Dual and multi-drug delivery nanoparticles towards neuronal survival and synaptic repair

Abstract

Among the macromolecular drug targets in neurodegenerative disorders, the neurotrophin brain-derived neurotrophic factor (BDNF) and its high-affinity tropomyosin-related kinase receptor (TrkB) present strong interest for nanomedicine development aiming at neuronal and synaptic repair. Currently, BDNF is regarded as the neurotrophic factor of highest therapeutic significance. However, BDNF has delivery problems as a protein drug. The enhanced activation of the transcription factor CREB (cAMP response element-binding protein) has been evidenced to increase the BDNF gene expression and hence the production of endogenous BDNF. We assume that BDNF delivery by nanocarriers and mitochondrial protection may provide high potential for therapeutic amelioration of the neuroregenerative strategies. Beneficial therapeutic outcomes may be expected for synergistic dual or multi-drug action aiming at (i) neurotrophic protein regulation in the central and peripheral nervous systems, and (ii) diminishment of the production of reactive oxygen species (ROS) and the oxidative damage in mitochondria. Our research strategy is based on a nanoarchitectonics approach for the design of nanomedicine assemblies by hierarchical self-assembly. We explore nanoarchitectonics concepts in soft-matter nanotechnology towards preparation of biodegradable self-assembled lipid nanostructures for safe neuro-therapeutic applications of multi-target nanomedicines.

Keywords: BDNF delivery; CREB; combination therapy; macromolecular drugs; nanomedicine; neuroprotective lipid nanocarriers; neurotrophic factor.

Figure 1

Perspective for combination therapy of neurodegenerative disorders requiring dual or multi-drug delivery in order to target a combination of signaling pathways in the disease mechanisms. BDNF: Brain-derived neurotrophic factor; ROS: reactive oxygen species; TrkB: tropomyosin-related kinase receptor.

Figure 2

Synthetic self-assembled nanoparticle systems for combination nanodrug delivery in neuroregenerative therapies. (A) Cubosome nanoparticle with a dense core of periodically ordered bilayer lipid membranes, which may provide high encapsulation rate for both hydrophilic proteins or peptides and poor water soluble antioxidant substances; (B) vesicle-type nanocarrier, in which a single lipid bilayer membrane surrounds an aqueous core. The drug release properties and the encapsulation capacity of vesicular nanocarriers for hydrophobic and hydrophilic drug molecules differ from those of the cubosome nanocarriers.