Delivery of nanocarrier-loaded hydrophobic drugs via the airways

BACKGROUND AND PURPOSE: Systemic delivery of hydrophobic therapeutics represents substantial formulation challenges impeding optimal benefits due to side effects and sub-therapeutic drug levels at the target site consequently leading to progression of multi-drug resistance. This thesis describes three distinct novel nanotechnology-based strategies with desirable aerosolization characteristics for delivery via the airways, aimed at enhancing the therapeutic efficacy of hydrophobic drugs for pulmonary and neurological disorders. METHODS: The first approach involved the development of dry powder microparticles for pulmonary delivery of antifungal amphotericin B nanocomplexes, prepared by co-grinding the drug with ascorbic acid. Nanocomplexes developed were characterized for molecular interactions by FT-IR, size, zeta potential, morphology, in vitro aerodynamic behavior and antifungal activity. The second strategy entailed design of liposomes co-encapsulating rifampicin and ibuprofen using Design of Experiment, targeted to the mannose and/or scavenger receptors on the alveolar macrophages where TB infection resides. Spray dried microparticles were characterized for in vitro aerodynamic behavior and macrophage uptake using the flow cytometer in RAW 264.7 cells. The third approach involved the development of Kolliphor® HS 15 micelles incorporating neuroprotective agents CNB001 or curcumin and Kolliphor® TPGS micelles encapsulating curcumin for the treatment of neurodegeneration and neuroblastoma respectively. Nasal delivery of these micellar systems was intended for brain targeting. Micelles were characterized for size, charge, aerosol droplet size distribution, drug release, morphology and in vitro cellular studies on SH-SY5Y cells. RESULTS: Successful development of nanocarrier-based systems with a high encapsulation efficiency greater than 80% for all the systems was achieved, with particle size desirable for the end-use. Spray dried microparticles of amphotericin B nanocomplexes with L-leucine showed a high fine particle fraction of around 58% signifying likely deposition in the peripheral airways, to the areas of fungal infection. There was no loss of antifungal activity against Candida spp on complexation of amphotericin B. Microparticles of liposomes encapsulating antitubercular drugs showed good aerosolization, and up to 65% fine particle fraction on addition of L-leucine could be achieved. An enhanced in vitro cellular uptake was evident for negative-charged liposomes targeted to the scavenger receptors and the mannosylated liposomes targeted to the mannose receptors on the macrophage cell line RAW 264.7. Finally, Kolliphor® micelles encapsulating CNB001 or curcumin showed desired aerosol droplet size for delivery to the posterior nasal olfactory epithelium with median size of 42.75-54.86 μm when aerosolized by the Nasal™ Mucosal Atomization Device. The formulations intended for neuroprotection showed improved cellular viability, reduction in reactive oxygen species and nuclear morphology in the in vitro Parkinson’s model. CONCLUSION: The nanotechnology-based formulations combined with administration to or through the airways using commercially available delivery devices, represent a highly attractive formulation strategy for delivery of hydrophobic agents to the target site at a therapeutic level to combat issues of multi-drug resistance

Ascorbyl palmitate/DSPE-PEG nanocarriers for oral iron delivery: Preparation, characterisation and in vitro evaluation

The objective of this study was to encapsulate iron in nanocarriers formulated with ascorbyl palmitate and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine polyethylene glycol (DSPE-PEG) for oral delivery. Blank and iron (Fe) loaded nanocarriers were prepared by a modified thin film method using ascorbyl palmitate and DSPE-PEG. Surface charge of the nanocarriers was modified by the inclusion of chitosan (CHI) during the formulation process. Blank and iron loaded ascorbyl palmitate/DSPE nanocarriers were visualised by transmission electron microscopy (TEM) and physiochemical characterisations of the nanocarriers carried out to determine the mean particle size and zeta potential. Inclusion of chitosan imparted a net positive charge on the nanocarrier surface and also led to an increase in mean particle size. Iron entrapment in ascorbyl palmitate-Fe and ascorbyl palmitate-CHI-Fe nanocarriers was 67% and 76% respectively, suggesting a beneficial effect of chitosan on nanocarrier Fe entrapment. Iron absorption was estimated by measuring Caco-2 cell ferritin formation using ferrous sulphate as a reference standard. Iron absorption from ascorbyl palmitate-Fe (592.17 ± 21.12 ng/mg cell protein) and ascorbyl palmitate-CHI-Fe (800.12 ± 47.6 ng/mg, cell protein) nanocarriers was 1.35-fold and 1.5-fold higher than that from free ferrous sulphate, respectively (505.74 ± 23.73 ng/mg cell protein) (n = 6, p < 0.05). This study demonstrates for the first time preparation and characterisation of iron loaded ascorbyl palmitate/DSPE PEG nanocarriers, and that engineering of the nanocarriers with chitosan leads to a significant augmentation of iron absorption

