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351. GOP Considers Grassley Stimulus; Baucus Meets Mods.

Author

Morton, Stephen

Subjects
*ECONOMICS, *LEGISLATIVE bills, *TAX credits
Abstract

Reports on the plan of Senate Finance member Charles Grassley to seek support for an economic stimulus proposal in the United States. Recommended budget for economic proposals; Omission of expiring tax credits in the proposal; Assertion of the agreement of President George W. Bush with extra spending.

Published
2001

353. Reading the Anthropocene through science and apocalypse in the selected contemporary fiction of J.G. Ballard, Kurt Vonnegut, Cormac McCarthy and Ian McEwan

Author

Fevyer, David, Morton, Stephen, and May, William

Subjects
813
Abstract

This thesis examines how six contemporary novels variously intervene in the current crisis of climate change. Through close readings of J G Ballard’s The Drowned World (1962) and Hello America (1981); Cormac McCarthy’s The Road (2006); Kurt Vonnegut’s Cat’s Cradle (1963) and Galapagos (1985); and Ian McEwan’s Solar (2010), the thesis aims to identify how the narrative and generic resources of contemporary fiction might help readers to think through and beyond the consequences of anthropocentric ways of thinking about the biosphere. Drawing upon the concept of the Anthropocene – and in particular the account of this concept provided by the historian Dipesh Chakrabarty – the thesis suggests that these novels raise profound questions about how climate change is represented and understood. If accounts of the human history of modernity have until recently overlooked the complex ways in which both the human species and its contemporary fossil fuel cultures are intertwined with the geologic history of the planet, how has contemporary fiction attended to this oversight? What light can imaginative apocalyptic future histories of the biosphere, such as those presented in the fiction of Ballard, Vonnegut and McCarthy, shed on predominant understandings of climate change? How has fiction highlighted the ways in which the insights offered by the Anthropocene complicate the promises of scientific ‘reason’ to explain and provide solutions to anthropogenic climate change? How do fictions such as those of Vonnegut and McEwan contribute to a more nuanced account of the limits of such reasoning? To address these questions, the thesis draws upon Martin Heidegger’s account of the anthropocentric enframing of nature through technology, and suggests a re-thinking of Louis Althusser’s account of ideology through which we can begin to understand how anthropocentric perspectives are naturalised in ways that illuminate some of the difficulties identified by Chakrabarty. By bringing these three perspectives together, the thesis seeks to develop a distinct critical approach to reading the responses of these literary fictions to climate change. The first section of the thesis examines how the generic resources of apocalyptic fiction defamiliarise assumed relationships between the human subjects and societies of industrial modernity and the biosphere. Chapter 1 suggests that J G Ballard’s novel The Drowned World (1962) imaginatively connects geologic and human history in order to disrupt key anthropocentric assumptions concerning the relationship between humanity and the biosphere, whilst his later novel Hello America (1981) foregrounds the anthropocentric inscription of industrial modernity through a self-consciously hallucinatory re-imagining of American history. Chapter 2 examines Cormac McCarthy’s recent novel The Road (2006), and suggests that the text presents a particular form of apocalyptic narrative that complicates the anthropocentric sub-text of traditional apocalyptic narratives. The second section of the thesis examines how the fictional representation of science and scientists can help to illuminate the ways in which an anthropocentric faith in the technoscientific promise of human power over nature serves to legitimate an illusion of human mastery over the biosphere. Chapter 3 considers how Kurt Vonnegut’s novel Cat’s Cradle (1963) offers a counterpoint to this faith by ironically depicting scientist characters whose assumptions of beneficial technoscientific progress are undermined by complex interconnections between individuals and the biosphere – connections that have apocalyptic consequences. Such complex interactions are also a feature of the insights offered by ecology and evolutionary science. Reading Vonnegut’s fiction after the Anthropocene underlines the ways in which Vonnegut’s literary techniques can help readers to think through and beyond the complex connections between natural and human history that these scientific disciplines begin to elucidate. As chapter 3 suggests, Vonnegut’s later novel Galapagos (1985) provides a particularly imaginative account of this complexity through its fictional narrative of an evolutionary future history across the longue durée of geologic time. Building on the insights developed in chapter 3, chapter 4 considers the significance of Ian McEwan’s ironic depiction of a fictional scientist who is unable to restrain his own overconsumption of resources in his novel Solar (2010). In my reading, McEwan’s scientist figure functions as an allegory for the paradoxes of a technoscientific culture that seems unable to apply scientific reason in meaningful responses to the dangers of the Anthropocene. In so doing, the chapter illustrates how the use of allegorical codes and irony in Solar draw attention to the ways in which a faith in technoscientific reason to provide solutions to anthropogenic climate change is misplaced. This misplaced faith also naturalises the on-going enframing of nature as a resource, with potentially apocalyptic consequences. The apocalyptic narratives of the Ballard and McCarthy novels can be understood as quasi-scientific literary speculations, which disrupt anthropocentric assumptions through the experimental futures they depict. Similarly, the ironic depictions of scientists and scientific thinking in the Vonnegut and McEwan novels draw attention to the anthropocentric limitations of conventional scientific thinking for fully understanding and productively responding to the apocalyptic implications of climate change. In bringing these readings together, the thesis attempts to provide valuable and timely insights into the techniques through which the literary fiction of Ballard, Vonnegut, McCarthy and McEwan can help readers to think differently about the complex relationship between human life and the biosphere. These readings also trace how such fiction can draw attention to the ways in which anthropocentric patterns of thought contribute to the catastrophic climatic implications of technoscientific culture.

