Current advances in delivery of biotherapeutics across the blood-brain barrier.
Abstract
Significant efforts through genomic approaches have been dedicated toward the identification of novel protein-protein interactions as promising therapeutic targets for indications such as Alzheimer's disease, Parkinson's disease and neuropsychiatric disorders. Additionally, the number of biotherapeutic agents entering the Pharmaceutical sector continues to increase and according to EvaluatePharma's "World Preview 2014" report, "the compounded annual growth rate of biologics is expected to be 8.5 percent from 2008-2014, eight to 10 times greater than the growth rate of small molecules". However, there are limited examples of success in developing biotherapeutic modalities for central nervous system (CNS) diseases in the drug development pipeline. A primary reason for the lack of application of biotherapeutics to neuroscience targets, is that the blood-brain barrier (BBB) isolates and protects CNS structures creating a unique biochemically and immunologically privileged environment, therefore passage of macromolecules across this barrier has additional challenges. An understanding of the anatomical and physiological properties of this barrier with respect to penetration of biotherapeutics is presented in this review document. In this summary, recent advances in biotherapeutic delivery mechanisms across the BBB including transcranial brain drug delivery, focused ultrasound technology, nasal delivery, absorptive endocytosis, and receptor mediated endocytosis are evaluated using an industrial perspective. With acknowledgement that each approach has advantages and disadvantages, this review discusses the opportunities and challenges that are encountered during application of these methods across a variety of therapeutic areas such as, pain, obesity, neuroscience, and oncology. Utilizing an industrial perspective, including consideration of cost of goods and commercial feasibility for these approaches, this review highlights technology features which would enable industry investments toward novel BBB delivery technologies for biologics. Through continued development and improvement of such technology, new therapeutic options to treat and potentially cure central nervous system diseases could eventually evolve.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A wide range of pharmaceutical nanocarriers including liposomes, PNPs, SLNs, micelles, dendrimers, and others have been developed.
“A wide range of pharmaceutical nanocarriers including liposomes, PNPs, SLNs, micelles, dendrimers, and some others have been developed (Rajadhyaksha et al., 2011; Wong et al., 2012; Ozkizilcik et al., 2017).”
From Nanotechnology: A Promising Approach for Delivery of Neuroprotective Drugs (2020) · cites this paper as Rajadhyaksha et al., 2011
Cited by
Sorted by citations
Kariolis, M. S., Wells, R. C., Getz, J. A., Kwan, W., Mahon, C. S., Tong, R. K., Kim, D. J., Srivastava, A., Bédard, C., Henne, K. R., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay1359 · Cited by 356 · see citing works
Strategies for transporting nanoparticles across the blood–brain barrier
Zhang, T.-T., Li, W., Meng, G., Wang, P., & Liao, W. (2016) · Biomaterials Science · doi:10.1039/c5bm00383k · Cited by 308 · see citing works
Nanotechnology: A Promising Approach for Delivery of Neuroprotective Drugs
Naqvi, S., Panghal, A., & Flora, S. J. S. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00494 · Cited by 305 · see citing works
Anti-neuroinflammatory Potential of Natural Products in Attenuation of Alzheimer’s Disease
Shal, B., Ding, W., Ali, H., Kim, Y. S., & Khan, S. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00548 · Cited by 234 · see citing works
“The ability of metabolites to penetrate the BBB depends upon the degree of lipophilicity, polarity, and molecular weight of each compound (Rajadhyaksha et al., 2011).”
BackgroundIntrathecal delivery of protein therapeutics to the brain: A critical reassessment
Calias, P., Banks, W. A., Begley, D. J., Scarpa, M., & Dickson, P. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.05.009 · Cited by 175 · see citing works
“Because promising reports for ICV and intranasal delivery and BBB disruption have been extensively described (Alam et al., 2010; Rajadhyaksha et al., 2011; Tayebati et al., 2013; Zhao et al., 2013), we will not recapitulate them here.”
