Novel nanoparticles demonstrate no adverse effects on blood-brain barrier baseline parameters in in vitro or in vivo preparations

IEC 21

David D. Allen1, Joanna Koziara2, Russell J. Mumper2, Thomas J. Abbruscato1, and Paul R. Lockman1. (1) Department of Pharmaceutical Sciences, Texas Tech University HSC School of Pharmacy, 1300 S. Coulter Dr, Amarillo, TX 79106, (2) Division of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, KY 40536
Nanoparticles (NPs) used as brain drug delivery agents may provide advantages over current drug delivery strategies. NPs mask the blood-brain barrier (BBB) limiting physicochemical characteristics of the drug molecule. There are conflicting data with regard to toxicity of NPs at the BBB. To assess effects of these novel NPs, barrier parameters were evaluated with 2 NPs (E78 and E72) in vivo (using the in situ brain perfusion method) and in vitro (bovine microendothelial endothelial transwell permeation). Estimated in situ control cerebrovascular flow values were 3.6 x 10-2 ml/s/g. NP addition caused no significant flow differences (E78: 3.6 x 10-2 ml/s/g; E72: 4.1 x 10-2 ml/s/g) compared to control. Baseline vascular volume was 7.0 x 10-3 ml/g. No changes in vascular volume occurred with in the presence of either NP (E78: 8.4 x 10-3 ml/g; E72 8.7 x 10-3 ml/g). To evaluate function, [14C]-thiourea and [3H]-choline brain uptake were evaluated. No significant thiourea permeability changes compared to control (2.3 x 10-4 ml/s/g) in the presence of either NP (E78: 2.4 x 10-4 ml/s/g; E2: 2.1 x 10-4 ml/s/g) were noted. Choline transport remained unchanged from control (1.24 x 10-3 ml/s/g) in comparison to the presence of the NPs (E78: 1.34 x 10-3 ml/s/g; E72: 1.49 x 10-3 ml/s/g). In vitro studies evaluated the effect of NPs on permeation of sucrose, thiourea or choline. Similar to in vivo data, no significant changes were observed in this preparation. E78 NPs made with emulsifying wax have no effect on vascular flow, barrier integrity or function. This study affords data that the described colloidal drug carriers lack adverse effects at the BBB.