Published
2016

354. Hasidic Judaism in American literature

Author

van Loenen, Eva, Jordan, James, Baum, Devorah, and Morton, Stephen

Subjects
810.9
Abstract

This thesis brings together literary texts that portray Hasidic Judaism in Jewish-American literature, predominantly of the 20th and 21st centuries. Although other scholars may have studied Rabbi Nachman, I.B. Singer, Chaim Potok and Pearl Abraham individually, no one has combined their works and examined the depiction of Hasidism through the codes and conventions of different literary genres. Additionally, my research on Judy Brown and Frieda Vizel raises urgent questions about the gendered foundations of Hasidism that are largely elided in the earlier texts. The thesis demonstrates how each text has engaged with Hasidic identity, thought, customs, laws, values and communities in its own particular way, creating tensions between the different literary interpretations. Furthermore, the thesis is structured chronologically and contributes to a cultural historical understanding of a people that has been threatened by modernity, nearly annihilated by the Nazis and uprooted from their motherlands in order to survive, and in fact thrive, in the United States. This historical development is described in the various texts used in this thesis, which belong to different genres from the short story, to the novel, to online Life writing. My research has been truly interdisciplinary, which is reflected in the use of different methodologies belonging to different academic fields such as history, sociology, anthropology, theology, Western esotericism and literary studies.

Published
2015

355. Violent southern spaces : myth, memory, and the body in literatures of South Africa and the American South

Author

Greenfield, Denise, Morton, Stephen, and McDonald, Gail

Subjects
820.9, PE English
Abstract

‘Violent Southern Spaces’ examines the narratives, archetypes and metaphors of memory, myth and the body that writers from South Africa and the American South have used to contest histories of racial oppression and segregation. In so doing, it seeks to identify significant transnational interactions and connections between the aesthetic forms, politics and histories of literary texts from South Africa and the United States. By analysing texts and situations that are both analogous and singular, this thesis utilizes Jean-Luc Nancy’s Inoperative Community as well as Sam Durrant’s Postcolonial Narrative and the Work of Mourning to depict how works of literature interrupt Southern and South African forms of community as well as the myths upon which they are founded. Chapter One examines the tension between the narrative and anti-narrative dimensions of trauma in William Faulkner’s Absalom, Absalom! and Zoë Wicomb’s David’s Story and considers the conditions under which cultural trauma not only exposes the subject as a singularity, but also serves to create community via a collective identification with a mythic past. In their focus on the interruption of community as well as the disruption of the trauma narrative, these texts help us to better understand how certain myths have come to define the nation or region. Chapter Two considers the manner in which community is enacted through departure in Toni Morrison’s Beloved and Achmat Dangor’s Bitter Fruit. Depicted as either a movement towards a more traditional notion of community and communion, or an exposure of the limits of community, there is a certain type of freedom evidenced in such departures—a freedom intimately connected to the being-in-common of community. Finally, in Chapter Three Dorothy Allison’s Bastard Out of Carolina and Marlene van Niekerk’s Triomf are compared in order to demonstrate how both writers interrogate the excessive accessibility that has come to define the poor white community whilst also writing communities akin to Nancy’s ‘community without unity’. This chapter further examines how both texts depict community as an active, interruptive idea, a continual unworking of totalising and exclusionary myths of collectivity upon which community (and the nation) is formed.

