Targeting Receptor-mediated Transport for Delivery of Biologics Across the Blood-brain Barrier

Overview

Journal Annu Rev Pharmacol Toxicol

Publisher Annual Reviews

Specialties Pharmacology
Toxicology

Date 2014 Oct 24

PMID 25340933

Citations 142

Authors

Jason M Lajoie

Eric V Shusta

Affiliations

Soon will be listed here.

Abstract

Biologics are an emerging class of medicines with substantial promise to treat neurological disorders such as Alzheimer's disease, stroke, and multiple sclerosis. However, the blood-brain barrier (BBB) presents a formidable obstacle that appreciably limits brain uptake and hence the therapeutic potential of biologics following intravenous administration. One promising strategy for overcoming the BBB to deliver biologics is the targeting of endogenous receptor-mediated transport (RMT) systems that employ vesicular trafficking to transport ligands across the BBB endothelium. If a biologic is modified with an appropriate targeting ligand, it can gain improved access to the brain via RMT. Various RMT-targeting strategies have been developed over the past 20 years, and this review explores exciting recent advances, emphasizing studies that show brain targeting in vivo.

Citing Articles

Drug Treatment Direction Based on the Molecular Mechanism of Breast Cancer Brain Metastasis.

Zhang Y, Shang H, Zhang J, Jiang Y, Li J, Xiong H Pharmaceuticals (Basel). 2025; 18(2).

PMID: 40006075 PMC: 11859690. DOI: 10.3390/ph18020262.

Utilization of nanotechnology to surmount the blood-brain barrier in disorders of the central nervous system.

Luo Q, Yang J, Yang M, Wang Y, Liu Y, Liu J Mater Today Bio. 2025; 31:101457.

PMID: 39896289 PMC: 11786670. DOI: 10.1016/j.mtbio.2025.101457.

Molecular and cellular characteristics of cerebrovascular cell types and their contribution to neurodegenerative diseases.

Garcia F, Heiman M Mol Neurodegener. 2025; 20(1):13.

PMID: 39881338 PMC: 11780804. DOI: 10.1186/s13024-025-00799-z.

Breaking boundaries: role of the brain barriers in metastatic process.

Izadi N, Solar P, Hasanova K, Zamani A, Akbar M, Mrazova K Fluids Barriers CNS. 2025; 22(1):3.

PMID: 39780275 PMC: 11708195. DOI: 10.1186/s12987-025-00618-z.

pH-Responsive Polyethylene Glycol Engagers for Enhanced Brain Delivery of PEGylated Nanomedicine to Treat Glioblastoma.

Meng J, Dong Z, Chen Y, Lin M, Liu Y, Roffler S ACS Nano. 2025; 19(1):307-321.

PMID: 39749925 PMC: 11752499. DOI: 10.1021/acsnano.4c05906.

References

Manich G, Cabezon I, Del Valle J, Duran-Vilaregut J, Camins A, Pallas M . Study of the transcytosis of an anti-transferrin receptor antibody with a Fab' cargo across the blood-brain barrier in mice. Eur J Pharm Sci. 2013; 49(4):556-64. DOI: 10.1016/j.ejps.2013.05.027. View

Alata W, Paris-Robidas S, Emond V, Bourasset F, Calon F . Brain uptake of a fluorescent vector targeting the transferrin receptor: a novel application of in situ brain perfusion. Mol Pharm. 2013; 11(1):243-53. DOI: 10.1021/mp400421a. View

Drappatz J, Brenner A, Wong E, Eichler A, Schiff D, Groves M . Phase I study of GRN1005 in recurrent malignant glioma. Clin Cancer Res. 2013; 19(6):1567-76. DOI: 10.1158/1078-0432.CCR-12-2481. View

Wang D, El-Amouri S, Dai M, Kuan C, Hui D, Brady R . Engineering a lysosomal enzyme with a derivative of receptor-binding domain of apoE enables delivery across the blood-brain barrier. Proc Natl Acad Sci U S A. 2013; 110(8):2999-3004. PMC: 3581871. DOI: 10.1073/pnas.1222742110. View

Hartz A, Bauer B . ABC transporters in the CNS - an inventory. Curr Pharm Biotechnol. 2010; 12(4):656-73. DOI: 10.2174/138920111795164020. View

