Nanoparticles for drug delivery to the brain
Part of the difficulty in finding cures for these central nervous system (CNS) disorders is that there is yet no truly efficient delivery method for drugs to cross the BBB.
[1] With the aid of nanoparticle delivery systems, however, studies have shown that some drugs can now cross the BBB, and even exhibit lower toxicity and decrease adverse effects throughout the body.
[3] Though there exist many obstacles that make developing a robust delivery system difficult, nanoparticles provide a promising mechanism for drug transport to the CNS.
[1][5] Most polymers used for nanoparticle drug delivery systems are natural, biocompatible, and biodegradable, which helps prevent contamination in the CNS.
Liposomes have the potential to protect the drug from degradation, target sites for action, and reduce toxicity and adverse effects.
This process can ultimately form a uniform dispersion of small droplets in a fluid substance by subdividing particles until the desired consistency is acquired.
These metallic nanoparticles are used due to their large surface area to volume ratio, geometric and chemical tunability, and endogenous antimicrobial properties.
Nanoparticle delivery through the BBB can be increased by introducing peptide conjugates to improve permeability to the central nervous system.
For instance, recent studies have shown an improvement in gold nanoparticle delivery efficiency by conjugating a peptide that binds to the transferrin receptors expressed in brain endothelial cells.
[13] Other nanoparticles are polymer-based, meaning they are made from a natural polymer such as polylactic acid (PLA), poly D,L-glycolide (PLG), polylactide-co-glycolide (PLGA),[15][16][17] and polycyanoacrylate (PCA).
PBCA undergoes degradation through enzymatic cleavage of its ester bond on the alkyl side chain to produce water-soluble byproducts.
PBCA also proves to be the fastest biodegradable material, with studies showing 80% reduction after 24 hours post intravenous therapy injection.
PIHCA, due to this slight advantage, is currently undergoing phase III clinical trials for transporting the drug doxorubicin as a treatment for hepatocellular carcinomas.
Using this relationship, researches have formed albumin nanoparticles that co-encapsulate two anticancer drugs, paclitaxel and fenretinide, modified with low weight molecular protamine (LMWP), a type of cell-penetrating protein, for anti-glioma therapy.
[18] Once injected into the patient's body, the albumin nanoparticles can cross the BBB more easily, bind to the proteins and penetrate glioma cells, and then release the contained drugs.
[18] Specifically, cationic bovine serum albumin-conjugated tanshinone IIA PEGylated nanoparticles injected into a MCAO rat model decreased the volume of infarction and neuronal apoptosis.
[21] Further, the stealth effect, caused in part by the hydrophilic and flexible properties of the PEG chains, facilitates an increase in localizing the drug at target sites in tissues and organs.
The mechanism for the transport of polymer-based nanoparticles across the BBB has been characterized as receptor-mediated endocytosis by the brain capillary endothelial cells.
Once bound to these receptors, transcytosis can commence, and this involves the formation of vesicles from the plasma membrane pinching off the nanoparticle system after internalization.
Due to the ME effect, MENs can provide a direct access to local intrinsic electric fields at the nanoscale to enable a two-way communication with the neural network at the single-neuron level.
[23][24] MENs, proposed by the research group of Professor Sakhrat Khizroev at Florida International University (FIU), have been used for targeted drug delivery and externally controlled release across the BBB to treat HIV and brain tumors, as well as to wirelessly stimulate neurons deep in the brain for treatment of neurodegenerative diseases such as Parkinson's Disease and others.
This physical interaction is believed to cause cavitation and ultimately the disintegration of the tight junction complexes[25] which may explain why this effect lasts for several hours.
For example, one study has shown that using focused ultrasound with oscillating bubbles loaded with a chemotherapeutic drug, carmustine, facilitates the safe treatment of glioblastoma in an animal model.
This drug, like many others, normally requires large dosages to reach the target brain tissue diffusion from the blood, leading to systemic toxicity and the possibilities of multiple harmful side effects manifesting throughout the body.
These low toxicity effects can most likely be attributed to the controlled release and modified biodistribution of the drug due to the traits of the nanoparticle delivery system.
These heavy metals generate reactive oxygen species, which causes oxidative stress and damages the cells' mitochondria and endoplasmic reticulum.
[30] Traces of silver accumulated in the rats' lungs, spleen, kidney, liver, and brain after the nanoparticles were injected subcutaneously.
[30] In addition, silver nanoparticles generate more reactive oxygen species compared to other metals, which leads to an overall larger issue of toxicity.