Published
2013

356. Health and well-being for all: an approach to accelerating progress to achieve the Sustainable Development Goals (SDGs) in countries in the WHO European Region.

Author

Menne, Bettina, Leon, Emilia Aragon de, Bekker, Marleen, Mirzikashvili, Nino, Morton, Stephen, Shriwise, Amanda, Tomson, Göran, Vracko, Pia, and Wippel, Christoph

Subjects
*HEALTH status indicators, *INTERVIEWING, *RESEARCH methodology, *HEALTH policy, *PUBLIC health, *SUSTAINABLE development, *QUALITATIVE research, *WELL-being
Abstract

Background Forty-three out of 53 of the WHO European Member States have set up political and institutional mechanisms to implement the United Nations (UN) 2030 Agenda for Sustainable Development. This includes governance and institutional mechanisms, engaging stakeholders, identifying targets and indicators, setting governmental and sectoral priorities for action and reporting progress regularly. Still, growing evidence suggests that there is room for advancing implementation of some of the Sustainable Development Goals (SDGs) and targets at a higher pace in the WHO European Region. This article proposes the E4A approach to support WHO European Member States in their efforts to achieve the health-related SDG targets. Methods The E4A approach was developed through a 2-year, multi-stage process, starting with the endorsement of the SDG Roadmap by all WHO European Member States in 2017. This approach resulted from a mix of qualitative methods: a semi-structured desk review of existing committal documents and tools; in-country policy dialogs, interviews and reports; joint UN missions and discussion among multi-lateral organizations; consultation with an advisory group of academics and health policy experts across countries. Results The E—engage—functions as the driver and pace-maker; the 4 As—assess, align, accelerate and account—serve as building blocks composed of policies, processes, activities and interventions operating in continuous and synchronized action. Each of the building blocks is an essential part of the approach that can be applied across geographic and institutional levels. Conclusion While the E4A approach is being finalized, this article aims to generate debate and input to further refine and test this approach from a public health and user perspective. [ABSTRACT FROM AUTHOR]

Published
2020
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357. Characteristics of hollows and hollow‐bearing trees in semi‐arid river red gum woodland and potential limitations for hollow‐dependent wildlife.

Author

Westerhuis, Erin L., Schlesinger, Christine A., Nano, Catherine E. M., Morton, Stephen R., and Christian, Keith A.

Subjects
*TREE cavities, *FORESTS & forestry, *RIVER channels, *EUCALYPTUS camaldulensis
Abstract

Up to 37 species of the birds and microbats inhabiting inland Australia are dependent on tree cavities for breeding or roosting. The river red gum (Eucalyptus camaldulensis), a well‐known hollow‐bearing tree species, occurs in linear semi‐arid woodland along thousands of kilometres of ephemeral river channels and is the only tree species that provides widespread, aggregated hollow resources across a landscape otherwise dominated by shrublands. Here we assess the type and quantity of hollows available along ephemeral rivers of the MacDonnell Ranges bioregion in central Australia and determine which characteristics of river red gums best predict the abundance and characteristics of different tree hollows, as first steps towards assessing the current availability of hollows in the region. Approximately a third of all river red gums sampled were hollow‐bearing, but individual trees with abundant hollows were rare. Further, 36% of hollows had an entrance ≤ 5 cm, and 37% had entrances which were 6–10 cm in diameter, whereas only 13% of hollows had an entrance diameter > 20 cm suitable for larger hollow‐using species. Large and high hollows only occurred on trees that did not display post‐disturbance resprouting. Trees with multiple and diverse hollows were rare and tended to be in advanced stages of senescence and had larger stems (82.3 ± 3.33 cm) and were taller (14.4 ± 0.53 m) compared to non‐hollow‐bearing trees (23.44 ± 1.68 cm, 8.0 ± 0.34 m). Further research is required to establish whether the current abundance of hollows and diversity of hollow types are limiting to cavity‐dependent wildlife, and to identify any threats to availability of hollows. [ABSTRACT FROM AUTHOR]

