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<p> Here, we describe a simple, efficient formulation of a novel library of β-cyclodextrin-poly (β-amino ester) networks (CDN) to achieve this goal. We observed that network architecture was a critical determinant of CDN encapsulation of candidate molecules, with a more hydrophobic core enabling effective self-assembly and a PEGylated surface enabling high loading (up to ~30% w/w), effective self assembly of the nanoparticle, and slow release of drug into aqueous media (24 days) for the model <i>HDACi</i> panobinostat. Optimized CDN nanoparticles were taken up by GL261 cells in culture, and released panobinostat was confirmed to be bioactive. Pharmacokinetic analyses demonstrated that panobinostat was delivered to the brainstem, cerebellum, and upper spinal cord following intrathecal administration via cisterna magna injection in healthy mice. We next constructed a library of CDNs to encapsulate various small, hydrophobic, ionizable molecules (panobinostat, quisinostat, dacinostat, givinostat, and bortezomib, camptothecin, nile red, and cytarabine), which yielded important insights into the structural requirements for effective drug loading and CDN self-assembly. Taken in sum, these studies present a novel nanocarrier platform for encapsulation of <i>HDACi</i> via both ionic and hydrophobic interactions, which is an important step toward better treatment of disease via <i>HDACi</i> therapy.</p>

Nanoparticle systems are often used to facilitate drug delivery to the central nervous system (CNS). There are many clinical situations in which CNS tissue might be removed prior to administration of a therapeutic nanoparticle; however, the iatrogenic effects of surgical resection on nanoparticle deposition in the brain remain unknown. We hypothesized that resection would facilitate nanoparticle delivery to peri-resection tissue as a function of timing of nanoparticle administration after removal of tissue. To test this hypothesis polystyrene nanoparticles surface modified with poly(ethylene glycol) (PEG) were administered either immediately, 2 hours, 24 hours, 4 days, or 7 days after resection of murine cortex. Fluorescence microscopy revealed that minimal nanoparticle delivery to brain vasculature was observed in healthy mice, yet significant nanoparticle delivery was observed in mice that received resection. Spatially, nanoparticles were confined to the vascular compartment and did not enter the parenchyma. Nanoparticle delivery was high near the resection boundary and declined with distance into the peri-resection tissue. The highest level of delivery was observed when nanoparticles were administered immediately after resection, and FNPs could be detected in the CNS when nanoparticles were administered up to 24 hours after resection. The diameter of blood vessels that contained nanoparticles was significantly greater than the diameter of blood vessels that did not contain nanoparticles, and larger vessels contained brighter clusters of nanoparticles. These relationships depended on time after resection, suggesting that a dynamic vascular response. These studies highlight important considerations that can be used to develop nanotechnology for neurosurgical applications.

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