ApoE-functionalization of Nanoparticles for Targeted Brain Delivery-a Feasible Method for Polyplexes?

Overview

Journal Drug Deliv Transl Res

Publisher Springer

Specialty Pharmacology

Date 2023 Dec 12

PMID 38087181

Authors

Natascha Hartl

Bettina Gabold

Philipp Uhl

Adrian Kromer

Ximian Xiao

Gert Fricker

Walter Mier

Runhui Liu

Olivia M Merkel

Affiliations

Soon will be listed here.

Abstract

The blood-brain barrier (BBB) poses a major obstacle in the treatment of all types of central nervous system (CNS) diseases. Small interfering RNA (siRNA) offers in principle a promising therapeutic approach by downregulating disease-related genes via RNA interference. However, the BBB is a formidable barrier for macromolecules such as nucleic acids. In an effort to develop a brain-targeted strategy for siRNA delivery systems formed by electrostatic interactions with cationic polymers (polyplexes (PXs)), we investigated the suitability of the well-known surfactant-based approach for Apolipoprotein E (ApoE)-functionalization of nanoparticles (NPs). The aim of this present work was to investigate if ApoE coating of siRNA PXs formed with cationic branched 25-kDa poly(ethyleneimine) (b-PEI) and nylon-3 polymers without or after precoating with polysorbate 80 (PS 80) would promote successful delivery across the BBB. We utilized highly hydrophobic NM/CP nylon-3 polymers to evaluate the effects of hydrophobic cyclopentyl (CP) subunits on ApoE binding efficacy and observed successful ApoE binding with and without PS 80 precoating to the nylon-3 but not the PEI polyplexes. Accordingly, ApoE-coated nylon-3 polyplexes showed significantly increased uptake and gene silencing in U87 glioma cells but no benefit in vivo. In conclusion, further optimization of ApoE-functionalized polyplexes and more sophisticated in vitro models are required to achieve more successful in vitro-in vivo translation in future approaches.

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References

Steiniger S, Kreuter J, Khalansky A, Skidan I, Bobruskin A, Smirnova Z . Chemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles. Int J Cancer. 2004; 109(5):759-67. DOI: 10.1002/ijc.20048. View

Liu M, Li H, Luo G, Liu Q, Wang Y . Pharmacokinetics and biodistribution of surface modification polymeric nanoparticles. Arch Pharm Res. 2008; 31(4):547-54. DOI: 10.1007/s12272-001-1191-8. View

Dobrovolskaia M, McNeil S . Understanding the correlation between in vitro and in vivo immunotoxicity tests for nanomedicines. J Control Release. 2013; 172(2):456-66. PMC: 5831149. DOI: 10.1016/j.jconrel.2013.05.025. View

Mulik R, Monkkonen J, Juvonen R, Mahadik K, Paradkar A . ApoE3 mediated poly(butyl) cyanoacrylate nanoparticles containing curcumin: study of enhanced activity of curcumin against beta amyloid induced cytotoxicity using in vitro cell culture model. Mol Pharm. 2010; 7(3):815-25. DOI: 10.1021/mp900306x. View

Kreuter J, Alyautdin R, Kharkevich D, Ivanov A . Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles). Brain Res. 1995; 674(1):171-4. DOI: 10.1016/0006-8993(95)00023-j. View

Ogris M, Brunner S, Schuller S, Kircheis R, Wagner E . PEGylated DNA/transferrin-PEI complexes: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery. Gene Ther. 1999; 6(4):595-605. DOI: 10.1038/sj.gt.3300900. View

Dehouck B, Dehouck M, Fruchart J, Cecchelli R . Upregulation of the low density lipoprotein receptor at the blood-brain barrier: intercommunications between brain capillary endothelial cells and astrocytes. J Cell Biol. 1994; 126(2):465-73. PMC: 2200038. DOI: 10.1083/jcb.126.2.465. View

Girotra P, Singh S . A Comparative Study of Orally Delivered PBCA and ApoE Coupled BSA Nanoparticles for Brain Targeting of Sumatriptan Succinate in Therapeutic Management of Migraine. Pharm Res. 2016; 33(7):1682-95. DOI: 10.1007/s11095-016-1910-8. View

Alyaudtin R, Reichel A, Lobenberg R, Ramge P, Kreuter J, Begley D . Interaction of poly(butylcyanoacrylate) nanoparticles with the blood-brain barrier in vivo and in vitro. J Drug Target. 2001; 9(3):209-21. DOI: 10.3109/10611860108997929. View

10.

Chollet P, Favrot M, Hurbin A, Coll J . Side-effects of a systemic injection of linear polyethylenimine-DNA complexes. J Gene Med. 2002; 4(1):84-91. DOI: 10.1002/jgm.237. View

11.

Pardridge W . Blood-brain barrier drug targeting: the future of brain drug development. Mol Interv. 2004; 3(2):90-105, 51. DOI: 10.1124/mi.3.2.90. View

12.

Ebrahimi Shahmabadi H, Movahedi F, Koohi Moftakhari Esfahani M, Alavi S, Eslamifar A, Mohammadi Anaraki G . Efficacy of Cisplatin-loaded polybutyl cyanoacrylate nanoparticles on the glioblastoma. Tumour Biol. 2014; 35(5):4799-806. DOI: 10.1007/s13277-014-1630-9. View

13.

Ren T, Xu N, Cao C, Yuan W, Yu X, Chen J . Preparation and therapeutic efficacy of polysorbate-80-coated amphotericin B/PLA-b-PEG nanoparticles. J Biomater Sci Polym Ed. 2009; 20(10):1369-80. DOI: 10.1163/092050609X12457418779185. View

14.

Burke R, Pun S . Extracellular barriers to in Vivo PEI and PEGylated PEI polyplex-mediated gene delivery to the liver. Bioconjug Chem. 2008; 19(3):693-704. DOI: 10.1021/bc700388u. View

15.

Schroeder U, Sommerfeld P, Ulrich S, Sabel B . Nanoparticle technology for delivery of drugs across the blood-brain barrier. J Pharm Sci. 1998; 87(11):1305-7. DOI: 10.1021/js980084y. View

16.

Jose S, Juna B, Cinu T, Jyoti H, Aleykutty N . Carboplatin loaded Surface modified PLGA nanoparticles: Optimization, characterization, and in vivo brain targeting studies. Colloids Surf B Biointerfaces. 2016; 142:307-314. DOI: 10.1016/j.colsurfb.2016.02.026. View

17.

Behlke M . Progress towards in vivo use of siRNAs. Mol Ther. 2006; 13(4):644-70. PMC: 7106286. DOI: 10.1016/j.ymthe.2006.01.001. View

18.

Gao K, Jiang X . Influence of particle size on transport of methotrexate across blood brain barrier by polysorbate 80-coated polybutylcyanoacrylate nanoparticles. Int J Pharm. 2006; 310(1-2):213-9. DOI: 10.1016/j.ijpharm.2005.11.040. View

19.

Ramge P, Kreuter J, Lemmer B . Circadian phase-dependent antinociceptive reaction in mice determined by the hot-plate test and the tail-flick test after intravenous injection of dalargin-loaded nanoparticles. Chronobiol Int. 1999; 16(6):767-77. DOI: 10.3109/07420529909016944. View

20.

Mittal G, Carswell H, Brett R, Currie S, Kumar M . Development and evaluation of polymer nanoparticles for oral delivery of estradiol to rat brain in a model of Alzheimer's pathology. J Control Release. 2010; 150(2):220-8. DOI: 10.1016/j.jconrel.2010.11.013. View