References 1. Chen Y, Dalwadi G, Benson HAE (2004) Drug delivery across the blood-brain barrier. Curr Drug Deliv 1:361–376. doi: 10.2174/1567201043334542 2. Kreuter J (2001) Nanoparticulate systems for brain delivery of drugs. Adv Drug Deliv Rev 47:65–81. doi:10.1016/S0169-409X (00)00122-8 3. Lockman PR, Mumper RJ, Khan MA, Allen DD (2002) Nanoparticle technology for drug delivery across the blood brain barrier. Drug Dev Ind Pharm 28:1–13. doi:10.1081/DDC120001481

123

J Neurooncol (2009) 93:285–286 4. Deeken JF, Lo¨scher W (2007) The blood-brain barrier and cancer: transporters, treatment and Trojan horses. Clin Cancer Res 13:1663–1674. doi:10.1158/1078-0432.CCR-06-2854 5. Liu G et al (2006) Nanoparticle iron chelators: a new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance. Neurosci Lett 406:189– 193. doi:10.1016/j.neulet.2006.07.020 6. Calvo P, Bruno G, IrSˇne B, Corinne L et al (2001) PEGylated polycyanoacrylate nanoparticles as vector for drug delivery in prion diseases. J Neurosci Methods 111:151–156. doi:10.1016/ S0165-0270(01)00450-2 7. Kreuter J (2004) Influence of the surface properties on nanoparticle-mediated transport of drugs to the brain. J Nanosci Nanotechnol 4:484–488. doi:10.1166/jnn.2003.077 8. Pardridge WM (2002) Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov 1:131–139. doi: 10.1038/nrd725 9. Ji B, Maeda J, Higuchi M, Inoue K, Akita H, Harashima H, Suhara T (2006) Pharmacokinetics and brain uptake of lactoferrin in rats. Life Sci 78:851–855. doi:10.1016/j.lfs.2005.05.085 10. Scherrmann JM, Temsamani J (2005) The use of Pep: trans vectors for the delivery of drugs into the central nervous system. Int Congr Ser 1277:199–211. doi:10.1016/j.ics.2005.02.023 11. Gabathuler R, Arthur G, Kennard M, Chen Q, Tsai S, Yang J, Schoorl W, Vitalis TZ, Jefferies WA (2005) Development of a potential protein vector (NeuroTrans) to deliver drugs across the bloodbrain barrier. Int Congr Ser 1277:171–184 12. Pardridge WM (2005) Drug and gene targeting to the brain via blood-brain barrier receptor-mediated transport systems. Int Congr Ser 1277:49–62. doi:10.1016/j.ics.2005.02.011 13. Olivier JC (2005) Drug transport to brain with targeted nanoparticles. NeuroRx 2:108–119. doi:10.1602/neurorx.2.1.108 14. Sun W, Xie C, Wang H, Hu Y (2004) Specific role of polysorbate 80 coating on the targeting of nanoparticles to the brain. Biomaterials 25:3065–3071. doi:10.1016/j.biomaterials.2003.09.087 15. Ringe K, Walz CM, Sabel BA (2004) Nanoparticle drug delivery to the brain. Encyclopedia of Nanoscience and Nanotechnology 7:91–104 16. Alyautdin RN, Tezikov EB, Ramge P, Kharkevich DA, Begley DJ (1998) Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polybutylcyanoacrylate nanoparticles: an in situ brain perfusion study. J Microencapsul 15:67–74. doi:10.3109/02652049809006836 17. Michaelis K, Hoffmann MM, Dreis S et al (2006) Covalent linkage of Apolipoprotein E to albumin nanoparticles strongly enhances drug transport into the brain. J Pharmacol Exp Ther 317:1246–1253. doi:10.1124/jpet.105.097139 18. Dreher KL (2004) Health and environmental impact of nanotechnology: toxicological assessment of manufactured nanoparticles. Toxicol Sci 77:3–5. doi:10.1093/toxsci/kfh041 19. Lon TC, Saleh N, Tilton RD, Lowry GV, Veronesi B (2006) Titanium Dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): implications for nanoparticle neurotoxicity. Environ Sci Technol 40:4346–4352. doi:10.1021/ es060589n 20. Kaur IP, Bhandari R, Bhandari S, Kakkar V (2008) Potential of solid lipid nanoparticles in brain targeting. J Control Release 127:97–109. doi:10.1016/j.jconrel.2007.12.018