No abstract

Therapeutic development of histone deacetylase inhibitors (HDACi) has been hampered by a number of barriers to drug delivery, including poor solubility and inadequate tissue penetration. Nanoparticle encapsulation could be one approach to improve the delivery of HDACi to target tissues; however, effective and generalizable loading of HDACi within nanoparticle systems remains a long-term challenge. We hypothesized that the common terminally ionizable moiety on many HDACi molecules could be capitalized upon for loading in polymeric nanoparticles. Here, we describe the 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 (up to 24 days) for the model HDACi panobinostat. We next constructed a library of CDNs to encapsulate various small, hydrophobic, terminally ionizable molecules (panobinostat, quisinostat, dacinostat, givinostat, bortezomib, camptothecin, nile red, and cytarabine), which yielded important insights into the structural requirements for effective drug loading and CDN self-assembly. Optimized CDN nanoparticles were taken up by GL261 cells in culture and a released panobinostat was confirmed to be bioactive. Panobinostat-loaded CDNs were next administered by convection-enhanced delivery (CED) to mice bearing intracranial GL261 tumors. These studies confirm that CDN encapsulation enables a higher deliverable dose of drug to effectively slow tumor growth. Matrix-assisted laser desorption/ionization (MALDI) analysis on tissue sections confirms higher exposure of tumor to drug, which likely accounts for the therapeutic effects. Taken in sum, these studies present a novel nanocarrier platform for encapsulation of HDACi via both ionic and hydrophobic interactions, which is an important step toward better treatment of disease via HDACi therapy.

Ketamine is being prescribed with greater frequency due to an emphasis on multimodal analgesia. With increasing use, uncommon adverse effects associated with ketamine are likely to surface. Limited reports of transient central diabetes insipidus (DI) occurring early after initiation (ie, within 10 hours) of ketamine have been reported. We present 2 cases of delayed onset (32 hours or more after initiation), ketamine-induced, transient central DI in patients cannulated for venovenous extracorporeal membranous oxygenation. No other causes of central DI were determined based upon physical examination or laboratory data, and both patients responded to treatment with desmopressin/vasopressin. The Naranjo adverse drug reaction probability scale noted a probable causation for each case. These cases demonstrate the possibility of a rare but serious complication of ketamine. Improvement after discontinuation of ketamine and administration of desmopressin/vasopressin appear to support a drug–effect association.

<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.