Surface-Modified Nanocarriers for Nose-to-Brain Delivery: From Bioadhesion to Targeting

Abstract

In the field of nasal drug delivery, nose-to-brain delivery is among the most fascinating applications, directly targeting the central nervous system, bypassing the blood brain barrier. Its benefits include dose lowering and direct brain distribution of potent drugs, ultimately reducing systemic side effects. Recently, nasal administration of insulin showed promising results in clinical trials for the treatment of Alzheimer’s disease. Nanomedicines could further contribute to making nose-to-brain delivery a reality. While not disregarding the need for devices enabling a formulation deposition in the nose’s upper part, surface modification of nanomedicines appears the key strategy to optimize drug delivery from the nasal cavity to the brain. In this review, nanomedicine delivery based on particle engineering exploiting surface electrostatic charges, mucoadhesive polymers, or chemical moieties targeting the nasal epithelium will be discussed and critically evaluated in relation to nose-to-brain delivery.

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90. 90.

    Luppi B., Bigucci F., Corace G., Delucca A., Cerchiara T., Sorrenti M., Catenacci L., Di Pietra A.M., Zecchi V. Albumin nanoparticles carrying cyclodextrins for nasal delivery of the anti-Alzheimer drug tacrine. Eur. J. Pharm. Sci. 2011;44:559-565.

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91. 91.

    Devkar T.B., Tekade A.R., Khandelwal K.R. Surface engineered nanostructured lipid carriers for efficient nose to brain delivery of ondansetron HCl using Delonix regia gum as a natural mucoadhesive polymer. Colloids Surf. B Biointerfaces. 2014;122:143-150.

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92. 92.

    Haque S., Md S., Fazil M., Kumar M., Sahni J.K., Ali J., Baboota S. Venlafaxine loaded chitosan NPs for brain targeting: Pharmacokinetic and pharmacodynamic evaluation. Carbohydr. Polym. 2012;89:72-79.

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    Deli M.A. Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery. Biochim. Biophys. Acta. 2009;1788:892-910.

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    Vllasaliu D., Exposito-Harris R., Heras A., Casettari L., Garnett M., Illum L., Stolnik S. Tight junction modulation by chitosan nanoparticles: Comparison with chitosan solution. Int. J. Pharm. 2010;400:183-193.

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95. 95.

    Wang X., He H., Leng W., Tang X. Evaluation of brain-targeting for the nasal delivery of estradiol by the microdialysis method. Int. J. Pharm. 2006;317:40-46.

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96. 96.

    Fazil M., Md S., Haque S., Kumar M., Baboota S., Sahni J.K., Ali J. Development and evaluation of rivastigmine loaded chitosan nanoparticles for brain targeting. Eur. J. Pharm. Sci. 2012;47:6-15.

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97. 97.

    Alam S., Khan Z.I., Mustafa G., Kumar M., Islam F., Bhatnagar A., Ahmad F.J. Development and evaluation of thymoquinone-encapsulated chitosan nanoparticles for nose-to-brain targeting: A pharmacoscintigraphic study. Int. J. Nanomed. 2012;7:5705-5718.

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98. 98.

    Md S., Khan R.A., Mustafa G., Chuttani K., Baboota S., Sahni J.K., Ali J. Bromocriptine loaded chitosan nanoparticles intended for direct nose to brain delivery: Pharmacodynamic, Pharmacokinetic and Scintigraphy study in mice model. Eur. J. Pharm. Sci. 2013;48:393-405.

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99. 99.

    Jafarieh O., Md S., Ali M., Baboota S., Sahni J.K., Kumari B., Bhatnagar A., Ali J. Design, characterization, and evaluation of intranasal delivery of ropinirole-loaded mucoadhesive nanoparticles for brain targeting. Drug Dev. Ind. Pharm. 2015;41:1674-1681.

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100. 100.

     Mittal D., Md S., Hasan Q., Fazil M., Ali A., Baboota S., Ali J. Brain targeted nanoparticulate drug delivery system of rasagiline via intranasal route. Drug Deliv. 2014;23:130-139.

