Macrophages offer a paradigm switch for CNS delivery of therapeutic proteins

Natalia L. Klyachko, Matthew J. Haney, Yuling Zhao, Devika S. Manickam, Vivek Mahajan, Poornima Suresh, Shawn D. Hingtgen, R Lee Mosley, Howard Eliot Gendelman, Alexander V. Kabanov, Elena V. Batrakova

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Aims: Active targeted transport of the nanoformulated redox enzyme, catalase, in macrophages attenuates oxidative stress and as such increases survival of dopaminergic neurons in animal models of Parkinson's disease. Optimization of the drug formulation is crucial for the successful delivery in living cells. We demonstrated earlier that packaging of catalase into a polyion complex micelle ('nanozyme') with a synthetic polyelectrolyte block copolymer protected the enzyme against degradation in macrophages and improved therapeutic outcomes. We now report the manufacture of nanozymes with superior structure and therapeutic indices. Methods: Synthesis, characterization and therapeutic efficacy of optimal cell-based nanoformulations are evaluated. Results: A formulation design for drug carriers typically works to avoid entrapment in monocytes and macrophages focusing on small-sized nanoparticles with a polyethylene glycol corona (to provide a stealth effect). By contrast, the best nanozymes for delivery in macrophages reported in this study have a relatively large size (200 nm), which resulted in improved loading capacity and release from macrophages. Furthermore, the cross-linking of nanozymes with the excess of a nonbiodegradable linker ensured their low cytotoxicity, and efficient catalase protection in cell carriers. Finally, the 'alternatively activated' macrophage phenotype (M2) utilized in these studies did not promote further inflammation in the brain, resulting in a subtle but statistically significant effect on neuronal regeneration and repair in vivo. Conclusion: The optimized cross-linked nanozyme loaded into macrophages reduced neuroinflammatory responses and increased neuronal survival in mice. Importantly, the approach for nanoformulation design for cell-mediated delivery is different from the common requirements for injectable formulations.

Original languageEnglish (US)
Pages (from-to)1403-1422
Number of pages20
JournalNanomedicine
Volume9
Issue number9
DOIs
StatePublished - Jul 1 2014

Fingerprint

Macrophages
drug
Switches
enzyme
paradigm
Proteins
protein
repair
corona
phenotype
brain
Catalase
regeneration
animal
Disease
degradation
Therapeutics
Enzymes
Drug Compounding
Drug Carriers

Keywords

  • blood-brain barrier
  • catalase
  • cell-mediated drug delivery
  • neuroinflammation

ASJC Scopus subject areas

  • Bioengineering
  • Medicine (miscellaneous)
  • Biomedical Engineering
  • Materials Science(all)

Cite this

Klyachko, N. L., Haney, M. J., Zhao, Y., Manickam, D. S., Mahajan, V., Suresh, P., ... Batrakova, E. V. (2014). Macrophages offer a paradigm switch for CNS delivery of therapeutic proteins. Nanomedicine, 9(9), 1403-1422. https://doi.org/10.2217/nnm.13.115

Macrophages offer a paradigm switch for CNS delivery of therapeutic proteins. / Klyachko, Natalia L.; Haney, Matthew J.; Zhao, Yuling; Manickam, Devika S.; Mahajan, Vivek; Suresh, Poornima; Hingtgen, Shawn D.; Mosley, R Lee; Gendelman, Howard Eliot; Kabanov, Alexander V.; Batrakova, Elena V.

In: Nanomedicine, Vol. 9, No. 9, 01.07.2014, p. 1403-1422.

Research output: Contribution to journalArticle

Klyachko, NL, Haney, MJ, Zhao, Y, Manickam, DS, Mahajan, V, Suresh, P, Hingtgen, SD, Mosley, RL, Gendelman, HE, Kabanov, AV & Batrakova, EV 2014, 'Macrophages offer a paradigm switch for CNS delivery of therapeutic proteins', Nanomedicine, vol. 9, no. 9, pp. 1403-1422. https://doi.org/10.2217/nnm.13.115
Klyachko NL, Haney MJ, Zhao Y, Manickam DS, Mahajan V, Suresh P et al. Macrophages offer a paradigm switch for CNS delivery of therapeutic proteins. Nanomedicine. 2014 Jul 1;9(9):1403-1422. https://doi.org/10.2217/nnm.13.115
Klyachko, Natalia L. ; Haney, Matthew J. ; Zhao, Yuling ; Manickam, Devika S. ; Mahajan, Vivek ; Suresh, Poornima ; Hingtgen, Shawn D. ; Mosley, R Lee ; Gendelman, Howard Eliot ; Kabanov, Alexander V. ; Batrakova, Elena V. / Macrophages offer a paradigm switch for CNS delivery of therapeutic proteins. In: Nanomedicine. 2014 ; Vol. 9, No. 9. pp. 1403-1422.
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