Polyelectrolyte Complex Optimization for Macrophage Delivery of Redox Enzyme Nanoparticles

Abstract

Background: We posit that cell-mediated drug delivery can improve transport of therapeutic enzymes to the brain and decrease inflammation and neurodegeneration seen during Parkinson‘s disease. Our prior works demonstrated that macrophages loaded with nanoformulated catalase (‘nanozyme‘) then parenterally injected protect the nigrostriatum in a murine model of Parkinson‘s disease. Packaging of catalase into block ionomer complex with a synthetic polyelectrolyte block copolymer precludes enzyme degradation in macrophages. Methods: We examined relationships between the composition and structure of block ionomer complexes with a range of block copolymers, their physicochemical characteristics, and loading, release and catalase enzymatic activity in bone marrow-derived macrophages. Results: Formation of block ionomer complexes resulted in improved aggregation stability. Block ionomer complexes with ε-polylysine and poly(L-glutamic acid)–poly(ethylene glycol) demonstrated the least cytotoxicity and high loading and release rates. However, these formulations did not efficiently protect catalase inside macrophages. Conclusion: Nanozymes with polyethyleneimine- and poly(L-lysine)₁₀–poly(ethylene glycol) provided the best protection of enzymatic activity for cell-mediated drug delivery.

Keywords::

• blood–brain barrier
• catalase
• cell-mediated drug delivery
• nanozyme
• neuroinflammation
• Parkinson‘s disease

Financial & competing interests disclosure

This study was supported by the NIH grants 1RO1 NS057748 (to Elena V Batrakova), 2R01 NS034239, 2R37 NS36126, P01 NS31492, P20RR 15635, P01 MH64570, 5P01 DA028555 and P01 NS43985 (to Howard E Gendelman), RR021937 (to Alexander V Kabanov), and Russian Ministry of Science and Education grant 02.740.11.5232 (to Natalia L Klyachko and Alexander V Kabanov) and 11.G4.31.0004 (to Natalia L Klyachko and Alexander V Kabanov). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was utilized in the production of this manuscript. We are grateful to Tatyana Kasperovich for the text editing.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Acknowledgements

The authors are grateful to Janice A Taylor and James R Talaska (Confocal Laser Scanning Microscope Core Facility, UNMC) for providing assistance with confocal microscopy and the Nebraska Research Initiative and the Eppley Cancer Center for their support of the Core Facility, and Lyudmila Shlyakhtenko for assistance with AFM studies.

Additional information

Funding

This study was supported by the NIH grants 1RO1 NS057748 (to Elena V Batrakova), 2R01 NS034239, 2R37 NS36126, P01 NS31492, P20RR 15635, P01 MH64570, 5P01 DA028555 and P01 NS43985 (to Howard E Gendelman), RR021937 (to Alexander V Kabanov), and Russian Ministry of Science and Education grant 02.740.11.5232 (to Natalia L Klyachko and Alexander V Kabanov) and 11.G4.31.0004 (to Natalia L Klyachko and Alexander V Kabanov). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.