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101. 101.

     Raj R., Wairkar S., Sridhar V., Gaud R. Pramipexole dihydrochloride loaded chitosan nanoparticles for nose to brain delivery: Development, characterization and in vivo anti-Parkinson activity. Int. J. Biol. Macromol. 2017;109:27-35.

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     Javia A., Thakkar H. Intranasal delivery of tapentadol hydrochloride–loaded chitosan nanoparticles: Formulation, characterisation and its in vivo evaluation. J. Microencapsul. 2017;34:644-658.

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     Kumar M., Pandey R.S., Patra K.C., Jain S.K., Soni M.L., Dangi J.S., Madan J. Evaluation of neuropeptide loaded trimethyl chitosan nanoparticles for nose to brain delivery. Int. J. Biol. Macromol. 2013;61:189-195.

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     Shahnaz G., Vetter A., Barthelmes J., Rahmat D., Laffleur F., Iqbal J., Perera G., Schlocker W., Dünnhaput S., Augustijns P., et al. Thiolated chitosan nanoparticles for the nasal administration of leuprolide: Bioavailability and pharmacokinetic characterization. Int. J. Pharm. 2012;428:164-170.

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105. 105.

     Patel D., Naik S., Misra A. Improved transnasal transport and brain uptake of tizanidine HCl-loaded thiolated chitosan nanoparticles for alleviation of pain. J. Pharm. Sci. 2012;101:690-706.

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     Patel D., Naik S., Chuttani K., Mathur R., Mishra A.K., Misra A. Intranasal delivery of cyclobenzaprine hydrochloride-loaded thiolated chitosan nanoparticles for pain relief. J. Drug Target. 2013;21:759-769.

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     Singh D., Rashid M., Hallan S.S., Mehra N.K., Prakash A., Mishra N. Pharmacological evaluation of nasal delivery of selegiline hydrochloride-loaded thiolated chitosan nanoparticles for the treatment of depression. Artif. Cells Nanomed. Biotechnol. 2016;44:865-877.

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108. 108.

     Di Gioia S., Trapani A., Mandracchia D., De Giglio E., Cometa S., Mangini V., Arnesano F., Belgiovine G., Castellani S., Pace L., et al. Intranasal delivery of dopamine to the striatum using glycol chitosan/sulfobutylether-β-cyclodextrin based nanoparticles. Eur. J. Pharm. Biopharm. 2015;94:180-193.

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109. 109.

     Chalikwar S.S., Mene B.S., Pardeshi C.V., Belgamwar V.S., Surana S.J. Self-Assembled, Chitosan Grafted PLGA Nanoparticles for Intranasal Delivery: Design, Development and Ex Vivo Characterization. Polym. Plast. Technol. Eng. 2013;52:368-380.

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110. 110.

     Salade L., Wauthoz N., Deleu M., Vermeersch M., De Vriese C., Amighi K., Goole J. Development of coated liposomes loaded with ghrelin for nose-to-brain delivery for the treatment of cachexia. Int. J. Nanomed. 2017;12:8531-8543.

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     Romana B., Batger M., Prestidge C., Colombo G., Sonvico F. Expanding the Therapeutic Potential of Statins by Means of Nanotechnology Enabled Drug Delivery Systems. Curr. Top. Med. Chem. 2014;14:1182-1193.

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     Sonvico F., Zimetti F., Pohlmann A.R., Guterres S.S. Drug delivery to the brain: How can nanoencapsulated statins be used in the clinic? Ther. Deliv. 2017;8:625-631.

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     Clementino A., Batger M., Garrastazu G., Pozzoli M., Del Favero E., Rondelli V., Gutfilen B., Barboza T., Sukkar M.B., Souza S.A.L., et al. The nasal delivery of nanoencapsulated statins—An approach for brain delivery. Int. J. Nanomed. 2016;11:6575-6590.

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114. 114.

     Kumar M., Misra A., Babbar A.K., Mishra A.K., Mishra P., Pathak K. Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int. J. Pharm. 2008;358:285-291.

