Inhalable PEGylated Phospholipid Liposheres Containing Paclitaxel for Targeted Pulmonary Delivery for Lung Cancer Applications

Despite the significant advances in the treatment of lung cancer, it is a disease that still signifies poor prognosis due to the challenges in implementation of treatment. Targeted pulmonary inhalation drug delivery offers many advantages for lung cancer patients in comparison to conventional systemic chemotherapy. These include the potential to deliver local therapeutically effective concentrations of drug directly to the lung, minimized side effects due to limited systemic delivery, and ease of use for the patient. Inhalable dry powder formulations of nanoparticles and microparticles (lipospheres) containing a chemotherapeutic are advantageous in their ability to deliver drug deep in the lung via optimally sized particles, higher local drug dose delivery, and long-term storage capability. In this work, novel advanced spray-dried inhalable PEGylated phospholipid liposphere powders containing the chemotherapeutic paclitaxel were successfully designed and produced via dilute organic solution advanced spray drying under various conditions. Fixed ratios of dipalmatoylphosphatidylcholine (DPPC) and dipalmatoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) at three different polymeric chain lengths were combined with various ratios of paclitaxel in a dilute methanol solution. Upon optimization of the spray drying conditions (e.g. pump rate), the physicochemical characterization of the particles was completed. Scanning electron microscopy (SEM) images showed the spherical particle morphology of the inhalable particles. The size of the particles was statistically analyzed using these images SigmaScan software, and these particles were determined to be 600 nm – 1.2 μm in diameter, which is optimal for efficient targeting of the deep lung alveolar and small airway regions for enhanced local deposition. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) were performed to analyze solid-state transitions and long-range molecular order, respectively, and allowed for the confirmation of the presence of phospholipid bilayers and/or paclitaxel and their phase transition behavior. The water content of the particles was very low as quantified analytically via Karl Fisher titration. The composition of the particles was confirmed using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. Confocal Raman microspectroscopy was employed in chemical imaging to assess particle composition and miscibility. The amount of paclitaxel loaded into the particles was analyzed via high performance liquid chromatography (HPLC), and their aerosol performance was evaluated using the Next Generation Impactor (NGI) and an approved dry powder inhaler (DPI) device for human use to determine the emitted dose, respirable dose, fine particle fraction and mass median aerodynamic diameter. Overall, these results demonstrate this novel therapeutic nanomedicine platform as one capable of effectively delivering paclitaxel directly to the lung in high local concentration for the treatment of lung cancer

SYNTHESIS AND CHARACTERIZATION OF MAGNETIC HYDROGEL NANOCOMPOSITES FOR CANCER THERAPY APPLICATIONS

Currently, cancer is the second leading cause of death in the United States. Conventional cancer treatment includes chemotherapy, radiation, and surgical resection, but unfortunately, all of these methods have significant drawbacks. Hyperthermia, the heating of cancerous tissues to between 41 and 45°C, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. In this work, a novel method for remotely administering heat is presented. This method involves heating of tumor tissue using hydrogel nanocomposites containing magnetic nanoparticles which can be remotely heated upon exposure to an external alternating magnetic field (AMF). The iron oxide nanoparticles contained in the hydrogel nanocomposites are able to heat via an AMF due to Brownian and Neel relaxation processes. The administration of hyperthermia via hydrogel nanocomposites allows for local delivery of heat to tumor tissue while also providing a drug depot to deliver chemotherapeutic agents. Both in vivo and in vitro studies have demonstrated that numerous chemotherapeutic agents, when used in conjunction with hyperthermia, show improved efficacy in treating cancer Various magnetic hydrogel nanocomposites were synthesized and characterized for this work including poly(ethylene glycol) (PEG)-based hydrogels, which were studied due to their inherent biocompatibility and “stealth” properties, as well as, poly(β-amino ester) (PBAE)-based hydrogels which have tailorable degradation properties. The PEG hydrogels were investigated for their temperature-responsiveness swelling, mechanical strength, heating capabilities, biocompatibility, ability to kill M059K glioblastoma cells via thermoablation, and the ability to deliver paclitaxel, a chemotherapeutic agent. PBAE hydrogels were also characterized for their degradation and swelling properties, ability to heat upon exposure to an AMF, biocompatibility, mechanical strength, and ability to deliver paclitaxel in a controlled fashion. Additionally, multiple cancer cell lines were exposed to a combination of paclitaxel and heat (at 42.5 °C) in vitro and it was shown that A539 lung carcinoma cells exhibit higher cytotoxicity when exposed to both heat and paclitaxel than either treatment alone. Overall, magnetic hydrogel nanocomposites are promising materials that can be utilized for the multi-modality treatment of cancer through the synergistic delivery of both heat and chemotherapeutic agents

Inhalable PEGylated Phospholipid Lipospheres Containing Paclitaxel for Trageted Pulmonary Delivery for Lung Cancer Applications