Nasal-nanotechnology: revolution for efficient therapeutics delivery
Kumar, A., Pandey, A. N., & Jain, S. K. (2014) · Drug Delivery · doi:10.3109/10717544.2014.920431 · Cited by 171 · see citing works
“Even though the clinical potential of this drug administration route still remains controversial, there is substantial curiosity in investigating nasal route for the treatment of many intra-cerebral diseases such as Parkinson’s and Alzheimer’s (Merkus et al., 2003; Illum, 2004; Merkus & van den Berg, 2007; Malerba et…”
BackgroundIn Vivo Specific Delivery of c-Met siRNA to Glioblastoma Using Cationic Solid Lipid Nanoparticles
Jin, J., Bae, K. H., Yang, H., Lee, S. J., Kim, H., Kim, Y., Joo, K. M., Seo, S. W., Park, T. G., & Nam, D. (2011) · Bioconjugate Chemistry · doi:10.1021/bc200406n · Cited by 149 · see citing works
Adenosine receptor signaling: a key to opening the blood–brain door
Bynoe, M. S., Viret, C., Yan, A., & Kim, D.-G. (2015) · Fluids and Barriers of the CNS · doi:10.1186/s12987-015-0017-7 · Cited by 139 · see citing works
“Researchers have focused on uncovering ways to manipulate the BBB to promote access to the CNS [86].”
BackgroundTeixeira, M. I., Lopes, C. M., Amaral, M. H., & Costa, P. C. (2020) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2020.01.005 · Cited by 132 · see citing works
Targeted DNA Mutagenesis for the Cure of Chronic Viral Infections
Schiffer, J. T., Aubert, M., Weber, N. D., Mintzer, E., Stone, D., & Jerome, K. R. (2012) · Journal of Virology · doi:10.1128/jvi.00052-12 · Cited by 111 · see citing works
“Noninvasive strategies include drug manipulation, carrier-mediated drug delivery, receptor/vector-mediated delivery, and intranasal drug delivery (131, 144), and some of these approaches may prove useful in gene therapy efforts.”
BackgroundNanotechnology-based drug delivery for the treatment of CNS disorders
Mittal, K. R., Pharasi, N., Sarna, B., Singh, M., Rachana, R., Haider, S., Singh, S. K., Dua, K., Jha, S. K., Dey, A., et al. (2022) · Translational Neuroscience · doi:10.1515/tnsci-2022-0258 · Cited by 112 · see citing works
Harnessing cerebrospinal fluid circulation for drug delivery to brain tissues
Naseri Kouzehgarani, G., Feldsien, T., Engelhard, H. H., Mirakhur, K. K., Phipps, C., Nimmrich, V., Clausznitzer, D., & Lefebvre, D. R. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.03.002 · Cited by 95 · see citing works
Nasal-to-CNS Drug Delivery: Where are We Now and Where are We heading? an Industrial Perspective
Landis, M. S., Boyden, T. L., & Pegg, S. (2012) · Therapeutic Delivery · doi:10.4155/tde.11.149 · Cited by 64 · see citing works
Self-citationRhaman, M. M., Islam, M. R., Akash, S., Mim, M., Noor alam, M., Nepovimova, E., Valis, M., Kuca, K., & Sharma, R. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.989471 · Cited by 63 · see citing works
“Liposomes, PNPs, SLNs, micelles, dendrimers, and numerous other pharmacological nanocarriers have all been created (Rajadhyaksha et al., 2011; Wong et al., 2012; Ozkizilcik et al., 2017).”
BackgroundNanotechnology for CNS delivery of bio-therapeutic agents
Shah, L. K., Yadav, S. K., & Amiji, M. M. (2013) · Drug Delivery and Translational Research · doi:10.1007/s13346-013-0133-3 · Cited by 64 · see citing works
“However, there are not as many biologics that have been successfully developed in clinic for treating CNS disorders [2].”
HIF-1 at the Blood-Brain Barrier: A Mediator of Permeability?
Ogunshola, O. O., & Al-Ahmad, A. J. (2012) · High Altitude Medicine & Biology · doi:10.1089/ham.2012.1052 · Cited by 54 · see citing works
Madadi, A. K., & Sohn, M. (2024) · Pharmaceuticals · doi:10.3390/ph17081070 · Cited by 52 · see citing works
Targeted Brain Delivery Nanoparticles for Malignant Gliomas
Pinto, M. P., Arce, M., Yameen, B., & Vilos, C. (2016) · Nanomedicine · doi:10.2217/nnm-2016-0307 · Cited by 47 · see citing works
Purinergic signaling: A gatekeeper of blood-brain barrier permeation
Wang, Y., Zhu, Y., Wang, J., Dong, L., Liu, S., Li, S., & Wu, Q. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1112758 · Cited by 47 · see citing works
“In addition, researchers concentrated on developing strategies to control the BBB in order to facilitate access to the CNS (Rajadhyaksha et al., 2011).”