Engineering hydrophobically modified chitosan for enhancing the dispersion of respirable microparticles of levofloxacin

The potential of amphiphilic chitosan formed by grafting octanoyl chains on the chitosan backbone for pulmonary delivery of levofloxacin has been studied. The success of polymer synthesis was confirmed using FT-IR and NMR, whilst antimicrobial activity was assessed against Pseudomonas aeruginosa. Highly dispersible dry powders for delivery as aerosols were prepared with different amounts of chitosan and octanoyl chitosan to study the effect of hydrophobic modification and varying concentration of polymer on aerosolization of drug. Powders were prepared by spray-drying from an aqueous solution containing levofloxacin and chitosan/amphiphilic octanoyl chitosan. L-leucine was also used to assess its effect on aerosolization. Following spray-drying, the resultant powders were characterized using scanning electron microscopy, laser diffraction, dynamic light scattering, HPLC, differential scanning calorimetry, thermogravimetric analysis and X-ray powder diffraction. The in vitro aerosolization profile was determined using a Next Generation Impactor, whilst in vitro antimicrobial assessment was performed using MIC assay. Microparticles of chitosan have the property of mucoadhesion leading to potential increased residence time in the pulmonary mucus, making it important to test the toxicity of these formulations. In-vitro cytotoxicity evaluation using MTT assay was performed on A549 cell line to determine the toxicity of formulations and hence feasibility of use. The MTT assay confirmed that the polymers and the formulations were non-cytotoxic. Hydrophobically modifying chitosan showed significantly lower MIC (4-fold) than the commercial chitosan against P. aeruginosa. The powders generated were of suitable aerodynamic size for inhalation having a mass median aerodynamic diameter less than 4.5 lm for formulations containing octanoyl chitosan. These highly dispersible powders have minimal moisture adsorption and hence an emitted dose of more than 90% and a fine particle fraction (FPF) of 52%. Powders with non-modified chitosan showed lower dispersibility, with an emitted dose of 72% and FPF of 20%, as a result of high moisture adsorption onto the chitosan matrix leading to cohesiveness and subsequently decreased dispersibility

Intensity-modulated radiotherapy of nasopharyngeal carcinoma: a comparative treatment planning study of photons and protons

<p>Abstract</p> <p>Background</p> <p>The aim of this treatment planning study was to investigate the potential advantages of intensity-modulated (IM) proton therapy (IMPT) compared with IM photon therapy (IMRT) in nasopharyngeal carcinoma (NPC).</p> <p>Methods</p> <p>Eight NPC patients were chosen. The dose prescriptions in cobalt Gray equivalent (Gy_E) for gross tumor volumes of the primary tumor (GTV-T), planning target volumes of GTV-T and metastatic (PTV-TN) and elective (PTV-N) lymph node stations were 72.6 Gy_E, 66 Gy_E, and 52.8 Gy_E, respectively. For each patient, nine coplanar fields IMRT with step-and-shoot technique and 3D spot-scanned three coplanar fields IMPT plans were prepared. Both modalities were planned in 33 fractions to be delivered with a simultaneous integrated boost technique. All plans were prepared and optimized by using the research version of the inverse treatment planning system KonRad (DKFZ, Heidelberg).</p> <p>Results</p> <p>Both treatment techniques were equal in terms of averaged mean dose to target volumes. IMPT plans significantly improved the tumor coverage and conformation (<it>P </it>< 0.05) and they reduced the averaged mean dose to several organs at risk (OARs) by a factor of 2–3. The low-to-medium dose volumes (0.33–13.2 Gy_E) were more than doubled by IMRT plans.</p> <p>Conclusion</p> <p>In radiotherapy of NPC patients, three-field IMPT has greater potential than nine-field IMRT with respect to tumor coverage and reduction of the integral dose to OARs and non-specific normal tissues. The practicality of IMPT in NPC deserves further exploration when this technique becomes available on wider clinical scale.</p

A collaborative approach to exploring the future of Cancer treatment and care in relation to Precision Medicine: A design perspective.

