Abstract 1314: Evaluating payload delivery to the CNS from surface-modified nanoparticles

The blood-brain barrier (BBB) remains a major obstacle to treatment of intracranial tumors. Most drugs are poorly bioavailable in the brain, and peripheral toxicity can severely limit administerable dose. Drug loaded nanoparticles are capable of accumulating preferentially in the core of angiogenic tumors by a mechanisms known as the enhanced permeation and retention (EPR) effect, which can improve therapeutic efficacy of encapsulated molecules compared to free form. However, to achieve complete tumor kill, chemotherapy must target both the leaky tumor core and cells that reside behind an intact blood-brain barrier. The goal of this work was to evaluate payload delivery to the CNS from nanoparticles modified with one of four targeting ligands: TAT, antennapedia (AP), angiopep2 (Ang2) or Tet-1. Poly(lactic acid)-co- poly(ethylene glycol) nanoparticles (NPs) encapsulating Nile Red, a small fluorescent dye, were produced by solvent-evaporation technique. Peptides were covalently attached to the nanoparticle surface by a maliemide-thiol reaction. The effect of targeting ligands on NP payload delivery to healthy brain and spinal cord compared to unmodified NPs was evaluated in mice at 2 and 6 hours post injection. Mice were perfused with saline, and the brains and spinal cord were removed, homogenized and payload delivery quantified by fluorescence. All targeting ligands evaluated significantly increased payload delivery to the brain at both 2 and 6 hours, with the cell-penetrating peptides, TAT and AP, producing the greatest effect of a 4-fold increase over control. Additionally, the cell-penetrating peptides significantly increased payload delivery to the spinal cord at 2 hours but had no significant effect on delivery at 6 hours. Interestingly, the receptor-mediated peptides, Ang2 and Tet-1, did not significantly change spinal cord delivery at 2 hours but significantly increased payload concentration at 6 hours. These data suggest both receptor and nonspecific targeting ligands affect payload delivery and kinetics in a regionally specific manner. Future work is focused on evaluating additional ligands to better understand how the type of cell-nanoparticle interactions affects payload distribution. Citation Format: Kyle T. Householder, Danielle DiPerna, Layla Ghaffari, Rachael Sirianni. Evaluating payload delivery to the CNS from surface-modified nanoparticles. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1314.