Macrophages Offer A Paradigm Switch for CNS Delivery of Therapeutic Proteins

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.

Exploiting macrophages as targeted carrier to guide nanoparticles into glioma

“…The release of drug from macrophages is a complicated process. Based on the results of our study and literature [13, 35, 36], we speculated that the drug could be released from macrophages in two ways. Firstly, NPs was excreted from macrophages by exocytosis, and the free drug diffused from NPs into extracellular medium subsequently.…”

Checkpoints to the Brain: Directing Myeloid Cell Migration to the Central Nervous System

“…In the gene modification arena, optimized methods including lentiviral/adenoviral vectors and, most recently, customizable nucleases such as zinc finger nucleases [211] and CRIPSR-cas9 [212] have recently been developed, although it remains to be seen whether the efficiency, stability, and long-term safety of these systems are sufficient for widespread use [213]. Likewise, microvesicle and nanoparticle-loaded cell delivery is beginning to receive attention as a viable method of CNS therapeutic delivery, with initial trials indicating it is possible to target the CNS with loaded macrophages [214]. Further study will likely be needed to establish the optimal components and safe clearance of these delivery vehicles.…”

Agile delivery of protein therapeutics to CNS

“…Batrakova and colleagues have investigated this paradigm as a potential strategy for the delivery of therapeutic antioxidant enzymes to treat PD in a series of studies [456–462]. To protect enzymes from degradation in the carrier cells they incorporated these enzymes in the BIC.…”