BackgroundWhich drug or drug delivery system can change clinical practice for brain tumor therapy?
Siegal, T. (2013) · Neuro-Oncology · doi:10.1093/neuonc/not016 · Cited by 45 · see citing works
McCaffrey, G., & Davis, T. P. (2012) · Journal of Investigative Medicine · doi:10.2310/jim.0b013e318276de79 · Cited by 42 · see citing works
Bao, H., Jin, X., Li, L., Lv, F., & Liu, T. (2012) · Journal of Materials Science Materials in Medicine · doi:10.1007/s10856-012-4658-7 · Cited by 42 · see citing works
Nair, S., Dileep, A., & Rajanikant, G. K. (2012) · Current Medicinal Chemistry · doi:10.2174/092986712798992138 · Cited by 36 · see citing works
Rodríguez, A., Castrejón-Godínez, M. L., & Monterrosas‐Brisson, N. (2025) · Stresses · doi:10.3390/stresses5020031 · Cited by 32 · see citing works
“Populations at highest risk include agricultural workers and communities living near areas treated with pesticides, who face higher levels of exposure.”
Cheng, Y., El‐Kattan, A. F., Zhang, Y., Ray, A. S., & Lai, Y. (2016) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.5b00511 · Cited by 26 · see citing works
Self-citationRussell-Jones, G. J. (2011) · Therapeutic Delivery · doi:10.4155/tde.11.129 · Cited by 23 · see citing works
Le Formiche Della Venezia Giulia E Della Dalmazia.
Müller, G. (1923) · INFM-OAR (INFN Catania) · doi:10.5281/zenodo.25749 · Cited by 20 · see citing works
Engineered Antibodies to Improve Efficacy against Neurodegenerative Disorders
Niazi, S. K., Mariam, Z., & Magoola, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126683 · Cited by 16 · see citing works
“Still, these approaches are invasive and incompatible with repeat dosing regimens [22–24].”
BackgroundTargeted Delivery Platforms for the Treatment of Multiple Sclerosis
Jan, Z., Mollazadeh, S., Abnous, K., Taghdisi, S. M., Danesh, A., Ramezani, M., & Alibolandi, M. (2022) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.1c00892 · Cited by 13 · see citing works
Kumar, A., & Jain, S. K. (2016) · Artificial Cells Nanomedicine and Biotechnology · doi:10.3109/21691401.2016.1160405 · Cited by 9 · see citing works
“…unbolt positive horizons for future understanding of brain function and future therapeutics of CNS diseases, for example, depression, epilepsy, schizophrenia, Parkinson’s, and Alzheimer’s (Illum 2004, Malerba et al. 2011, Merkus and van den Berg 2007, Merkus et al. 2003, Rajadhyaksha et al. 2011).”
BackgroundLong acting injectables for therapeutic proteins
Ryan, S. E., Shortall, K., Dully, M., et al. (2022) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2022.112644 · Cited by 8 · see citing works
“[1],[2],[3] Unlike small molecule drugs that are generally delivered orally, biotherapeutics have low bioavailability after oral administration and can be degraded in the alimentary canal.”
BackgroundManibalan, S., Kandasamy, T., Varshni, M., Shobana, A., & Achary, A. (2020) · Biotechnology and Genetic Engineering Reviews · doi:10.1080/02648725.2020.1858395 · Cited by 7 · see citing works
Nanoparticulate systems as drug carriers: the need
Patravale, V. B., Dandekar, P. P., & Jain, R. D. (2012) · Elsevier eBooks · doi:10.1533/9781908818195.1 · Cited by 8 · see citing works
“In the non-invasive category, nanoparticulate drug carriers have demonstrated great potential for successful therapies [74] .”
