Vantage in the structural versatility of this kind of polymer.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript6. Particle-based carriers for CNS delivery of proteinsNumerous studies have shown that encapsulation of therapeutic PDE2 list proteins in nano- or micron size particles decreases protein immunogenicity and improves protein stability and circulation time (Figure 4). Liposomes and PLGA nanoparticles are possibly one of the most extensively investigated forms of carriers for protein delivery. Other systems investigated within the context of CNS delivery consist of poly(butylcyanoacrylate) (PBCA) nanoparticles, and more recently, polyion complexes. Some other materials like PEG-silica, bolaamphiphilies, chitosan, PEG-polylactide (PLA), PEG-poly(-caprolactone) (PCL) and PLA-D–Tocopheryl polyethylene glycol succinate (TPGS) have been also evaluated for brain delivery [283, 37177]. Unfortunately, such particle-based carriers generally don’t cross BBB. Surface modification with precise brain targeting moieties may perhaps offer opportunities to P2Y6 Receptor custom synthesis enhance brain the delivery of particles however the effectiveness remains questionable [378380]. Nevertheless interest in particle-based systems for delivery of therapeutic agents to CNS persists due to ongoing efforts in application of those systems with drugs possessing a peripheral mode of action. Notably, majority of such studies using particle-based carriers involve delivery of low molecular mass therapeutics towards the CNS [381, 382], with onlyJ Control Release. Author manuscript; available in PMC 2015 September 28.Yi et al.Pagerelatively few examples reporting CNS delivery of proteins [383]. Due to the fact most carrierbased technologies were originally created for delivery of low molecular mass drugs, in some situations there’s an added challenge in modifying the carrier technologies to facilitate protein formulation, make sure higher protein loading and stability. Beneath we take into consideration some of these carries and their applications for protein delivery towards the brain. 6.1 Liposomal carriers Liposomes have been extensively investigated as carriers for delivery of small drugs, proteins, DNA, siRNA and imaging agents [38487]. Couple of of these research involved delivery of proteins towards the brain. By way of example, more than 30-years ago it was reported that encapsulation of proteins (-galactosidase, thyrotrophin-releasing hormone (TRH)) in neutral (phosphatidylcholine (Computer), cholesterol (Chol)) or anionic (Computer, Chol, dicetylphosphate or phosphatidylserine (PS)) liposomes can improve brain accumulation of these proteins soon after i.v. administration [388, 389]. Interestingly, TRH loaded in neutral liposomes showed higher brain uptake and physiological impact (rise in body temperature) than TRH in anionic liposomes. Incorporation of TRH in cationic liposomes (Computer, Chol and stearylamine) also improved the protein brain uptake. On the other hand, stearylamine brought on epileptic seizures and cerebral tissue necrosis this and for that reason, as a consequence of toxicity this formulation was not pursued [389]. Nevertheless, cationic liposomes have been additional employed to deliver SOD1. Numerous studies demonstrated that SOD1 formulated in cationic liposomes administered i.v. can decrease cerebral infarct volume size in ischemic stroke and brain trauma animal models [39093]. Though reasons for the enhanced brain delivery from the liposomeincorporated proteins remained unknown, it was speculated that liposome could crosslipophilic membranes of brain endothelial cells [389]. To the greatest of our kno.