AN UPDATED REVIEW ON THE APPLICATION OF DENDRIMERS AS SUCCESSFUL NANOCARRIERS FOR BRAIN DELIVERY OF THERAPEUTIC MOIETIES
It’s been nearly 100 y of effort to study the organization and role of the blood brain-barrier and still, we strive to find better techniques to overcome this barrier to deliver the drugs to the brain effectively with reduced systemic side effects. The advances in nanotechnology have given newer horizons in achieving this goal since the nano-scaled systems can modify an existing drug to have a high degree of sensitivity to the physiological conditions and specificity to reach the target organ. Among the various nanocarriers, dendrimers owing to their unique physical and chemical characteristics, represent a potential therapeutic tool in biomedical and pharmaceutical science. Dendrimers, an established polymeric nanocarrier system of the time, can deliver both drugs and genetic material and are being extensively studied to target the brain. The surface modification of dendrimers can reduce their innate toxicity problems and increase the therapeutic efficacy of brain disorders. This review article is an attempt to update on the potential of dendrimers explored in the past five years as a drug delivery avenue that can be considered as a promising solution in the management of a wide range of disorders affecting the central nervous system, including neoplastic, degenerative, and ischemic conditions. The following search criteria were used to expand the review article with the keywords dendrimers, novel drug delivery, nanoparticles, site-specific drug delivery etc.
2. Chen Z, Dehmer M, Emmert Streib F, Shi Y. Entropy bounds for dendrimers. Appl Math Comput 2014;242:462-72.
3. Siddiqui MK, Imran M, Ahmad A. On zagreb indices, zagreb polynomials of some nanostar dendrimers. Appl Math Comput 2016;280:132-9.
4. Arseneault M, Wafer C, Morin JF. Recent advances in click chemistry applied to dendrimer synthesis. Molecules 2015;20:9263-94.
5. Xi W, Scott TF, Kloxin CJ, Bowman CN. Click chemistry in materials science. Adv Funct Mater 2014;24:2572-90.
6. Such GK, Johnston AP, Liang K, Caruso F. Synthesis and functionalization of nanoengineered materials using click chemistry. Prog Polym Sci 2012;37:985-1003.
7. Han SC, Choi IH, Jin SH, Lee JW. Efficient synthesis of carbazole core diblock dendrimer by double click chemistry. Mol Cryst Liq Cryst 2014;599:86-95.
8. Soto Castro D, Magana Vergara NE, Farfan N, Santillan R. Synthesis of steroidal dendrimers modified by ‘click chemistry with PAMAM dendrons as unimolecular micelles. Tetrahedron Lett 2014;55:1014-9.
9. Fedeli E, Lancelot A, Serrano JL, Calvo P, Sierra T. Self-assembling amphiphilic Janus dendrimers: mesomorphic properties and aggregation in water. New J Chem 2015;39:1960-7.
10. Lowe AB, Harvison MA. Thiol-based ‘click chemistries in polymer synthesis and modification. Aust J Chem 2010;63:1251-66.
11. Banks WA. From blood-brain barrier to blood-brain interface: new opportunities for CNS drug delivery. Nat Rev Drug Discovery 2016;15:275.
12. Georgieva JV, Hoekstra D, Zuhorn IS. Smuggling drugs into the brain: an overview of ligands targeting transcytosis for drug delivery across the blood-brain barrier. Pharmaceutics 2014;6:557-83.
13. Saunders NR, Daneman R, Dziegielewska KM, Liddelow SA. Transporters of the blood-brain and blood–CSF interfaces in development and in the adult. Mol Aspects Med 2013;34:742-52.
14. Kazemi A, Majidinia M, Jamali AA. The question of ethics in nanomedicine. J Clin Res Bioethics 2014;5:1.
15. Ostafin AE, Batenjany MM. Nanomedicine making headway across blood-brain barrier. J Nanomed Nanotechnol 2012;3:1.
16. Arya MA, Kumar MK, Sabitha M, Menon KN, Nair SC. Nanotechnology approaches for enhanced CNS delivery in treating Alzheimer's disease. J Drug Delivery Sci Technol 2019;51:297-309.