BackgroundHalpern, W., & Hutto, D. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-415759-0.00025-x · Cited by 4 · see citing works
The Economics of Drug Development: A Comparison between Orphan and Non-orphan Drugs
Gomase, V. S., Sharma, R., Sardana, S., et al. (2025) · Current Drug Discovery Technologies · doi:10.2174/0115701638379700250713040806 · Cited by 3 · see citing works
Phipps, M. D., Sanders, V. A., & Deri, M. A. (2021) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.1c00180 · Cited by 3 · see citing works
Nanomedicine Based Drug Targeting in Alzheimer’s Disease: High Impact of Small Carter
Ahmad, M. Z., Akhter, S., Rahman, Z., Ahmad, J., Ahmad, I., & Ahmad, F. J. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-803959-5.50016-7 · Cited by 3 · see citing works
Twenty-First-Century Neuroscience: The Potential for Innovative Therapies for Brain Disorders
Miksys, S. L., Uhl, K., & Tyndale, R. F. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2011.310 · Cited by 2 · see citing works
Rao, V. A. (2015) · AAPS advances in the pharmaceutical sciences series · doi:10.1007/978-1-4939-2543-8_11 · Cited by 2 · see citing works
Khanna, A. K., & Farag, E. S. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-805299-0.00003-8 · Cited by 2 · see citing works
Nanotechnology for efficient delivery of TCM active ingredients in treating brain diseases
Yang, Y., Gao, Y., Li, J., Zou, J., Luan, F., Shi, Y., Zhai, B., & Huang, Q. (2026) · Materials Today Bio · doi:10.1016/j.mtbio.2026.103265 · Cited by 2 · see citing works
“The ability of a drug to penetrate the BBB is largely determined by its physicochemical properties, such as molecular size, lipophilicity, and degree of ionization [9,10].”
Image-Guided Delivery of Therapeutics to the Brain
Shah, L. K., Iyer, A. K., Talekar, M., & Amiji, M. M. (2014) · Advances in delivery science and technology · doi:10.1007/978-3-319-11355-5_4 · Cited by 2 · see citing works
“is becoming increasingly popular for brain imaging due to exquisite sensitivity to functional changes through intrinsic contrast as well as ease of synthesis and availability of optical probes that can be used as exogenous contrast agents [ 3 ].”
BackgroundMethod(2012) · The Brain Sciences Journal · doi:10.7214/brainsciences/000 · Cited by 1 · see citing works
Pharmacoeconomic Considerations in CNS Drug Development
Gray, D. L. (2013) · AAPS advances in the pharmaceutical sciences series · doi:10.1007/978-1-4614-9105-7_13
Tedesco, A. C., Castilho–Fernandes, A., & Lopes, T. G. (2013) · Vigilância Sanitária em Debate · doi:10.3395/vd.v1i4.98en
Antibodies as Ion Channel Modulators
Edwards, W., & Wickenden, A. D. (2014) · Royal Society of Chemistry eBooks · doi:10.1039/9781849735087-00320
Multifunctional combinatorial-designed nanoparticles for nucleic acid therapy
Amiji, M. M. (2016) · Proceedings of SPIE, the International Society for Optical Engineering/Proceedings of SPIE · doi:10.1117/12.2224764
“These large molecular weight and sometimes highly negatively-charged hydrophilic molecules are prone to rapid clearance due to poor systemic stability and cannot efficiently access the tissue and cellular targets when administered into the blood stream (6-9).”
BackgroundWhich Drug or Drug Delivery Method Can Change Clinical Practice for Brain Tumor Therapy?
Siegal, T. (2013) · AAPS advances in the pharmaceutical sciences series · doi:10.1007/978-1-4614-9105-7_24
Understanding blood–brain barrier
Helou, M., & Farag, E. S. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-22273-3.00004-3
- Authors
- Rajadhyaksha, M., Boyden, T., Liras, J., El-Kattan, A., & Brodfuehrer, J.
- Affiliations
- Pfizer (United States) (US)
- Venue
- Current Drug Discovery Technologies
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2011-06-01
- Volume
- 8
- Issue
- 2
- Pages
- 87-101
- ISSN
- 1570-1638 (ISSN-L)
- OpenAlex
- W2086570466
- Cited by
- 49
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 5 · 2021: 2 · 2020: 4 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 3 · 2014: 5 · 2013: 6 · 2012: 9
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Drug Discovery Technologies (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- blood-brain barrier, biologic therapy, drug delivery, focused ultrasound, intranasal drug delivery, receptor-mediated endocytosis, central nervous system disorders, biologics, commercial feasibility, cost of goods manufactured
- MeSH terms
- Animals, Biological Products, Biological Transport, Blood-Brain Barrier, Central Nervous System Agents, Chemistry, Pharmaceutical, Drug Administration Routes, Drug Carriers, Humans, Permeability, Technology, Pharmaceutical, Drug Delivery Systems
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
