Nanoparticles as carriers for drug delivery of macromolecules across the blood-brain barrier.

Introduction: Current therapies of neurodegenerative or neurometabolic diseases are, to a large extent, hampered by the inability of drugs to cross the blood-brain barrier (BBB). This very tight barrier severely restricts the entrance of molecules from the blood into the brain, especially macromolecular substances (i.e. neurotrophic factors, enzymes, proteins, as well as genetic materials). Due to their size, physicochemical properties, and instability, the delivery of these materials is particularly difficult.Areas covered: Recent research showed that biocompatible and biodegradable nanoparticles possessing tailored surface properties can enable a delivery of drugs and specifically of macromolecules across the blood-brain barrier by using carrier systems of the brain capillary endothelium (Trojan Horse strategy). In the present review, the state-of-art of nanoparticle-mediated drug delivery of different macromolecular substances into the brain following intravenous injection is summarized, and different nanomedicines that are used to enable the transport of neurotrophic factors and enzymes across the blood-brain barrier into the CNS are critically analyzed.Expert opinion: Brain delivery of macromolecules by an intravenous application using nanomedicines is now a growing area of interest which could be really translated into clinical application if dedicated effort will be given to industrial scale-up production.

Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver.

A novel class of PEGylated polyacridine peptides was developed that mediate potent stimulated gene transfer in the liver of mice. Polyacridine peptides, (Acr-X)(n)-Cys-polyethylene glycol (PEG), possessing 2-6 repeats of Lys-acridine (Acr) spaced by either Lys, Arg, Leu or Glu, were Cys derivatized with PEG (PEG(5000 kDa)) and evaluated as in vivo gene transfer agents. An optimal peptide of (Acr-Lys)(6)-Cys-PEG was able to bind to plasmid DNA (pGL3) with high affinity by polyintercalation, stabilize DNA from metabolism by DNAse and extend the pharmacokinetic half-life of DNA in the circulation for up to 2 h. A tail vein dose of PEGylated polyacridine peptide pGL3 polyplexes (1 µg in 50 µl), followed by a stimulatory hydrodynamic dose of normal saline at times ranging from 5 to 60 min post-DNA administration, led to a high level of luciferase expression in the liver, equivalent to levels mediated by direct hydrodynamic dosing of 1 µg of pGL3. The results establish the unique properties of PEGylated polyacridine peptides as a new and promising class of gene delivery peptides that facilitate reversible binding to plasmid DNA, protecting it from DNase in vivo resulting in an extended circulatory half-life, and release of transfection-competent DNA into the liver to mediate a high-level of gene expression upon hydrodynamic boost.