Nanoparticles blood-brain barrier

Alyautdin RN, Petrov VE, Langer K, Berthold A, Kharkevich DA, Kreuter J (1997) Delivery of loperamide across the blood-brain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles. Pharm Res 14 325-328. 

One possibility to enhance, in a controlled manner, entry of drugs into the CNS would be to alter P-glycoprotein function at the blood-brain barrier. Such an enhancement could result from (1) direct modification of export pump function by inhibitors and intracellular signals or (2) bypassing the export pump by delivery systems not being recognized as substrates (e.g., nanoparticles or vector-coupled liposomes, which are taken up by endocytotic mechanisms) [58-65],... 

Kreuter J, Shamenkov D, Petrov V, Ramge P, Cychutek K, Koch-Brandt C, Alyautdin R (2002) Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J Drug Target 10 317-325... 

Lockman, P.R., et al. 2002. Nanoparticle technology for drug delivery across the blood-brain barrier. Drug Dev Ind Pharm 28 1. 

Yang, C., et al. 2004. Nanoparticle-based in vivo investigation on blood-brain barrier permeability following ischemia and reperfusion. Anal Chem 76 4465. 

As of today, there are no commercially available pharmaceutical products of this technology. The pharmaceutical industry however, is involved in developing nanoparticle-based delivery systems. Use of nanospheres to modify the blood-brain barrier (BBB)—limiting characteristics of the drug enables targeted brain delivery via BBB transporters and provides a sustained release in brain tissue and vaccine delivery systems to deliver therapeutic protein antigens into the potent immune cells are under investigation.103... 

New functions can be obtained by modifications of SLNs. Incorporation of Tween 80 and Poloxamer 188 can stabilize SLNs to achieve long-circulating or crossing blood-brain barrier effects [112], Recently, novel nanoparticles called polymer-lipid hybrid nanoparticles (PLNs) were developed [113]. They can entrap cationic anticancer agents (e.g., doxorubicin) effectively by incorporation of an anionic lipophilic polymer into lipids to treat multidrug-resistant (MDR) cancers. 

Costantino, L., et al. (2005), Peptide-derivatized biodegradable nanoparticles able to cross the blood-brain barrier, J. Controlled Release, 108(1), 84-96. 

Alyaudtin RN, Reichel A, Lobenberg R, Ramge P, Kreuter J, Begley DJ (2001) Interaction of poly(butylcyanoacrylate) nanoparticles with the blood-brain barrier in vivo and in vitro. J Dmg Target 9 209-221. 

Roney C, KuUcami P, Arora V, Antich P, Bonte F, Wu A, Mallikar-juana NN, Manohar S, Liang HF, KuUcami AR, Sung HW, Sairam M, Aminabhavi TM (2005) Targeted nanoparticles for dmg delivery through the blood-brain barrier for Alzheimer s disease. J Control Release 108 193-214. 

Yang C, Chang C, Tsai P, Chen W, T seng F, Lo L (2004) Nanoparticle-Based in Vivo Investigation on Blood-Brain Barrier Permeability Following Ischemia and Reperfusion. Anal Chem 76 4465 4471. 

A novel nanoparticulate lipid-based carrier system was developed by Mumper et al. at the University of Kentucky. ° This carrier system is composed of a lipophilic-emulsifying wax such as cetyl alcohol/ polysorbate 60 and other surfactants such as Brij 72, Brij 78, and Tween 80. The nanoparticles were formed through a warm microemulsion technique where encapsulates have included paclitaxel and plasmid DNA. The emulsification process is spontaneous, and cooling of the emulsion causes solidification of the nanoparticle-containing drug. This novel carrier has shown high efficiency in drug delivery across the blood-brain barrier. 

Evidence indicates exposure to nanoparticles can induce an inflammatory response in the CNS. For example, when a sample of mice were exposed to airborne particle matter, increased levels of pro-inflammatory cytokines (TNF-a IL-la), transcription factor, and nuclear factor-kappa beta (NF-k/3) were observed (114). TNF-a serves a neuroprotective function (115), but given certain pathogens TNF-a can be neurotoxic (116-120). IL-a activates cyclooxygenase (COX)-2, phospholipase A2, and inducible nitric oxide synthase (iNOS) activity, which are all associated with inflammation and immune response (121). IL-a is also partially responsible for increasing the permeability of the blood-brain barrier (122, 123). Thus, there is great interest in better understanding how nanoparticles enter the body and translocate as this will impact all organs and thus the toxicity of nanomaterials. 

BBS, blood-brain barrier LDL, low-density lipoprotein PLN, polymer-lipid hybrid nanoparticles SLN, solid lipid nanoparticles. 

Weiss CK, Kohnle M-V, Landfester K, et al. (2008) The first step into the brain uptake of NIO-PBCA nanoparticles by endothelial cells in vitro and in vivo, and direct evidence for their blood-brain barrier permeation. Chem Med Chem 3 1395-1403... 

Moreover, PBCA nanoparticles were also applied to in vivo studies on their ability to permeate the blood-brain barrier (BBB). The results (Fig. 5) showed that, depending on the particle dose applied to rats, the particles are located in the brain blood vessels (45 mg) or can cross the BBB (200 mg). The results were confirmed through investigations of the blood-retina barrier (comparable to BBB) [45]. 

FIGURE 22.1 Breaches in the blood-brain barrier (BBB). In various CNS diseases, the BBB becomes leaky to macromolecules, and in CNS injuries, destruction of the endothelial lining creates permeability. By taking advantage of these characteristics, extravasation by nanoparticles, that is, liposomes, dendrimers, polymer-based diagnostics systems, can reach deep within the CNS. Figure adapted from Ref. [34]. 

R. Rempe, et al.. Transport of Poly (n-butylcyano-acrylate) nanoparticles aCTOSS the blood-brain barrier in vitro and their influence on barrier integrity, Biochem. Biophys. Res. Commun. 406 (1) (2011) 64-69. 

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