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     Samia O., Hanan R., Kamal E.T. Carbamazepine mucoadhesive nanoemulgel (MNEG) as brain targeting delivery system via the olfactory mucosa. Drug Deliv. 2012;19:58-67.

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116. 116.

     Perez A.P., Mundiña-Weilenmann C., Romero E.L., Morilla M.J. Increased brain radioactivity by intranasal P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels. Int. J. Nanomed. 2012;7:1373-1385.

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117. 117.

     Jain D.S., Bajaj A.N., Athawale R.B., Shikhande S.S., Pandey A., Goel P.N., Gude R.P., Patil S., Raut P. Thermosensitive PLA based nanodispersion for targeting brain tumor via intranasal route. Mater. Sci. Eng. C Mater. Biol. Appl. 2016;63:411-421.

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     Wavikar P.R., Vavia P.R. Rivastigmine-loaded in situ gelling nanostructured lipid carriers for nose to brain delivery. J. Liposome Res. 2015;25:141-149.

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     Hao J., Zhao J., Zhang S., Tong T., Zhuang Q., Jin K., Chen W., Tang H. Fabrication of an ionic-sensitive in situ gel loaded with resveratrol nanosuspensions intended for direct nose-to-brain delivery. Colloids Surf. B Biointerfaces. 2016;147:376-386.

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     Sigurdsson H.H., Kirch J., Lehr C.-M. Mucus as a barrier to lipophilic drugs. Int. J. Pharm. 2013;453:56-64.

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     Lieleg O., Ribbeck K. Biological hydrogels as selective diffusion barriers. Trends Cell Biol. 2011;21:543-551.

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     Cone R.A. Barrier properties of mucus. Adv. Drug Deliv. Rev. 2009;61:75-85.

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     Vila A., Gill H., McCallion O., Alonso M.J. Transport of PLA-PEG particles across the nasal mucosa: Effect of particle size and PEG coating density. J. Control. Release. 2004;98:231-244.

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     Schuster B.S., Suk J.S., Woodworth G.F., Hanes J. Nanoparticle diffusion in respiratory mucus from humans without lung disease. Biomaterials. 2013;34:3439-3446.

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     Lai S.K., Suk J.S., Pace A., Wang Y.-Y., Yang M., Mert O., Chen J., Kim J., Hanes J. Drug carrier nanoparticles that penetrate human chronic rhinosinusitis mucus. Biomaterials. 2011;32:6285-6290.

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     Mert O., Lai S.K., Ensign L., Yang M., Wang Y.-Y., Wood J., Hanes J. NANOMEDICINE. J. Control. Release. 2012;157:455-460.

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     Xu Q., Boylan N.J., Cai S., Miao B., Patel H., Hanes J. Scalable method to produce biodegradable nanoparticles that rapidly penetrate human mucus. J. Control. Release. 2013;170:279-286.

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     Kirch J., Schneider A., Abou B., Hopf A., Schaefer U.F., Schneider M., Schall C., Wagner C., Lehr C.-M. Optical tweezers reveal relationship between microstructure and nanoparticle penetration of pulmonary mucus. Proc. Natl. Acad. Sci. USA. 2012;109:18355-18360.

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129. 129.

     Sharma D., Sharma R.K., Bhatnagar A., Nishad D.K., Singh T., Gabrani R., Sharma S.K., Ali J., Dang S. Nose to Brain Delivery of Midazolam Loaded PLGA Nanoparticles: In Vitro and In Vivo Investigations. Curr. Drug Deliv. 2016;13:557-564.

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130. 130.

     Sekerdag E., Lüle S., Bozdağ Pehlivan S., Öztürk N., Kara A., Kaffashi A., Vural I., Işıkay I., Yavuz B., Oguz K.K., et al. A potential non-invasive glioblastoma treatment: Nose-to-brain delivery of farnesylthiosalicylic acid incorporated hybrid nanoparticles. J. Control. Release. 2017;261:187-198.

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131. 131.

