Dendrimer nanomedicine - developing efficient therapeutic strategies for the treatment of neurological disorders

(Nanowerk Spotlight) A dendrimer is a polymeric nanostructure built around a core unit. There are several branching units around the core units in a layer-by-layer fashion which defines the growth, size, and the microenvironment within the dendrimer.
Dendrimers are composed of a large number of smaller units known as dendrons. Dendrons are formed after removal of core units and can be divided into (empty) core, the interior (branching units), and the periphery (end groups). The empty space lying inside the dendrons can be used for the entrapment of drug molecules for solubilization, controlled release, targeting, or protection from surrounding degrading environment.
Research efforts in the area of nanotechnology in healthcare have benefitted from these nanostructures and they have emerged as a powerful class of nanomaterials in nanomedicine due to their unique structural features: globular, well-defined, highly branched and controllable nanostructures where the presence of several terminal groups can be functionalized with different ligands simulating the multivalency present in different biological systems.
Selected administration routes for dendrimers and other nanoparticles
Selected administration routes for dendrimers and other nanoparticles. The main advantages associated with each procedure are depicted in the green box and the main disadvantages in the red box. (© Wiley-VCH Verlag) (click on image to enlarge)
A recent review article in Advanced Functional Materials ("Dendrimers as Powerful Building Blocks in Central Nervous System Disease: Headed for Successful Nanomedicine") by scientists in Portugal identifies the currently existing dendritic systems and discusses their strengths and caveats in the context of attaining efficient therapeutic strategies for the treatment of neurological disorders.
Besides the diagnosis and/or in vitro dendrimer-based products already in the market, dendritic systems have already reached the clinical evaluation as contrast-enhancer magnetic resonance imaging agents (Gadomer®-17), anti-microbicides (Vivagel®), and drug carriers for solid tumors therapy (DEP™ docetaxel).
Notwithstanding, despite all these documented applications, the use of dendrimers within the central nervous system (CNS) is still in its infancy and there are no reports of marketed products or current clinical trials using dendrimers for CNS diseases therapy.
One of the most significant challenges in CNS disease therapy is the ability of therapeutic bioactives to permeate the blood-brain barrier (BBB) and reach CNS in an adequate bioavailability.
Due to their controllable nanosize, several reports have recognized the ability of dendrimers to permeate this barrier and gain access to the CNS after systemic administration.
Moreover, dendrimers have not only shown potential to act by themselves as therapeutic or theranostic agents but also as vectors for the protection and delivery of bioactives to the CNS. However, the proper in vivo dendrimer biodistribution and safety profile is yet to be determined in depth, which may hinder their passage for clinical evaluation.
Dendritic nanoparticle
a) Dendrimer multifunctionalization and “dendritic box”. b) Dendritic nanoparticle (cargo = drug, nucleic acid, protein, peptide, among others). (© Wiley-VCH Verlag) (click on image to enlarge)

Dendrimers as CNS Delivery, Imaging and Diagnosis Systems

Due to the easy tuning regarding composition, structure, and size, dendrimers are versatile systems to serve as vectors for numerous biomedical applications, including brain delivery and diagnosis. They are being explored as promising carriers of chemical drugs, therapeutic nucleic acids, proteins and peptides, as well as macromolecular contrast agents and biosensor platforms for CNS therapies, imaging, and diagnosis.

Tailoring Dendrimer-Based Delivery Systems for CNS Applications: (Bio)functionalization, Targeting and Labeling

In this section, the authors briefly discuss the strategies of preparation of the bioactive-dendrimer systems, according to the type of bioactive that is being linked/transported.
The tunable chemistry of dendrimers permits a precise 'chemical makeup' that allows the design, in principle, of an almost unlimited number of molecules. This, together with the possibility of an accurate chemical multi-decoration with several (bioactive) ligands and/or target molecules, permits dendrimers to act as 'smart' nanosystems for the efficient and site-specific delivery of several agents to the CNS.

Applications of Dendrimers in the CNS

The incidence of CNS diseases, especially those related to aging, has sharply increased in recent years due to the increment in life expectancy. This has put great pressure in the development of CNS therapeutics and its effective delivery.
To support the use of dendrimers as promising delivery vectors to the CNS it is important that their mechanism of action is understood. To investigate the uptake of dendrimers specifically by the key cellular unit of the nervous system – the neuron – the process and kinetics of internalization of these macromolecules has been studied.
The authors go on to review and discuss in detail the dendrimer-based therapeutic and theranostics explored so far in the context of CNS:
  • – vascular diseases neurodegenerative diseases (like Alzheimer's and Parkinson's)
  • – neuroimmunomodulation
  • – neuroinfection
  • – CNS tumors
  • – spinal cord injury
  • – macromolecular contrast agents and nanosensors.
  • All in all, successfully bringing forward dendrimers as powerful tools in the treatment of CNS diseases will definitely require a multi- and interdisciplinary effort due to the uniqueness and paramount importance of this system," the authors conclude. "Dendrimers can be used in the CNS with various purposes, not only to deliver active therapeutic molecules but also to assess brain function and to diagnose CNS diseases or even to perform a combination of these purposes. Such a remarkable ability highlights their tremendous potential as a precise theranostic multifunctional agent, which we predict in the future to be extended to other unexplored CNS disorders."
    Michael Berger By – Michael is author of three books by the Royal Society of Chemistry:
    Nano-Society: Pushing the Boundaries of Technology,
    Nanotechnology: The Future is Tiny, and
    Nanoengineering: The Skills and Tools Making Technology Invisible
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