John D. Hoekman

Novel Gd Nanoparticles Enhance Vascular Contrast for High-Resolution Magnetic Resonance Imaging

Background Gadolinium (Gd), with its 7 unpaired electrons in 4f orbitals that provide a very large magnetic moment, is proven to be among the best agents for contrast enhanced MRI. Unfortunately, the most potent MR contrast agent based on Gd requires relatively high doses of Gd. The Gd-chelated to diethylene-triamine-penta-acetic acid (DTPA), or other derivatives (at 0.1 mmole/kg recommended dose), distribute broadly into tissues and clear through the kidney. These contrast agents carry the risk of Nephrogenic Systemic Fibrosis (NSF), particularly in kidney impaired subjects. Thus, Gd contrast agents that produce higher resolution images using a much lower Gd dose could address both imaging sensitivity and Gd safety. Methodology/Principal Findings To determine whether a biocompatible lipid nanoparticle with surface bound Gd can improve MRI contrast sensitivity, we constructed Gd-lipid nanoparticles (Gd-LNP) containing lipid bound DTPA and Gd. The Gd-LNP were intravenously administered to rats and MR images collected. We found that Gd in Gd-LNP produced a greater than 33-fold higher longitudinal (T1) relaxivity, r1, constant than the current FDA approved Gd-chelated contrast agents. Intravenous administration of these Gd-LNP at only 3% of the recommended clinical Gd dose produced MRI signal-to-noise ratios of greater than 300 in all vasculatures. Unlike current Gd contrast agents, these Gd-LNP stably retained Gd in normal vasculature, and are eliminated predominately through the biliary, instead of the renal system. Gd-LNP did not appear to accumulate in the liver or kidney, and was eliminated completely within 24 hrs. Conclusions/Significance The novel Gd-nanoparticles provide high quality contrast enhanced vascular MRI at 97% reduced dose of Gd and do not rely on renal clearance. This new agent is likely to be suitable for patients exhibiting varying degrees of renal impairment. The simple and adaptive nanoparticle design could accommodate ligand or receptor coating for drug delivery optimization and in vivo drug-target definition in system biology profiling, increasing the margin of safety in treatment of cancers and other diseases.

Enhanced Analgesic Responses After Preferential Delivery of Morphine and Fentanyl to the Olfactory Epithelium in Rats

BACKGROUND: Centrally acting opioid analgesics such as morphine and fentanyl are effective, but their efficacy is often limited by a delayed response or side effects resulting from systemic first pass before reaching the brain and the central nervous system (CNS). It is generally accepted that drugs applied to the nasal cavity can directly access the brain and the CNS, which could provide therapeutic advantages such as rapid onset and lower systemic exposure. The olfactory region of the nasal cavity has been implicated in facilitating this direct nose-to-CNS transfer. If the fraction of opioid administered to the olfactory region could be improved, there could be a larger fraction of drug directly delivered to the CNS, mediating greater therapeutic benefit. METHODS: We have developed a pressurized olfactory delivery (POD) device to consistently and noninvasively deposit a majority of drug on the olfactory region of the nasal cavity in Sprague-Dawley rats. Using the tail-flick latency test and analysis of plasma and CNS tissue drug exposure, we compared distribution and efficacy of the opioids morphine and fentanyl administered to the nasal olfactory region with the POD device or the nasal respiratory region with nose drops or systemically via intraperitoneal injection. RESULTS: Compared with nose drop administration, POD administration of morphine resulted in a significantly higher overall therapeutic effect (area under the curve [over the time course] [AUC]effect) without a significant increase in plasma drug exposure (AUCplasma). POD of morphine resulted in a nose-to-CNS direct transport percentage of 38% to 55%. POD of fentanyl led to a faster (5 vs 10 minutes) and more intense analgesic effect compared with nasal respiratory administration. Unlike intraperitoneal injection or nose drop administration, both morphine and fentanyl given by the POD device to olfactory nasal epithelium exhibited clockwise (plasma) versus effect hysteresis after nasal POD administration, consistent with a direct nose-to-CNS drug transport mechanism. CONCLUSIONS: Deposition of opioids to the olfactory region within the nasal cavity could have a significant impact on drug distribution and pharmacodynamic effect, and thus should be considered in future nasally administered opioid studies.

Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

Many nasally applied compounds gain access to the brain and the central nervous system (CNS) with varying degree. Direct nose-to-brain access is believed to be achieved through nervous connections which travel from the CNS across the cribriform plate into the olfactory region of the nasal cavity. However, current delivery strategies are not targeted to preferentially deposit drugs to the olfactory at cribriform. Therefore, we have developed a pressurized olfactory delivery (POD) device which consistently and non-invasively deposited a majority of drug to the olfactory region of the nasal cavity in rats. Using both a hydrophobic drug, mannitol (log P = −3.1), and a hydrophobic drug, nelfinavir (log P = 6.0), and POD device, we compared brain and blood levels after nasal deposition primarily on the olfactory region with POD or nose drops which deposited primarily on the respiratory region in rats. POD administration of mannitol in rats provided a 3.6-fold (p < 0.05) increase in cortex-to-blood ratio, compared to respiratory epithelium deposition with nose drop. Administration of nelfinavir provided a 13.6-fold (p < 0.05) advantage in cortex-to-blood ratio with POD administration, compared to nose drops. These results suggest that increasing the fraction of drug deposited on the olfactory region of the nasal cavity will result in increased direct nose-to-brain transport.

Aerosol-stable peptide-coated liposome nanoparticles: a proof-of-concept study with opioid fentanyl in enhancing analgesic effects and reducing plasma drug exposure.

Previously, we reported a novel pressurized olfactory drug (POD) delivery device that deposits aerosolized drug preferentially to upper nasal cavity. This POD device provided sustained central nervous system (CNS) levels of soluble morphine analgesic effects. However, analgesic onset of less soluble fentanyl was more rapid but brief, likely because of hydrophobic fentanyl redistribution readily back to blood. To determine whether fentanyl incorporated into an aerosol-stable liposome that binds to nasal epithelial cells will enhance CNS drug exposure and analgesic effects and reduce plasma exposure, we constructed Arg-Gly-Asp (RGD) liposomes anchored with acylated integrin-binding peptides (palmitoyl-Gly-Arg-Gly-Asp-Ser). The RGD liposomes, which assume gel phase membrane structure at 25 °C, were stable under the stress of aerosolization as only 2.2 ± 0.5% calcein leakage was detected. The RGD-mediated integrin binding of liposome is also verified to be unaffected by aerosolization. Rats treated with fentanyl in RGD liposome and POD device exhibited greater analgesic effect, as compared with the free drug counterpart (AUC(effect) = 1387.1% vs. 760.1% MPE*min), whereas approximately 20% reduced plasma drug exposure was noted (AUC(0-120) = 208.2 vs. 284.8 ng min/mL). Collectively, fentanyl incorporated in RGD liposomes is physically and biologically stable under aerosolization, enhanced the overall analgesic effects, and reduced plasma drug exposure for the first 2 h.

RESEARCH ARTICLE – Drug Discovery Development InterfaceAerosol-Stable Peptide-Coated Liposome Nanoparticles: A Proof-of-Concept Study with Opioid Fentanyl in Enhancing Analgesic Effects and Reducing Plasma Drug Exposure

Previously, we reported a novel pressurized olfactory drug (POD) delivery device that deposits aerosolized drug preferentially to upper nasal cavity. This POD device provided sustained central nervous system (CNS) levels of soluble morphine analgesic effects. However, analgesic onset of less soluble fentanyl was more rapid but brief, likely because of hydrophobic fentanyl redistribution readily back to blood. To determine whether fentanyl incorporated into an aerosol-stable liposome that binds to nasal epithelial cells will enhance CNS drug exposure and analgesic effects and reduce plasma exposure, we constructed Arg-Gly-Asp (RGD) liposomes anchored with acylated integrin-binding peptides (palmitoyl-Gly-Arg-Gly-Asp-Ser). The RGD liposomes, which assume gel phase membrane structure at 25 °C, were stable under the stress of aerosolization as only 2.2 ± 0.5% calcein leakage was detected. The RGD-mediated integrin binding of liposome is also verified to be unaffected by aerosolization. Rats treated with fentanyl in RGD liposome and POD device exhibited greater analgesic effect, as compared with the free drug counterpart (AUC(effect) = 1387.1% vs. 760.1% MPE*min), whereas approximately 20% reduced plasma drug exposure was noted (AUC(0-120) = 208.2 vs. 284.8 ng min/mL). Collectively, fentanyl incorporated in RGD liposomes is physically and biologically stable under aerosolization, enhanced the overall analgesic effects, and reduced plasma drug exposure for the first 2 h.