Published
2019
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368. Inhibition of vein graft stenosis with a c-jun targeting DNAzyme in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE).

Author

Li, Yue, Bhindi, Ravinay, Deng, Zhou J., Morton, Stephen W., Hammond, Paula T., and Khachigian, Levon M.

Subjects
*CORONARY artery stenosis, *DEOXYRIBOZYMES, *LIPOSOMES, *ETHANOLAMINES, *CORONARY artery bypass, *CARDIAC surgery, *SAPHENOUS vein, *SURGERY
Abstract

Abstract: Background/objectives: Coronary artery bypass grafting (CABG) is among the most commonly performed heart surgical procedures. Saphenous vein graft failure due to stenosis impedes the longer-term success of CABG. A key cellular event in the process of vein graft stenosis is smooth muscle cell hyperplasia. In this study, we evaluated the effect of a DNAzyme (Dz13) targeting the transcription factor c-Jun in a rabbit model of vein graft stenosis in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Dz13 in DOTAP/DOPE has undergone preclinical toxicological testing, and a Phase I clinical trial we recently conducted in basal cell carcinoma cancer patients demonstrates that it is safe and well tolerated after local administration. Methods: Effects of Dz13 in a formulation containing DOTAP/DOPE on smooth muscle cell (SMC) growth and c-Jun expression were assessed. Dz13 transfection was determined by cellular uptake of carboxyfluorescein-labeled Dz13. Autologous jugular vein to carotid artery transplantation was performed in New Zealand White rabbits to investigate the effect of the Dz13 in DOTAP/DOPE formulation on intimal hyperplasia. Results: Dz13/DOTAP/DOPE reduced SMC proliferation and c-Jun protein expression in vitro compared with an impotent form of Dz13 bearing a point mutation in its catalytic domain (Dz13.G>C). The Dz13(500μg)/DOTAP/DOPE formed lipoplexes that were colloidally stable for up to 1h on ice (0°C) and 30min at 37°C, allowing sufficient uptake by the veins. Dz13 (500μg) inhibited neointima formation 28d after end-to-side transplantation. Conclusions: This formulation applied to veins prior to transplantation may potentially be useful in efforts to reduce graft failure. [Copyright &y& Elsevier]

Published
2013
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369. Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER).

Author

Eun-Ae Cho, Molaney, Fergal J., Hang Cai, Av-Yeung, Annie, China, Carlos, Scolyer, Richard A., Yosufi, Benafsha, Raftery, Mark J., Deng, Jason Z., Morton, Stephen W., Hammond, Pavia T., Arkenav, Hendrik-Tobias, Damian, Diana L., Francis, Douglas J., Chesterman, Colin N., St C. Barnetson, Ross, Halliday, Gary M., and Khachigian, Levon M.