     Zhang Q.-Z., Zha L.-S., Zhang Y., Jiang W.-M., Lu W., Shi Z.-Q., Jiang X.-G., Fu S.-K. The brain targeting efficiency following nasally applied MPEG-PLA nanoparticles in rats. J. Drug Target. 2006;14:281-290.

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     Wang Y.-Y., Lai S.K., Suk J.S., Pace A., Cone R., Hanes J. Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that “slip” through the human mucus barrier. Angew. Chem. 2008;47:9726-9729.

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     Behrens I., Pena A.I.V., Alonso M.J., Kissel T. Comparative uptake studies of bioadhesive and non-bioadhesive nanoparticles in human intestinal cell lines and rats: The effect of mucus on particle adsorption and transport. Pharm. Res. 2002;19:1185-1193.

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134. 134.
     Stealth Properties to Improve Therapeutic Efficacy of Drug Nanocarriers · 2013

     No notice
135. 135.

     Guo Y., Luo J., Tan S., Otieno B.O., Zhang Z. The applications of Vitamin E TPGS in drug delivery. Eur. J. Pharm. Sci. 2013;49:175-186.

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136. 136.

     Jain R., Nabar S., Dandekar P., Patravale V. Micellar nanocarriers: Potential nose-to-brain delivery of zolmitriptan as novel migraine therapy. Pharm. Res. 2010;27:655-664.

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137. 137.

     Jain R., Nabar S., Dandekar P., Hassan P., Aswal V., Talmon Y., Shet T., Borde L., Ray K., Patravale V. Formulation and evaluation of novel micellar nanocarrier for nasal delivery of sumatriptan. Nanomedicine. 2010;5:575-587.

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     Salama H.A., Mahmoud A.A., Kamel A.O., Abdel Hady M., Awad G.A.S. Phospholipid based colloidal poloxamer-nanocubic vesicles for brain targeting via the nasal route. Colloids Surf. B Biointerfaces. 2012;100:146-154.

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139. 139.

     Abdelrahman F.E., Elsayed I., Gad M.K., Elshafeey A.H., Mohamed M.I. Response surface optimization, Ex vivo and In vivo investigation of nasal spanlastics for bioavailability enhancement and brain targeting of risperidone. Int. J. Pharm. 2017;530:1-11.

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     Zhao Y.-Z., Li X., Lu C.-T., Lin M., Chen L.-J., Xiang Q., Zhang M., Jin R.R., Jiang X., Shen X.-T., et al. Gelatin nanostructured lipid carriers-mediated intranasal delivery of basic fibroblast growth factor enhances functional recovery in hemiparkinsonian rats. Nanomedicine. 2014;10:755-764.

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141. 141.

     Bhatt R., Singh D., Prakash A., Mishra N. Development, characterization and nasal delivery of rosmarinic acid-loaded solid lipid nanoparticles for the effective management of Huntington’s disease. Drug Deliv. 2015;22:931-939.

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     Illum L. Nasal drug delivery--possibilities, problems and solutions. J. Control. Release. 2003;87:187-198.

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     Abd-Elal R.M.A., Shamma R.N., Rashed H.M., Bendas E.R. Trans-nasal zolmitriptan novasomes: In vitro preparation, optimization and in vivo evaluation of brain targeting efficiency. Drug Deliv. 2016;23:3374-3386.

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     Singh A.P., Saraf S.K., Saraf S.A. SLN approach for nose-to-brain delivery of alprazolam. Drug Deliv. Transl. Res. 2012;2:498-507.

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145. 145.

     Mehra N.K., Mishra V., Jain N.K. Receptor-based targeting of therapeutics. Ther. Deliv. 2013;4:369-394.

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     Ruenraroengsak P., Cook J.M., Florence A.T. Nanosystem drug targeting: Facing up to complex realities. J. Control. Release. 2010;141:265-276.

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148. 148.

     Broadwell R.D., Balin B.J. Endocytic and exocytic pathways of the neuronal secretory process and trans synaptic transfer of wheat germ agglutinin-horseradish peroxidasein vivo. J. Comp. Neurol. 1985;242:632-650.