17. Satapathy MK. Shaping safer future nanotechnology through wise worthy scientific research. J Bioprocess Biotech 2015;5:243.
18. Muthuraman A, Mehdi S, Rishitha N. Current trends in site and target-specific delivery of nanomedicine for gene therapy. Nanopart Pharmacother 2019;73-112. DOI:10.1016/ B978-0-12-816504-1.00010-7
19. Madaan K, Kumar S, Poonia N, Lather V, Pandita D. Dendrimers in drug delivery and targeting: drug-dendrimer interactions and toxicity issues. J Pharm Bioallied Sci 2014;6:139.
20. Majumder J, Taratula O, Minko T. Nanocarrier-based systems for targeted and site-specific therapeutic delivery. Adv Drug Delivery Rev 2019;144:57-77.
21. Martinez Perez B, Quintanar Guerrero D, Tapia Tapia M, Cisneros Tamayo R, Zambrano Zaragoza ML, Alcala Alcala S, et al. Controlled-release biodegradable nanoparticles: from preparation to vaginal applications. Eur J Pharm Sci 2018;115:185-95.
22. Bamrungsap S, Zhao Z, Chen T, Wang L, Li C, Fu T, et al. Nanotechnology in therapeutics: a focus on nanoparticles as a drug delivery system. Nanomedicine 2012;7:1253-71.
23. Huang D, Wu D. Biodegradable dendrimers for drug delivery. Mater Sci Eng C 2018;90:713-27.
24. Wang H, Huang Q, Chang H, Xiao J, Cheng Y. Stimuli-responsive dendrimers in drug delivery. Biomater Sci 2016;4:375-90.
25. Lim J, Simanek EE. Triazine dendrimers as drug delivery systems: from synthesis to therapy. Adv Drug Delivery Rev 2012;64:826-35.
26. Akbarzadeh A, Khalilov R, Mostafavi E, Annabi N, Abasi E, Kafshdooz T, et al. Role of dendrimers in advanced drug delivery and biomedical applications: a review. Exp Oncol 2018;40:178-83.
27. Sau S, Sahu P, Kashaw SK, Iyer AK. Multitasking role of dendrimers: drug delivery and disease targeting. Nanomed Treatment Disease: Concept Application 2019;25:17.
28. Peng CL, Yang LY, Luo TY, Lai PS, Yang SJ, Lin WJ, et al. Development of pH sensitive 2-(diisopropylamino) ethyl methacrylate-based nanoparticles for photodynamic therapy. Nanotechnology 2010;21:155103.
29. Mignani S, El Kazzouli S, Bousmina M, Majoral JP. Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems: a concise overview. Adv Drug Delivery Rev 2013;65:1316-30.
30. Kaminskas LM, McLeod VM, Kelly BD, Sberna G, Boyd BJ, Williamson M, et al. A comparison of changes to doxorubicin pharmacokinetics, antitumor activity, and toxicity mediated by PEGylated dendrimer and PEGylated liposome drug delivery systems. Nanomedicine 2012;8:103-11.
31. Kambhampati SP, Kannan RM. Dendrimer nanoparticles for ocular drug delivery. J Ocul Pharmacol Ther 2013;29:151-65.
32. Fu F, Wu Y, Zhu J, Wen S, Shen M, Shi X. Multifunctional lactobionic acid-modified dendrimers for targeted drug delivery to liver cancer cells: investigating the role played by PEG spacer. ACS Appl Mater Interfaces 2014;6:16416-25.
33. Paleos CM, Tsiourvas D, Sideratou Z, Tziveleka LA. Drug delivery using multifunctional dendrimers and hyperbranched polymers. Expert Opin Drug Delivery 2010;7:1387-98.