Subjects
*DEOXYRIBOZYMES, *DNA, *DEOXYRIBOSE, *BASAL cell carcinoma, *SKIN cancer
Abstract

Background The nuclear transcription factor c-Jun is preferentially expressed in basal-cell carcinoma. Dz13 is a deoxyribozyme that targets JUN messenger RNA and has inhibited the growth of a range of tumours in mice. We did a phase 1 study to assess safety and tolerability in human beings. Methods Adults with nodular basal-cell carcinoma were recruited from Royal Prince Alfred Hospital, Sydney, Australia, between September, 2010, and October, 2011. Patients were assigned to receive one intratumoral injected dose of 10, 30, or 100 pg Dz13, in a 50 μL volume of lipid carder, and were assessed for adverse effects in the first 24 h then at 7, 14, and 28 days after injection. Treated tumours were surgically excised 14 days after injection and compared with the baseline biopsy samples for expression of c-Jun and tumorigenesis markers. Findings Nine patients were recruited, of whom three received each dose of Dz13. All patients completed the study with no drug-related serious adverse events. No systemic Dz13 exposure was detected, c-Jun expression was reduced in the excised tumours of all nine (100%) patients, compared with baseline, and histological tumour depth had decreased in five (56%) of nine. Proportions of cells positive for caspases 3, 8, and 9 and P53 were increased, but those of cells positive for Bd-2 and MMP-9 were decreased. Infiltration by inflammatory and immune cells was stimulated. Interpretation Dz13 was safe and well tolerated after single intratumoral injections at all doses. Funding Cancer Institute NSW, Cancer Council Australia, and National Health and Medical Research Council. [ABSTRACT FROM AUTHOR]

Published
2013
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370. A plug-and-play ratiometric pH-sensing nanoprobe for high-throughput investigation of endosomal escape

Author

Hooisweng Ow, Stephen W. Morton, Daniel K. Bonner, Zhou J. Deng, Paula T. Hammond, Li Gu, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Deng, Zhou, Morton, Stephen Winford, Bonner, Daniel Kenneth, Gu, Li, and Hammond, Paula T

Subjects
Materials science, Plug and play, Endosome, Cytosolic delivery, Intracellular Space, Biophysics, Nanoprobe, Bioengineering, Nanotechnology, Endosomes, Hydrogen-Ion Concentration, Transfection, Article, Nanomaterials, Biomaterials, Mechanics of Materials, Cell Line, Tumor, Molecular Probes, Ceramics and Composites, Ph sensing, Humans, Nanoparticles, Throughput (business)
Abstract

An important aspect in the design of nanomaterials for delivery is an understanding of its uptake and ultimate release to the cytosol of target cells. Real-time chemical sensing using a nanoparticle-based platform affords exquisite insight into the trafficking of materials and their cargo into cells. This versatile and tunable technology provides a powerful tool to probe the mechanism of cellular entry and cytosolic delivery of a variety of materials, allowing for a simple and convenient means to screen materials towards efficient delivery of therapeutics such as nucleic acids.

Published
2015

371. Rational design of multistage drug delivery vehicles for pulmonary RNA interference therapy.

Author

Silva, A. Sofia, Shopsowitz, Kevin E., Correa, Santiago, Morton, Stephen W., Dreaden, Erik C., Casimiro, Teresa, Aguiar-Ricardo, Ana, and Hammond, Paula T.

Subjects
*DRUG design, *DRUG carriers, *INHALERS, *CARBON dioxide, *SMALL interfering RNA, *NON-small-cell lung carcinoma
Abstract

• siRNA nanovehicles were micronized using supercritical CO 2 -assisted spray drying. • The siRNA integrity was preserved through the micronization process. • The ultrafine dry powders showed aerodynamic diameters of 3.5 μm and FPF above 40% • The micronized siRNA powders achieved 90% of silencing for the mutant KRAS gene. • Alveolar in vivo biodistribution was achieved in healthy mice following inhalation. Small interfering RNA (siRNA) therapy has significant potential for the treatment of myriad diseases, including cancer. While intravenous routes of delivery have been found to be effective for efficient targeting to the liver, achieving high accumulations selectively in other organs, including lung tissues, can be a challenge. We demonstrate the rational design and engineering of a layer-by-layer (LbL) nanoparticle-containing aerosol that is able to achieve efficient, multistage delivery of siRNA in vitro. For the purpose, LbL nanoparticles were, for the first time, encapsulated in composite porous micro scale particles using a supercritical CO2-assisted spray drying (SASD) apparatus using chitosan as an excipient. Such particles exhibited aerodynamic properties highly favorable for pulmonary administration, and effective silencing of mutant KRAS in lung cancer cells derived from tumors of a non-small cell lung cancer (NSCLC) autochthonous model. Furthermore, efficient alveolar accumulation following inhalation in healthy mice was also observed, corroborating in vitro aerodynamic results, and opening new perspectives for further studies of effective lung therapies These results show that multistage aerosols assembled by supercritical CO 2 -assisted spray drying can enable efficient RNA interference therapy of pulmonary diseases including lung cancer. [ABSTRACT FROM AUTHOR]