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149. 149.

     Thorne R.G., Emory C.R., Ala T.A., Frey W.H. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res. 1995;692:278-282.

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     Gao X., Tao W., Lu W., Zhang Q., Zhang Y., Jiang X., Fu S. Lectin-conjugated PEG-PLA nanoparticles: Preparation and brain delivery after intranasal administration. Biomaterials. 2006;27:3482-3490.

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151. 151.

     Liu Q., Shen Y., Chen J., Gao X., Feng C., Wang L., Zhang Q., Jiang X. Nose-to-brain transport pathways of wheat germ agglutinin conjugated PEG-PLA nanoparticles. Pharm. Res. 2012;29:546-558.

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152. 152.

     Gao X., Wu B., Zhang Q., Chen J., Zhu J., Zhang W., Rong Z., Chen H., Jiang X. Brain delivery of vasoactive intestinal peptide enhanced with the nanoparticles conjugated with wheat germ agglutinin following intranasal administration. J. Control. Release. 2007;121:156-167.

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153. 153.

     Gao X., Chen J., Chen J., Wu B., Chen H., Jiang X. Quantum Dots Bearing Lectin-Functionalized Nanoparticles as a Platform for In Vivo Brain Imaging. Bioconjug. Chem. 2008;19:2189-2195.

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154. 154.

     Chen J., Zhang C., Liu Q., Shao X., Feng C., Shen Y., Zhang Q., Jiang X. Solanum tuberosumlectin-conjugated PLGA nanoparticles for nose-to-brain delivery: In vivo and in vitro evaluations. J. Drug Target. 2011;20:174-184.

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155. 155.

     Gao X., Chen J., Tao W., Zhu J., Zhang Q., Chen H., Jiang X. UEA I-bearing nanoparticles for brain delivery following intranasal administration. Int. J. Pharm. 2007;340:207-215.

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156. 156.

     Wen Z., Yan Z., He R., Pang Z., Guo L., Qian Y., Jiang X., Fang L. Brain targeting and toxicity study of odorranalectin-conjugated nanoparticles following intranasal administration. Drug Deliv. 2011;18:555-561.

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157. 157.

     Piazza J., Hoare T., Molinaro L., Terpstra K., Bhandari J., Selvaganapathy P.R., Gupta B., Mishra R.K. Haloperidol-loaded intranasally administered lectin functionalized poly(ethylene glycol)–block-poly(d,l)-lactic-co-glycolic acid (PEG–PLGA) nanoparticles for the treatment of schizophrenia. Eur. J. Pharm. Biopharm. 2014;87:30-39.

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158. 158.

     Wen Z., Yan Z., Hu K., Pang Z., Cheng X., Guo L., Zhang Q., Jiang X., Fang L., Lai R. Odorranalectin-conjugated nanoparticles: Preparation, brain delivery and pharmacodynamic study on Parkinson’s disease following intranasal administration. J. Control. Release. 2011;151:131-138.

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159. 159.

     Liu Q., Shao X., Chen J., Shen Y., Feng C., Gao X., Zhao Y., Li J., Zhang Q., Jiang X. In vivo toxicity and immunogenicity of wheat germ agglutinin conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles for intranasal delivery to the brain. Toxicol. Appl. Pharmacol. 2011;251:79-84.

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160. 160.

     Fonseca S.B., Pereira M.P., Kelley S.O. Recent advances in the use of cell-penetrating peptides for medical and biological applications. Adv. Drug Deliv. Rev. 2009;61:953-964.

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161. 161.

     Lin T., Liu E., He H., Shin M.C., Moon C., Yang V.C., Huang Y. Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides. Acta Pharm. Sin. B. 2016;6:352-358.

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     Xia H., Gao X., Gu G., Liu Z., Zeng N., Hu Q., Song Q., Yao L., Pang Z., Jiang X., et al. Low molecular weight protamine-functionalized nanoparticles for drug delivery to the brain after intranasal administration. Biomaterials. 2011;32:9888-9898.

