This is the 1 million dollar-question everyone would like to know the answer!

All the properties you mentioned are important, for the fact the you have to guarantee a certain stability and allowed the particles to reach the blood brain barrier. That's already quite tricky, if you ask me. Once you are in the proximity of the BBB -and especially if we are talking about a compromise BBB- then I would prioritise protein interaction, size and hydrophilicity, in this order. However, if your particles are already VERY small and VERY hydrophilic, then you may be lucky and not require any ligand moiety on the surface.

What to target? Difficult question, the consensus goes to insulin and transferrin receptors. In practice, the story is much more complicated.

This is very interesting question and there is no direct answer ( I think) but I would try PEGylation which could help due to it make the particle more stabilized. Another suggestion if you could formulate the particle with hydrophobic third component ( acyl groups) ... But the question is how it will affect the function of your particle.. could they have ( anti-vasccular activity then) or not? 

That´s a big question and to date there´s no a clear answer for that. All the chemical and physical properties are important. I have worked with polycations and some of those polymer (PEI, PDMAEMA) have been suggested to "open" the BBB by action of the cationic groups. So you can try to do a cationic surface on your NP for instance.

There´s a recent publication exploring a good method to pass the BBB and it seems that the authors overcame the challenge. See it here: http://onlinelibrary.wiley.com/doi/10.1002/anie.201411408/abstract

Regards!

We made nanoparticles from polysaccharides, so no PEGylation is needed. They are highly hydrophilic - contain about 95% water - so rather cloud like structures. May they are too hydrophylic to pass BBB?

Hi Tomasz,

Jörg Kreuter worked a lot in this field and observed that polysorbate 20 or 80 (also called Tween20 / 80) coated particles with a drug can pass the bbb. He suggested that apolipoprotein E (apo E) absorbs on the surface of these particles. These functionalized particles mimic low density lipoprotein particles and could interact with the LDL receptor leading to their uptake by the endothelial cells. After this the drug may be released in these cells and diffuse into the brain interior or the particles may be transcytosed. Later, he showed that he observed the same effect with particles covalently linked to apo E.

Kreuter, J.; Alyautdin, R. N.; Kharkevich, D. A.; Ivanov, A. A., Passage of Peptides through the Blood-Brain Barrier with Colloidal Polymer Particles (Nanoparticles). Brain Res. 1995, 674 (1), 171-174.

Kreuter, J., Nanoparticulate Systems for Brain Delivery of Drugs. Adv. Drug Delivery Rev. 2001, 47 (1), 65-81.

Kreuter, J., Application of Nanoparticles for the Delivery of Drugs to the Brain. Int Congr Ser 2005, 1277 (0), 85-94.

I've heard that this is also possible with very small particles or with gycoconjugation. I hope this helps at least a little bit…

Best,

Christian

Dear Friends, thank You a lot for Your input, I go back to the lab...

Is there a reliable model of BBB for NP transportation research, so I don't have to kill animals?

Contact Prof. Romeo Cecchelli

Vice President of the University of Artois in charge of the research.

Director of BBB Laboratory.

Best wishes,

Ylva

Hi Tomasz,

To let the NPs cross BBB is a bit tricky. Approaches like surface modification using peptides (eg. transferrin, lectin), Targeting the tight junctions using Poloxamers are followed to cross BBB. 

You can also try the intranasal route in which the particles are hypothesized to reach brain by olfactory pathway. Good luck. 

I believe that components should be selected in accordance with your therapeutic goal, taking in account the extent of hydrophilicity/hydrophobicity of your nanoparticles. However, even without knowing that, I would suggest using purified   free curcumin and/or chitosan oligomers  to promote penetration through BBB. Both these natural substances have multiple health benefits, which, most likely, will have additive or synergistic effect with your actives. And both of them cross the blood brain barrier. If hydrophilicity remains the main problem, I'd consider adding hyaluronan or PLGA which may be prepared both as hydrophilic and hydrophobic.

With regard to animal tests – use in-vivo fluorescent markers and in-vivo fluorescent imaging, if possible. In this case you may monitor the same animal at multiple time points during the whole study duration.  Link to PDF manual: http://bme.columbia.edu/files/seasdepts/biomedical-engineering/pdf-files/Maestro_2_Brochure.pdf 

Try magnetic nanoparticles or radiolabeling the NPs inorder to prevent killing the animals and just take an image

IF YOU WISH TO TARGET BBB IN CNS DISORDER ITS ASTROCYTE SHEATH  BECOME LESS STRINGENT IN THIS CASE I KNOW YOU KNOW IT.BUT MORE LIGAND WE MAY ADD WHICH TARGET BRAIN .

Neuropharmacology. 2014 Oct;85:517-27. doi: 10.1016/j.neuropharm.2014.06.009. Epub 2014 Jun 19.

A novel multi-target ligand (JM-20) protects mitochondrial integrity, inhibits brain excitatory amino acid release and reduces cerebral ischemia injury in vitro and in vivo.

Nuñez-Figueredo Y1, Ramírez-Sánchez J1, Hansel G2, Simões Pires EN2, Merino N1, Valdes O1, Delgado-Hernández R1, Parra AL1, Ochoa-Rodríguez E3, Verdecia-Reyes Y3, Salbego C2, Costa SL4, Souza DO2, Pardo-Andreu GL5

I think you should add some amino acids in order to pass the BBB

I think Christian Schmidtke said it all.  a new review on this topic is the following:

Kreuter, J.; Drug delivery to the central nervous system by polymeric nanoparticles: What do we know? Adv. Drug Deliv. Rev. 71 (2014) 2 - 14.

Try to modify surface of NP by attaching some sugar moieties

Size does not seem to play a major role (Voigt et al., Eur. J. Pharm. Biopharm. 87, 19-29 (2014)).   Don't open the tight junctions = tox problems!  Target one of the BBB receptors!  BBB models are fine, the truth comes with an animal experiment.