Benchenane K, Berezowski V, Ali C, Fernandez-Monreal M, Lopez-Atalaya J, Brillault J . Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis. Circulation. 2005; 111(17):2241-9. DOI: 10.1161/01.CIR.0000163542.48611.A2. View

Spencer B, Verma I . Targeted delivery of proteins across the blood-brain barrier. Proc Natl Acad Sci U S A. 2007; 104(18):7594-9. PMC: 1857226. DOI: 10.1073/pnas.0702170104. View

Strazielle N, Ghersi-Egea J . Physiology of blood-brain interfaces in relation to brain disposition of small compounds and macromolecules. Mol Pharm. 2013; 10(5):1473-91. DOI: 10.1021/mp300518e. View

Wagner S, Zensi A, Wien S, Tschickardt S, Maier W, Vogel T . Uptake mechanism of ApoE-modified nanoparticles on brain capillary endothelial cells as a blood-brain barrier model. PLoS One. 2012; 7(3):e32568. PMC: 3291552. DOI: 10.1371/journal.pone.0032568. View

10.

Pardridge W . Blood-brain barrier delivery. Drug Discov Today. 2007; 12(1-2):54-61. DOI: 10.1016/j.drudis.2006.10.013. View

11.

Boado R, Hui E, Lu J, Pardridge W . Glycemic control and chronic dosing of rhesus monkeys with a fusion protein of iduronidase and a monoclonal antibody against the human insulin receptor. Drug Metab Dispos. 2012; 40(10):2021-5. PMC: 3463822. DOI: 10.1124/dmd.112.046375. View

12.

Kumagai A, Eisenberg J, Pardridge W . Absorptive-mediated endocytosis of cationized albumin and a beta-endorphin-cationized albumin chimeric peptide by isolated brain capillaries. Model system of blood-brain barrier transport. J Biol Chem. 1987; 262(31):15214-9. View

13.

Dehouck B, Fenart L, Dehouck M, Pierce A, Torpier G, Cecchelli R . A new function for the LDL receptor: transcytosis of LDL across the blood-brain barrier. J Cell Biol. 1997; 138(4):877-89. PMC: 2138047. DOI: 10.1083/jcb.138.4.877. View

14.

Sumbria R, Hui E, Lu J, Boado R, Pardridge W . Disaggregation of amyloid plaque in brain of Alzheimer's disease transgenic mice with daily subcutaneous administration of a tetravalent bispecific antibody that targets the transferrin receptor and the Abeta amyloid peptide. Mol Pharm. 2013; 10(9):3507-13. DOI: 10.1021/mp400348n. View

15.

Herweijer H, Wolff J . Gene therapy progress and prospects: hydrodynamic gene delivery. Gene Ther. 2006; 14(2):99-107. DOI: 10.1038/sj.gt.3302891. View

16.

Yu Y, Zhang Y, Kenrick M, Hoyte K, Luk W, Lu Y . Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med. 2011; 3(84):84ra44. DOI: 10.1126/scitranslmed.3002230. View

17.

Atwal J, Chen Y, Chiu C, Mortensen D, Meilandt W, Liu Y . A therapeutic antibody targeting BACE1 inhibits amyloid-β production in vivo. Sci Transl Med. 2011; 3(84):84ra43. DOI: 10.1126/scitranslmed.3002254. View

18.

Sumbria R, Zhou Q, Hui E, Lu J, Boado R, Pardridge W . Pharmacokinetics and brain uptake of an IgG-TNF decoy receptor fusion protein following intravenous, intraperitoneal, and subcutaneous administration in mice. Mol Pharm. 2013; 10(4):1425-31. PMC: 3615110. DOI: 10.1021/mp400004a. View

19.

Nolan D, Ginsberg M, Israely E, Palikuqi B, Poulos M, James D . Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration. Dev Cell. 2013; 26(2):204-19. PMC: 3873200. DOI: 10.1016/j.devcel.2013.06.017. View

20.

Boado R, Zhang Y, Wang Y, Pardridge W . Engineering and expression of a chimeric transferrin receptor monoclonal antibody for blood-brain barrier delivery in the mouse. Biotechnol Bioeng. 2008; 102(4):1251-8. PMC: 2729652. DOI: 10.1002/bit.22135. View