The blood-brain barrier (BBB) protects the brain from foreign or harmful material, but also blocks access of many potentially therapeutic molecules that could be used to treat conditions of the central nervous system, such as gliomas, infections, and neurotoxin exposure. However, it is known that the vasculature cells comprising the BBB actively transport molecules such as apolipoprotein A1, a component of high-density lipoprotein particles (HDLs), into the brain. With the intention of exploiting these existing transport mechanisms to shuttle therapeutics into the brain, we have developed a synthetic nanoparticle that mimics apo A1 HDLs (referred to as nanolipoprotein particles, or NLPs) that are comprised of lipids and a scaffold protein derived from apo A1. Using small molecules (fluorophore-labeled lipids) as surrogate therapeutic cargo, we have demonstrated that these particles have circulation times <i>in vivo</i> on the order of several hours, and that these labels can be seen to be distributed throughout the brain following injection. Importantly, <sup>14</sup>C-labeled lipids may be incorporated into these particles, and quantification of the dose delivered to the brain and cerebrospinal fluid was carried out using accelerator mass spectrometry. This combined data indicate that NLPs prepared with apo A1 derivatives are a promising therapeutic vehicle for CNS delivery.

Nanolipoprotein particles for delivery of therapeutics to the brain

253rd National Meeting (2017)

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