Published
2020
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372. Osteotropic Therapy via Targeted Layer-by-Layer Nanoparticles

Author

Nisarg J. Shah, Paula T. Hammond, Mohiuddin A. Quadir, Zhou J. Deng, Zhiyong Poon, Stephen W. Morton, Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Morton, Stephen Winford, Shah, Nisarg J., Quadir, Mohiuddin A., Deng, Zhou J., Poon, Zhiyong, and Hammond, Paula T.

Subjects
Materials science, medicine.medical_treatment, Transplantation, Heterologous, Acrylic Resins, Biomedical Engineering, Mice, Nude, Pharmaceutical Science, Bone Neoplasms, Article, Polyethylene Glycols, Targeted therapy, Biomaterials, Mice, Cell Line, Tumor, medicine, Animals, Humans, Doxorubicin, Drug Carriers, Mice, Inbred BALB C, Osteosarcoma, Liposome, Alendronate, Bone Density Conservation Agents, Bisphosphonate, medicine.disease, Radiography, Liposomes, Immunology, Cancer research, Systemic administration, Nanoparticles, Surface modification, Drug carrier, Half-Life, medicine.drug
Abstract

Current treatment options for debilitating bone diseases such as osteosarcoma, osteoporosis, and bone metastatic cancer are suboptimal and have low efficacy. New treatment options for these pathologies require targeted therapy that maximizes exposure to the diseased tissue and minimizes off-target side effects. This work investigates an approach for generating functional and targeted drug carriers specifically for treating primary osteosarcoma, a disease in which recurrence is common and the cure rate has remained around 20%. This approach utilizes the modularity of Layer-by-Layer (LbL) assembly to generate tissue-specific drug carriers for systemic administration. This is accomplished via surface modification of drug-loaded nanoparticles with an aqueous polyelectrolyte, poly(acrylic acid) (PAA), side-chain functionalized with alendronate, a potent clinically used bisphosphonate. Nanoparticles coated with PAA-alendronate are observed to bind and internalize rapidly in human osteosarcoma 143B cells. Encapsulation of doxorubicin, a front-line chemotherapeutic, in an LbL-targeted liposome demonstrates potent toxicity in vitro. Active targeting of 143B xenografts in NCR nude mice with the LbL-targeted doxorubicin liposomes promotes enhanced, prolonged tumor accumulation and significantly improved efficacy. This report represents a tunable approach towards the synthesis of drug carriers, in which LbL enables surface modification of nanoparticles for tissue-specific targeting and treatment., National Institutes of Health (U.S.) (P30 CA14051 (NCI)), National Institutes of Health (U.S.) (5 U54 CA151884–02 (CCNE)), National Institutes of Health (U.S.) (R01 AG029601 (NIA)), National Institutes of Health (U.S.) (R01 EB010246 (NIBIB)), David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Swanson Biotechnology Center), National Science Foundation (U.S.) (Graduate Research Fellowship), National Health and Medical Research Council (Australia), Massachusetts Institute of Technology (David H. Koch (1962) Chair Professorship in Engineering)

Published
2013

373. Scalable Manufacture of Built-to-Order Nanomedicine: Spray-Assisted Layer-by-Layer Functionalization of PRINT Nanoparticles

Author

Paula T. Hammond, Zhou J. Deng, Charles J. Bowerman, Kevin S. Chu, Kevin P. Herlihy, Stephen W. Morton, Joseph M. DeSimone, Kevin E. Shopsowitz, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Morton, Stephen Winford, Shopsowitz, Kevin, Deng, Zhou J., and Hammond, Paula T.