34. Namazi H, Hamrahloo YT. Novel PH sensitive nanocarrier agents based on citric acid dendrimers containing conjugated ?-cyclodextrins. Adv Pharm Bull 2011;1:40.
35. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2005;2:3-14.
36. Bors LA, Erdo F. Overcoming the blood-brain barrier. Challenges and tricks for CNS drug delivery. Sci Pharma 2019;87:6.
37. Noha M Zaki. CNS delivery of drugs: challenges and Chances. J Bioequivalence Bioavailability 2012;4:xxiii-xxiv.
38. Oldendorf WH, Cornford ME, Brown WJ. The large apparent work capability of the blood?brain barrier: a study of the mitochondrial content of capillary endothelial cells in the brain and other tissues of the rat. Annals Neurol 1977;1:409-17.
39. Fenstermacher J, Gross P, Sposito N, Acuff V, Pettersen S, Gruber K. Structural and functional variations in capillary systems within the Brain a. Ann N Y Acad Sci 1988;529:21-30.
40. Pardridge WM. Recent advances in blood-brain barrier transport. Annu Rev Pharmacol Toxicol 1988;28:25-39.
41. de Lange EC. The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects. Fluids Barriers CNS 2013;10:12.
42. Mannhold R. The impact of lipophilicity in drug research: a case report on beta-blockers. Mini Rev Med Chem 2005;5:197-205.
43. Bergstrom CA. In silico predictions of drug solubility and permeability: two rate-limiting barriers to oral drug absorption. Basic Clin Pharmacol Toxicol 2005;96:156–16.
44. Alavijeh MS, Chishty M, Qaiser MZ, Palmer AM. Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery. NeuroRx 2005;2:554-71.
45. Nagpal K, Singh SK, Mishra DN. Drug targeting to the brain: a systematic approach to study the factors, parameters and approaches for prediction of permeability of drugs across BBB. Expert Opin Drug Delivery 2013;10:927-55.
46. Jarkko Rautio, Krista Laine, Mikko Gynther. Prodrug approaches for CNS delivery. AAPS J 2008;10:92–102.
47. S Kasai, H Nagasawa, M Shimamura, Y Uto, H Hori. Design and synthesis of antiangiogenic/heparin-binding arginine dendrimer mimicking the surface of endostatin. Bioorg Med Chem Lett 2002;12:951–54.
48. Wu D, Yang J, Li J, Chen L, Tang B, Chen X, et al. Hydroxyapatite-anchored dendrimer for in situ remineralizations of human tooth enamel. Biomaterials 2013;34:5036-47.
49. GA Kinberger, W Cai, M Goodman. Collagen mimetic dendrimers. J Am Chem Soc 2002;124:15162–3.
50. Noriega Luna B, Godinez LA, Rodriguez FJ, Rodriguez A, Zaldivar Lelo de Larrea G, Sosa Ferreyra CF, et al. Applications of dendrimers in drug delivery agents, diagnosis, therapy, and detection. J Nanomater 2014. https://doi.org/10.1155/2014/507273
51. Bhairavi Srinageshwar, Sarah Peruzzaro, Melissa Andrews, Pamam. Dendrimers cross the blood-brain barrier when administered through the carotid artery in C57BL/6J mice. Int J Mol Sci 2017;18:628.
52. Sharma A, Porterfield JE, Smith E, Sharma R, Kannan S, Kannan RM. Effect of mannose targeting of hydroxyl PAMAM dendrimers on cellular and organ biodistribution in a neonatal brain injury model. J Controlled Release 2018;283:175-89.
53. Leonyza A, Surini S. Optimization of sodium deoxycholate-based transferosomes for percutaneous delivery of peptides and proteins. Int J Appl Pharm 2019;11:329-32.
54. Prathita T, Djauharie NK, Meidyawati R. Antimicrobial activity of mineral trioxide aggregate and calcium hydroxide sealer on enterococcus faecalis strain ATCC29212. Int J Appl Pharm 2019;11:123-5.