Despite the significant advances in the treatment of lung cancer, it is a disease that still signifies poor prognosis due to the challenges in implementation of treatment. Targeted pulmonary inhalation drug delivery offers many advantages for lung cancer patients in comparison to conventional systemic chemotherapy. These include the potential to deliver local therapeutically effective concentrations of drug directly to the lung, minimized side effects due to limited systemic delivery, and ease of use for the patient. Inhalable dry powder formulations of nanoparticles and microparticles (lipospheres) containing a chemotherapeutic are advantageous in their ability to deliver drug deep in the lung via optimally sized particles, higher local drug dose delivery, and long-term storage capability. In this work, novel advanced spray-dried inhalable PEGylated phospholipid liposphere powders containing the chemotherapeutic paclitaxel were successfully designed and produced via dilute organic solution advanced spray drying under various conditions. Fixed ratios of dipalmatoylphosphatidylcholine (DPPC) and dipalmatoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) at three different polymeric chain lengths were combined with various ratios of paclitaxel in a dilute methanol solution. Upon optimization of the spray drying conditions (e.g. pump rate), the physicochemical characterization of the particles was completed. Scanning electron microscopy (SEM) images showed the spherical particle morphology of the inhalable particles. The size of the particles was statistically analyzed using these images SigmaScan software, and these particles were determined to be 600 nm – 1.2 μm in diameter, which is optimal for efficient targeting of the deep lung alveolar and small airway regions for enhanced local deposition. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) were performed to analyze solidstate transitions and long-range molecular order, respectively, and allowed for the confirmation of the presence of phospholipid bilayers and/or paclitaxel and their phase transition behavior. The water content of the particles was very low as quantified analytically via Karl Fisher titration. The composition of the particles was confirmed using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. Confocal Raman microspectroscopy was employed in chemical imaging to assess particle composition and miscibility. The amount of paclitaxel loaded into the particles was analyzed via high performance liquid chromatography (HPLC), and their aerosol performance was evaluated using the Next Generation Impactor (NGI) and an approved dry powder inhaler (DPI) device for human use to determine the emitted dose, respirable dose, fine particle fraction and mass median aerodynamic diameter. Overall, these results demonstrate this novel therapeutic nanomedicine platform as one capable of effectively delivering paclitaxel directly to the lung in high local concentration for the treatment of lung cancer

Transportation Optimization Modeling for Washington State Hay Shipments: Mode and Cost Implications Due to Loss of Container Services at the Port of Portland

A recent issue impacting hay shipments in Washington State involves the reduction of container services at the Port of Portland, Oregon. Prior to this change, containers filled with hay were shipped almost exclusively via barge on the Columbia River to the Port of Portland. After reaching Portland, the containers were then loaded onto one of three steamship lines: Hyundai, K-Line, or Hanjin and destined to markets in Japan and China. As of September 2004, Hanjin is the only carrier that calls on the Port of Portland. This research effort collected firm level data on the production, transportation and marketing of hay in Washington and utilizes this information to develop an optimization model of regional hay movements. One alternative evaluated in this study is determining industry shifts in transportation usage and modal choice in reaction to the transportation changes after September 2004. The results indicate that after all barge and hay shipments were eliminated into Portland, total transportation costs decrease initially overall, while some producers experience shipping cost increase. Both rail and truck volumes increase substantially in the absence of container shipments on barge. The total industry impact is a $6.3 million increase in transportation costs from the Base Scenario to Scenario 3. Also, once trucks rates are allowed to increase due to the shortage of trucks and the increased demand for truck services, the total transportation cost increased by$8.7 million.International Relations/Trade,

Synthesis and Characterization of Nanocomposite Microparticles (nCmP) for the Treatment of Cystic Fibrosis-Related Infections

Purpose: Pulmonary antibiotic delivery is recommended as maintenance therapy for cystic fibrosis (CF) patients who experience chronic infections. However, abnormally thick and sticky mucus present in the respiratory tract of CF patients impairs mucus penetration and limits the efficacy of inhaled antibiotics. To overcome the obstacles of pulmonary antibiotic delivery, we have developed nanocomposite microparticles (nCmP) for the inhalation application of antibiotics in the form of dry powder aerosols. Methods: Azithromycin-loaded and rapamycin-loaded polymeric nanoparticles (NP) were prepared via nanoprecipitation and nCmP were prepared by spray drying and the physicochemical characteristics were evaluated. Results: The nanoparticles were 200 nm in diameter both before loading into and after redispersion from nCmP. The NP exhibited smooth, spherical morphology and the nCmP were corrugated spheres about 1 μm in diameter. Both drugs were successfully encapsulated into the NP and were released in a sustained manner. The NP were successfully loaded into nCmP with favorable encapsulation efficacy. All materials were stable at manufacturing and storage conditions and nCmP were in an amorphous state after spray drying. nCmP demonstrated desirable aerosol dispersion characteristics, allowing them to deposit into the deep lung regions for effective drug delivery. Conclusions: The described nCmP have the potential to overcome mucus-limited pulmonary delivery of antibiotics