The Precision Medicine and the Future of Cancer project was jointly conceived by the Innovation School at Glasgow School of Art and the Institute of Cancer Sciences at the University of Glasgow. Graduating year Product Design students from the Innovation School were presented with a challenge-based project to produce a vision of the future based on current trends that relate to Precision Medicine(PM) and Cancer treatment. This project involved working closely with scientists, clinicians, patients, industry and academic professionals from Glasgow University, staff at Queen Elizabeth University Hospital and Clinical Innovation Zone, staff at Beatson West of Scotland Cancer Centre, Patient Representatives and external design experts from Studio AndThen and GOODD design consultancy. The objective of this project was to investigate, in both analytical and speculative ways, future forms and functions of cancer treatment and care in relation to Precision Medicine, to develop future scenarios and design artefacts, services, and the experiences associated with them. One of the most significant societal shifts currently taking place within the field of PM is the transformation around what it means to be a patient and a professional working within this context. The public’s role is developing beyond once-passive patients into stakeholders valued within the medical industry and healthcare sector for their participation in clinical trials, and contribution towards policy-making and decision-making committees. This new dynamic is changing the traditional patient-doctor relationship and challenging the hegemony of medical practice at an institutional level. The impetus for this shift is relentless technological acceleration and increased scientific research, in particular driven by advances in PM. This project asked students to consider what will happen in a cancer landscape ten years from now, where PM has evolved to the extent that new forms of medical practice, cancer treatment and care transform how we interact with each other, with professionals and the world around us. The brief gave students the opportunity to reflect on the underlying complexities regarding the future of health, technological acceleration, post-capitalism and human agency, to envision a future world context, develop it as an experiential exhibit, and produce the designed products, services and experiences for the people who might live and work within it. The project was divided into two sections: The first was a collaborative stage where groups of students were assigned a specific area of focus from Social, Technological, Economic, Ethical, Educational, Political, Legal, Ecological [STEEEPLE]. These groups focused on researching and exploring their specific lenses and gathering as much information and understanding while working with external experts to further their knowledge. This group stage culminated in an exhibition of the collaborative understanding of what the future could look like in 10 years from now, after exploring the possible consequences of current actions. The second stage saw students explore their individual response to the world that had been defined in the first stage. Each student had their own response to the research by iteratively creating a design outcome that was appropriate to the subject matter. This culminated in each student having created a design product/service/experience relating to the future scenario. A full report (Project Process Journal [PPJ]) is included within the repository of each student which breaks down their process of designing and the outcome they have designed. The project aims to tackle the emerging possibilities where medical professionals and design can collaborate, to create a future where forms of medical practice are more preventative and are more appropriate for an aging population now and into the future. The deposited materials are arranged as follows: Readme files - two readme files relate to stage one and stage two of the project as outlined above. Overview poster - gives a visual overview of the structure and timeline of the project. Data folders - the data folders for stage one of the project are named for the lens through which each group viewed possible futures. The data folders for stage two of the project are named for the individual students who conducted the work

Envisioning the future of Royal Schiphol Group as a multi modal ecosystem: A strategy to redefine and improve the future experiences of mobility by exploring successful facilitation of multi modalities at RSG

IntroductionAn assignment for Royal Schiphol Group, the project aimed to create a future vision that aligns all stakeholders towards a shared ambition to transform towards a multi modal hub as well as identify user needs that could facilitate new strategic initiatives for Schiphol group as a MMH.In order to create the future vision a trend analysis and co-creation workshop was conducted that resulted in insights such as; 1) Water Natives due to increase in water levels, redefined work culture due to remote workers and 3) isolation over socialisation. Stakeholders reacted to these trends which led to insights such as; 1) People will remain resilient, 2) congestion might increase if not dealt with properly and 3) the future is experience economy.Future VisionBased on the research, a future vision for RSG’s MMH was created that states, ‘‘By 2050, Schiphol Group should envision, a flex mobility ecosystem that adapts to situations and user needs resulting in an antifragile way of working. The goal is to create tailored services and seamless experiences for users and passengers. The ambition is achieved by increasing proactive collaboration, on time network performance, and decentralizing hub functions.’Strategic SolutionsThe future vision can be achieved through strategic solutions such as;1) Preparing change by creating a team of strategic advisors.2) Proposing initiatives significant to transformation of a MME by creating a digital platform.3) Facilitating change by creating a better experience for their users through pop up experiences. In the process learning and gathering new insights that could lead to expanding into new opportunity windows.These solutions perfectly fit RSG’s overall vision of having the most sustainable and high quality airports in Europe. It also allows RSG to implement multi modality correctly, anticipate the transformation of the mobility industry and design a user centred multi modal ecosystem.Strategic Product Desig