55. Wei Lu. Adsorptive mediated brain delivery systems. Curr Pharm Biotechnol 2012;13:2340-8.
56. Pardridge WM. Drug transport across the blood-brain barrier. J Cerebral Blood Flow Metab 2012;32:1959-72.
57. Victor M. Pulgar, transcytosis to cross the blood-brain barrier, new advancements and challenges. Front Neurosci 2018;12:1019.
58. Loscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2005;2:86-98.
59. Vlieghe P, Khrestchatisky M. Peptide-based vectors for blood-brain barrier targeting and delivery of drugs to the central nervous system. Ther Delivery 2010;1:489-94.
60. Rapoport SI. Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications. Cellular Mol Neurobiol 2000;20:217-30.
61. Bellavance MA, Blanchette M, Fortin D. Recent advances in blood–brain barrier disruption as a CNS delivery strategy. AAPS J 2008;10:166-77.
62. Black KL. Biochemical opening of the blood-brain barrier. Adv Drug Delivery Rev 1995;15:37-52.
63. Erdlenbruch B, Alipour M, Fricker G, Miller DS, Kugler W, Eibl H, et al. Alkylglycerol opening of the blood–brain barrier to small and large fluorescence markers in normal and C6 glioma?bearing rats and isolated rat brain capillaries. Br J Pharmacol 2003;140:1201-10.
64. Pardridge WM. Molecular trojan horses for blood–brain barrier drug delivery. Curr Opinion Pharmacol 2006;6:494-500.
65. Lengyel M, Kállai Szabo N, Antal V, Laki AJ, Antal I. Microparticles, microspheres, and microcapsules for advanced drug delivery. Sci Pharm 2019;87:20.
66. Ramachandran R, Junnuthula VR, Gowd GS, Ashokan A, Thomas J, Peethambaran R, et al. Theranostic 3-Dimensional nano brain-implant for prolonged and localized treatment of recurrent glioma. Sci Rep 2017;7:43271.
67. Vyas TK, Shahiwala A, Marathe S, Misra A. Intranasal drug delivery for brain targeting. Curr Drug Delivery 2005;2:165-75.
68. Debinski W, Tatter SB. Convection-enhanced delivery for the treatment of brain tumors. Expert Rev Neurother 2009;9:1519-27.
69. Narayanan Kasinathan, Hitesh V Jagani, Angel Treasa Alex, Subrahmanyam M Volety, J Venkata Rao. Strategies for drug delivery to the central nervous system by systemic route. Drug Delivery 2015;22:243-57.
70. Joseph SK, Sabitha M, Nair SC. Stimuli-responsive polymeric nanosystem for colon specific drug delivery. Adv Pharm Bull 2019;10:1-2.
71. Vidal F, Vasquez P, Diaz C, Nova D, Alderete J, Guzman L. Mechanism of PAMAM dendrimers internalization in hippocampal neurons. Mol Pharm 2016;13:3395-403.
72. Zhang F, Magruder JT, Lin YA, Crawford TC, Grimm JC, Sciortino CM, et al. Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model. J Controlled Release 2017;249:173-82.
73. Elham Abbasi, Sedigheh Fekri Aval, Abolfazl Akbarzadeh, Morteza Milani, Hamid Tayefi Nasrabadi, Sang Woo Joo, et al. Dendrimers: synthesis, applications, and properties. Nanoscale Res Lett 2014;9:247.
74. Ebelegi Newton Augustus, Ekubo Tobin Allen, Ayawei Nimibofa, Wankasi Donbebe W. Review of synthesis, characterization and applications of functionalized dendrimers. Am J Polym Sci 2017;7:8-14.