Metadata Creation Methods: A Study

Metadata makes information meaningful. Creation of metadata records is a continuous and sequential task. Assignment of metadata values manually is time consuming as it depends on the skill(s) of the individuals involved. Metadata extraction can be availed with the help of machine enabled methods. Semi-automatic metadata creation is a reliable method that is being used effectively for resource description. Automatic metadata extraction tools correctly retrieve various technical values from objects. This paper discusses about different metadata creation methods available in the literature

Performing biography: creating, embodying and shifting history [2 parts]

Performing Biography: creating, embodying and shifting history is a practice-led research project that builds upon and challenges Canton’s (2011) research into biographical theatre. Canton suggests that biographical theatre cannot shift audience perception of an historical figure if it counters their previous 'life world knowledge', regardless of the modernist or postmodernist theatrical devices employed. Through three cycles of observation, reflection, planning and, action two original biographical theatre works are created, embodied and performed. They are designed to test whether biographical theatre can shift audience perception of an historical figure if three emergent biographical theatre-making principles are considered. The modernist Ms. Garland at Twilight and the postmodernist Judy Strikes Back prove that biographical theatre could shift audience perception. In extant biographical theatre works featuring the actress Judy Garland, her life is constructed through the tragedy plotting pattern. According to White (1978), Davis (1992), Heddon (2008) and Dortins (2009) such a pattern, or dominant narrative, has the power to limit, distort or police control over the life story of an historical figure. By successfully disrupting the tragedy narrative associated with Garland, this study proposes that ‘khorobiognosis’ can occur. That is, audience perception can be shifted if the biographer and biographical performers commit to their super-objective, include other people’s thinking, and embrace liveness. This study provides a narrative of my biographical theatre-making practice to ensure that new narratives of historical figures can be revealed and forgotten narratives can be uncovered

Synthesis and Characterization of CREKA-Conjugated Iron Oxide Nanoparticles for Hyperthermia Applications

One of the current challenges in the systemic delivery of nanoparticles in cancer therapy applications is the lack of effective tumor localization. Iron oxide nanoparticles coated with crosslinked dextran were functionalized with the tumor homing peptide CREKA, which binds to fibrinogen complexes in the extracellular matrix of tumors. This allows for the homing of these nanoparticles to tumor tissue. The iron oxide nanoparticle core allows for particle heating upon exposure to an alternating magnetic field (AMF) while the dextran coating stabilizes the particles in suspension and decreases the cytotoxicity of the system. Magnetically mediated hyperthermia (MMH) allows for the heating of tumor tissue to increase the efficacy of traditional cancer treatments using the iron oxide nanoparticles. While MMH provides the opportunity for localized heating, this method is currently limited by the lack of particle penetration into tumor tissue, even after effective targeted delivery to the tumor site. The CREKA-conjugated nanoparticles presented were characterized for their size, stability, biocompatibility, and heating capabilities. The particles were stable in PBS and media over at least twelve hours, had a hydrated diameter of 52 nm, and generated enough heat to raise solution temperatures well into the hyperthermia range (41 – 45 °C) when exposed to an AMF. Biocompatibility studies demonstrated that the particles have low cytotoxicity over long exposure times at low concentrations. A fibrinogen clotting assay was used to determine the binding affinity of CREKA-conjugated particles, which was significantly greater than the binding affinity of dextran, only coated iron oxide nanoparticles demonstrating the potential for this particle system to effectively home to a variety of tumor locations. Finally, it was shown that in vitro MMH increased the effects of cisplatin compared to cisplatin or MMH treatments alone

Characterization and Aerosol Dispersion Performance of Spray-Dried Chemotherapeutic PEGylated Phospholipid Particles for Dry Powder Inhalation Delivery in Lung Cancer

Pulmonary inhalation chemotherapeutic drug delivery offers many advantages for lung cancer patients in comparison to conventional systemic chemotherapy. Inhalable particles are advantageous in their ability to deliver drug deep in the lung by utilizing optimally sized particles and higher local drug dose delivery. In this work, spray-dried and co-spray dried inhalable lung surfactant-mimic PEGylated lipopolymers as microparticulate/nanoparticulate dry powders containing paclitaxel were rationally designed via organic solution advanced spray drying (no water) in closed-mode from dilute concentration feed solution. Dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) with varying PEG chain length were mixed with varying amounts of paclitaxel in methanol to produce co-spray dried microparticles and nanoparticles. Scanning electron microscopy showed the spherical particle morphology of the inhalable particles. Thermal analysis and X-ray powder diffraction confirmed the retention of the phospholipid bilayer structure in the solid-state following spray drying, the degree of solid-state molecular order, and solid-state phase transition behavior. The residual water content of the particles was very low as quantified analytically Karl Fisher titration. The amount of paclitaxel loaded into the particles was quantified which indicated high encapsulation efficiencies (43-99%). Dry powder aerosol dispersion performance was measure in vitro using the Next Generation Impactor™ (NGI™) coupled with the Handihaler® dry powder inhaler device and showed mass median aerodynamic diameters in the range of 3.4 – 7μm. These results demonstrate that this novel microparticulate/nanoparticulate chemotherapeutic PEGylated phospholipid inhalation aerosol platform has great potential in lung cancer drug delivery