Integrated course assessments in an undergraduate nursing program

Curriculum integration is a partnership amongst multidisciplinary members to create a cohesive curriculum and improve education. Basic and clinical science integration helps students learn deeply. Integrated curricula facilitate students to become lifelong learners. It encourages critical thinking and clinical reflection and helps students become active, self-directed learners. A comprehensive integrated exam was conducted at Aga Khan University, School of Nursing and midwifery to establish meaningful learning and enhance theoretical knowledge application in clinical practice, using competencies from four different courses in second year of study.Comprehensive Integrated Exam prepared students to assess a client and design complete nursing care based on health assessment, adult health nursing, pharmacology, and pathophysiology course concepts. This integrated exam was very effective as 97 % of students who took the exam passed on their first attempt. Faculty members involved found the comprehensive integrated exam a successful strategy to evaluate students learning, whereas the students related that this exam helped them to bridge the gap between applying theoretical concepts from different courses to clinical practice

Patient, Provider, and System Factors Associated With Failure to Follow-Up Elevated Glucose Results in Patients Without Diagnosed Diabetes

Background: Although elevated glucose values are strongly associated with undiagnosed diabetes, they are frequently overlooked. Patient, provider, and system factors associated with failure to follow-up elevated glucose values in electronic medical records (EMRs) are not well described. Methods: We conducted a chart review in a comprehensive EMR with a patient portal and results management features. Established primary care patients with no known diagnosis of diabetes and ≥ 1 glucose value >125 mg/dL were included. Follow-up failure was defined as (1) no documented comment on the glucose value or result communication to the patient within 30 days or (2) no hemoglobin A 1c (HbA 1c ) ordered within 30 days or resulted within 12 months. Associations were examined using Wilcoxon and χ 2 tests. Results: Of 150 charts reviewed, 97 met inclusion criteria. The median glucose was 133 mg/dL, and 20% of patients had multiple values >125 mg/dL. Only 36% of elevated glucose values were followed up. No associations were observed between patient characteristics, diabetes risk factors, or provider characteristics and follow-up failures. Automated flagging of glucose values ≥140 mg/dL by highlighting them red in the EMR was not associated with improved follow-up (46% vs 32%; P = .19). Even when follow-up occurred (n = 35), only 31% completed gold standard diabetes testing (HbA 1c ) within 12 months. Of the resulted HbA 1c tests (n = 11), 55% were in the prediabetes range (5.7%-6.4%). Conclusions: Two-thirds of elevated glucose values were not followed up, despite EMR features facilitating results management. Greater understanding of the results management process and improved EMR functionalities to support results management are needed

Synthesis, biological and in silico evaluation of pure nucleobase-containing spiro (Indane-Isoxazolidine) derivatives as potential inhibitors of MDM2-p53 interaction

Nucleobase-containing isoxazolidines spiro-bonded to an indane core have been synthesized in very good yields by regio- and diastereoselective 1,3-dipolar cycloaddition starting from indanyl nitrones and N-vinylnucleobases by using environmentally benign microwave technology. The contemporary presence of various structural groups that are individually active scaffolds of different typology of drugs, has directed us to speculate that these compounds may act as inhibitors of MDM2-p53 interaction. Therefore, both computational calculations and antiproliferative screening against A549 human lung adenocarcinoma cells and human SH-SY5Y neuroblastoma cells were carried out to support this hypothesis.We thank the Italian Ministry of University and Scientific Research (MIUR) for a doctoral grant and the University of Calabria for financial support. We also acknowledge the MINECO and FEDER Program (Madrid, Spain, project CTQ2016-76155-R) and the Gobierno de Aragon (Zaragoza, Spain. Biological & Computational Chemistry Group. E34_R17)