75. Kawaguchi T, Walker KL, Wilkins CL, Moore JS. Double exponential dendrimer growth. J Am Chem Soc 1995;117:2159-65.
76. Sowinska M, Urbanczyk Lipkowska Z. Advances in the chemistry of dendrimers. New J Chem 2014;38:2168-203.
77. Kim Y, Zimmerman SC. Applications of dendrimers in bio-organic chemistry. Curr Opin Chem Biol 1998;2:733-42.
78. Arseneault M, Wafer C, Morin JF. Recent advances in click chemistry applied to dendrimer synthesis. Molecules. 2015;20:9263-94.
79. Zolotarskaya OY, Xu L, Valerie K, Yang H. Click synthesis of a polyamidoamine dendrimer-based camptothecin prodrug. RSC Adv 2015;5:58600-8.
80. Radhika R, Rohith V, Anil Kumar NC, Varun Gopal K, Krishnan Namboori PK, Deepak OM. Insilico analysis of nano polyamidoamine (PAMAM) dendrimers for cancer drug delivery. Int J Recent Trends Eng Technol 2010;4:142-4.
81. Ding L, Lyu Z, Dhumal D, Kao CL, Bernard M, Peng L. Dendrimer-based magnetic resonance imaging agents for brain cancer. Sci China Materials 2018;61:1420-43.
82. Prajapati SK, Maurya SD, Das MK, Tilak VK, Verma KK, Dhakar RC. Dendrimers in drug delivery, diagnosis and therapy: basics and potential applications. J Drug Delivery Ther 2016;6:67-92.
83. Noriega Luna B, Godínez LA, Rodriguez FJ, Rodriguez A, Zaldívar Lelo de Larrea G, Sosa Ferreyra CF, et al. Applications of dendrimers in drug delivery agents, diagnosis, therapy, and detection. J Nanomater 2014. https://doi.org/10.1155/ 2014/507273.
84. Kasai S, Nagasawa H, Shimamura M, Uto Y, Hori H. Design and synthesis of antiangiogenic/heparin-binding arginine dendrimer mimicking the surface of endostatin. Bioorg Med Chem Lett 2002;12:951-4.
85. Wu D, Yang J, Li J, Chen L, Tang B, Chen X, et al. Hydroxyapatite-anchored dendrimer for in situ remineralization of human tooth enamel. Biomaterials 2013;34:5036-47.
86. Kinberger GA, Cai W, Goodman M. Collagen mimetic dendrimers. J Am Chem Soc 2002;124:15162-3.
87. Xu L, Zhang H, Wu Y. Dendrimer advances for the central nervous system delivery of therapeutics. ACS Chem Neurosci 2013;5:2-13.
88. Beg S, Samad A, I Alam M, Nazish I. Dendrimers as novel systems for delivery of neuropharmaceuticals to the brain. CNS Neurol Disorders Drug Targets 2011;10:576-88.
89. Mignani S, Bryszewska M, Zablocka M, Klajnert Maculewicz B, Cladera J, Shcharbin D, et al. Can dendrimer based nanoparticles fight neurodegenerative diseases? Current situation versus other established approaches. Prog Polym Sci 2017;64:23-51.
90. Kannan RM, Nance E, Kannan S, Tomalia DA. Emerging concepts in dendrimer?based nanomedicine: from design principles to clinical applications. J Intern Med 2014;276:579-617.
91. Sharma A, Porterfield JE, Smith E, Sharma R, Kannan S, Kannan RM. Effect of mannose targeting of hydroxyl PAMAM dendrimers on cellular and organ biodistribution in a neonatal brain injury model. J Controlled Release 2018;283:175-89.
92. Sharma R, Kim SY, Sharma A, Zhang Z, Kambhampati SP, Kannan S, et al. Activated microglia targeting dendrimer–minocycline conjugate as therapeutics for neuroinflammation. Bioconjugate Chem 2017;28:2874-86.
93. Patel HK, Gajbhiye V, Kesharwani P, Jain NK. Ligand anchored poly (propyleneimine) dendrimers for brain targeting: comparative in vitro and in vivo assessment. J Colloid Interface Sci 2016;482:142-50.