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163. 163.

     Kanazawa T., Taki H., Tanaka K., Takashima Y., Okada H. Cell-penetrating peptide-modified block copolymer micelles promote direct brain delivery via intranasal administration. Pharm. Res. 2011;28:2130-2139.

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164. 164.
     Intranasal Delivery of Camptothecin-Loaded Tat-Modified Nanomicells for Treatment of Intracranial Brain Tumors · 2012

     Not checked
165. 165.

     Kanazawa T., Akiyama F., Kakizaki S., Takashima Y., Seta Y. Delivery of siRNA to the brain using a combination of nose-to-brain delivery and cell-penetrating peptide-modified nano-micelles. Biomaterials. 2013;34:9220-9226.

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166. 166.

     Rassu G., Soddu E., Posadino A.M., Pintus G., Sarmento B., Giunchedi P., Gavini E. Nose-to-brain delivery of BACE1 siRNA loaded in solid lipid nanoparticles for Alzheimer’s therapy. Colloids Surf. B Biointerfaces. 2017;152:296-301.

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167. 167.

     Frenkel D., Solomon B. Filamentous phage as vector-mediated antibody delivery to the brain. Proc. Natl. Acad. Sci. USA. 2002;99:5675-5679.

     Not in our library10.1073/pnas.072027199

168. 168.

     Janda K.J. Delivery of Active Proteins to the Central Nervous System Using Phage Vectors. European Patent. 2008.

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169. 169.

     Suzuki Y.A., Lopez V., Lönnerdal B. Mammalian lactoferrin receptors: Structure and function. Cell. Mol. Life Sci. 2005;62:2560-2575.

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170. 170.

     Elfinger M., Maucksch C., Rudolph C. Characterization of lactoferrin as a targeting ligand for nonviral gene delivery to airway epithelial cells. Biomaterials. 2007;28:3448-3455.

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171. 171.

     Liu Z., Jiang M., Kang T., Miao D., Gu G., Song Q., Yao L., Hu Q., Tu Y., Pang Z., et al. Lactoferrin-modified PEG-co-PCL nanoparticles for enhanced brain delivery of NAP peptide following intranasal administration. Biomaterials. 2013;34:3870-3881.

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172. 172.

     Bi C.C., Wang A.P., Chu Y.C., Liu S., Mu H.J., Liu W.H., Wu Z.M., Sun K.X., Li Y.X. Intranasal delivery of rotigotine to the brain with lactoferrin-modified PEG-PLGA nanoparticles for Parkinson’s disease treatment. Int. J. Nanomed. 2016;11:6547-6559.

     Not in our library10.2147/ijn.s120939

173. 173.

     Pan L., Zhou J., Ju F., Zhu H. Intranasal delivery of α-asarone to the brain with lactoferrin-modified mPEG-PLA nanoparticles prepared by premix membrane emulsification. Drug Deliv. Transl. Res. 2018;8:83-96.

     Not in our library10.1007/s13346-017-0438-8

174. 174.

     Liu L., Zhang X., Li W., Sun H., Lou Y., Zhang X., Li F. Transferrin receptor antibody-modified α-cobrotoxin-loaded nanoparticles enable drug delivery across the blood–brain barrier by intranasal administration. J. Nanopart. Res. 2013;15:2059.

     Not in our library10.1007/s11051-013-2059-6

175. 175.

     Hoekman J.D., Srivastava P., Ho R.J.Y. Aerosol-stable peptide-coated liposome nanoparticles: A proof-of-concept study with opioid fentanyl in enhancing analgesic effects and reducing plasma drug exposure. J. Pharm. Sci. 2014;103:2231-2239.

     Not in our library10.1002/jps.24022

Cited by papers we hold 3

• Nanotherapeutics for Nose-to-Brain Drug Delivery: An Approach to Bypass the Blood Brain Barrier · 2021
  No notice
• Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors · 2019
  No notice
• Nanoemulsions for “Nose-to-Brain” Drug Delivery · 2019
  No notice

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