Nanowired-Drug Delivery Enhances Neuroprotective Efficacy of Compounds and Reduces Spinal Cord Edema Formation and Impro
The possibility that drugs attached to nanowires enhance their therapeutic efficacy was examined in a rat model of spinal cord injury (SCI). Three Acure compounds AP-173, AP-713 and AP-364 were tagged with TiO2-based nanowires (50–60 nm) and applied over
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Abstract The possibility that drugs attached to nanowires enhance their therapeutic efficacy was examined in a rat model of spinal cord injury (SCI). Three Acure compounds AP-173, AP-713 and AP-364 were tagged with TiO2-based nanowires (50–60 nm) and applied over the traumatized cord either 5 or 60 min after SCI in rats produced by a longitudinal incision into the right dorsal horn of the T10-11 segments under equithesin anaesthesia. Normal compounds were used for comparison. After 5 h SCI, behavioral outcome, blood–spinal cord barrier (BSCB) permeability, edema formation and cell injury were examined. Topical application of nanowired compound AP-713 (10 µg in 20 µL) when applied either 5 or 60 min after injury markedly attenuated behavioral dysfunction at 2–3 h after SCI and reduces BSCB disruption, edema formation and cord pathology at 5 h compared to other compounds. Whereas normal compounds applied at 5 min after injury (but not
H.S. Sharma (*) and A. Sharma Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anaesthesiology and Intensive Care Medicine, University Hospital, Frödingsgaton 12:28, Uppsala, SE-75421, Sweden and Neurochemistry Laborartory, Division of Neurotoxicology, National Centre for Toxicological Research/FDA, Jefferson, AR, USA e-mail: [email protected] S. F. Ali Neurochemistry Laboratory, Division of Neurotoxicology, National Centre for Toxicological Research/FDA, Jefferson, AR, USA Z. R. Tian Department of Chemistry and Biochemistry, University of Arkansas Fayetteville, AR 72701, USA R. Patnaik and S. Patnaik Department of Biomedical Engineering, Institute of Technology, Banaras Hindu University, Varanasi-221 005, India A. Boman, P. Lek and E. Seifert AcurePharma AB, Ulleråkersv 38, Uppsala, Sweden T. Lundstedt Acure Pharma AB, Ulleråkersv 38, Uppsala, Sweden and Institutionen för läkemedelskemi, Avdelningen för Organisk farmaceutisk kemi, Uppsala University, Uppsala, Sweden
after 60 min) had some significant but less beneficial effects compared to their nanowired combinations. On the other hand, nanowires alone did not influence spinal cord pathology or motor function after SCI. Taken together, our results indicate that the nanowired-drug-delivery enhances the neuroprotective efficacy of drugs in SCI and reduces functional outcome compared to normal compounds even applied at a later stage following trauma, not reported earlier. Keywords Nanoparticles • nanowire • titanium dioxide • spinal cord injury • AP-713 • Blood–spinal cord barrier • spinal cord edema • Tarlov scale • motor function
Introduction Recent advancement in nanotechnology has resulted in the development of nanowires that can be used to enhance drug delivery by coating them with suitable neuroprotective agents for enhanced drug delivery (2,6,8,9,20). About a decade ago, Kreuter (7) was the first to show the rapid analgesic effects of the peptide “dalargin” after its administration with polysorbate 80-coated polybutylcyanoacrylate (PBCA) nanoparticles into CNS. This suggests that drug-delivery to the
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