94. Fang Zhang, Chun Lei Xu, Chun Mei Liu. Drug delivery strategies to enhance the permeability of the blood–brain barrier for treatment of glioma. Drug Des Dev Ther 2015;9:2089–100.
95. Pradhan D, Tambe V, Raval N, Gondalia P, Bhattacharya P, Kalia K, et al. Dendrimer grafted albumin nanoparticles for the treatment of post cerebral stroke damages: a proof of concept study. Colloids Surf B 2019;184:110488.
96. Zhang F, Nance E, Zhang Z, Jasty V, Kambhampati SP, Mishra MK, et al. Surface functionality affects the biodistribution and microglia-targeting of intra-amniotically delivered dendrimers. J Controlled Release 2016;237:61-70.
97. Bhairavi Srinageshwar, Sarah Peruzzaro, Melissa Andrews, Pamam. Dendrimers cross the blood–brain barrier when administered through the carotid artery in C57BL/6J mice. Int J Mol Sci 2017;18:628.
98. Yi X, Manickam DS, Brynskikh A, Kabanov AV. Agile delivery of protein therapeutics to CNS. J Controlled Release 2014;190:637-63.
99. Pierpaolo Moscariello, David YW Ng, Malin Jansen, Tanja Weil, Heiko J Luhmann, Jana Hedrich. Brain delivery of multifunctional dendrimer protein bioconjugates. Adv Sci 2018;5:1700897.
100. Bobbin ML, Burnett JC, Rossi JJ. RNA interference approaches for treatment of HIV-1 infection. Genome Med 2015;7:50.
101. Serramia MJ, Alvarez S, Fuentes Paniagua E, Clemente MI, Sanchez Nieves J, Gomez R, et al. In vivo delivery of siRNA to the brain by carbosilane dendrimer. J Controlled Release 2015;200:60-70.
102. Ibrahim NA, Bakry MM, Ishak SH, Shah NM. A review of antibiotic used in suspected early-onset neonatal sepsis from Malasyian perspective: which one to choose and how long to give. Asian J Pharm Clin Res 2019;12:529-36.
103. Najafi F, Moghimi HR, Hemmati M, Deevband MR, Kazemi B. SRL-coated PAMAM dendrimer nano-carrier for targeted gene delivery to the glioma cells and competitive inhibition by lactoferrin. Iran J Pharm Res 2016;15:629.
104. Thayyilakandy S, PS G, K KA, Krishnakumar G, Nair SC. Fast dissolving sublingual patch of phenobarbital sodium: formulation and in vitro evaluation. Int J Appl Pharm 2020;12:158-65.
105. Jiang Y, Lv L, Shi H, Hua Y, Lv W, Wang X, et al. PEGylated polyamidoamine dendrimer conjugated with tumor homing peptide as a potential targeted delivery system for glioma. Colloids Surf B 2016;147:242-9.
106. Yanping Lu, Shunping Han, Hongyue Zheng, Rui Ma, Yuting Ping, Jiafeng Zou, et al. A novel RGDyC/PEG co-modified PAMAM dendrimer-loaded arsenic trioxide of glioma targeting delivery system. Int J Nanomed 2018;13:5937–52.
107. Pathan M, Kshirasagar A. Development of validated stability indicating method by RP-HPLC for simultaneous estimation of meropenam and vaborabactam in bulk and pharmaceutical formulation. Int J Pharm Pharm Sci 2019;11:102-8.
108. Kiran G, Kumar ND. The importance of antibiotics in various unique metastasis along with cytotoxic therapy at tertiary care hospital: a prospective cohort study. Int J Curr Pharm Res 2020;12:41-4.
109. Ravichandran V, Shalini S, Sundram KM, Harish R. Validation of analytical methods–strategies and importance. Int J Pharm Pharm Sci 2010;2:18-22.
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