Subjects
Fabrication, Materials science, Nanoparticle, Nanotechnology, Microscopy, Atomic Force, Article, Polylactic Acid-Polyglycolic Acid Copolymer, Cell Line, Tumor, parasitic diseases, Humans, Polylysine, General Materials Science, Lactic Acid, Thin film, Drug Carriers, Microscopy, Confocal, business.industry, Mechanical Engineering, Layer by layer, Carbocyanines, Modular design, Nanomedicine, Mechanics of Materials, Polyvinyl Alcohol, Drug delivery, Nanoparticles, Surface modification, business, Polyglycolic Acid
Abstract

Scalable methods, PRINT particle fabrication, and spray-assisted Layer-by-Layer deposition are combined to generate uniform and functional nanotechnologies with precise control over composition, size, shape, and surface functionality. A modular and tunable approach towards design of built-to-order nanoparticle systems, spray coating on PRINT particles is demonstrated to achieve technologies capable of targeted interactions with cancer cells for applications in drug delivery., National Cancer Institute (U.S.) (Center for Cancer Nanotechnology Excellence Grant 5 U54 CA151884-02), National Science Foundation (U.S.). Graduate Research Fellowship, Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship)

Published
2013

374. Fluorescent Multiblock π-Conjugated Polymer Nanoparticles for In Vivo Tumor Targeting

Author

Paula T. Hammond, Eilaf Ahmed, Stephen W. Morton, Timothy M. Swager, Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Chemistry, Ahmed, Eilaf, Morton, Stephen Winford, Hammond, Paula T., and Swager, Timothy Manning

Subjects
Tumor targeting, Materials science, Polymers, Mice, Nude, Nanoparticle, Nanotechnology, Conjugated system, Article, Mice, Folic Acid, Targeted nanoparticles, In vivo, Cell Line, Tumor, Neoplasms, Animals, Humans, Whole Body Imaging, General Materials Science, Fluorescent Dyes, chemistry.chemical_classification, Mechanical Engineering, Optical Imaging, Polymer, Fluorescence, Folic acid, chemistry, Mechanics of Materials, Biophysics, Nanoparticles
Abstract

Highly fluorescent multiblock conjugated polymer nanoparticles with folic acid surface ligands are highly effective for bioimaging and in vivo tumor targeting. The targeted nanoparticles were preferentially localized in tumor cells in vivo, thereby illustrating their potential for diagnostic and therapeutic applications., Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (W911NF-13-D-0001), UNCF-Merck Postdoctoral Fellowship, National Science Foundation (U.S.). Graduate Research Fellowship Program, Massachusetts Institute of Technology. Dr. Martin Luther King, Jr. Visiting Professors and Scholars Program (Postdoctoral Fellowship), National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051), National Cancer Institute (U.S.). Center for Cancer Nanotechnology Excellence (Grant 5 U54 CA151884-02)

Published
2013

375. Tumor-Targeted Synergistic Blockade of MAPK and PI3K from a Layer-by-Layer Nanoparticle

Author

Erik C. Dreaden, Yi Wen Kong, Ki Young Choi, Kasper Renggli, Michael B. Yaffe, Santiago Correa, Ronny Drapkin, Stephen W. Morton, Paula T. Hammond, Kevin E. Shopsowitz, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Dreaden, Erik, Kong, Yi Wen, Morton, Stephen Winford, Correa Echavarria, Santiago, Choi, Ki Young, Shopsowitz, Kevin, Renggli-Frey, Kasper, Yaffe, Michael B, and Hammond, Paula T

Subjects
MAPK/ERK pathway, Cancer Research, medicine.medical_treatment, Antineoplastic Agents, Tumor initiation, Pharmacology, Article, Targeted therapy, Mice, Phosphatidylinositol 3-Kinases, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Protein Kinase Inhibitors, PI3K/AKT/mTOR pathway, Phosphoinositide-3 Kinase Inhibitors, Mitogen-Activated Protein Kinase Kinases, Kinase, Chemistry, Drug Synergism, Xenograft Model Antitumor Assays, 3. Good health, Disease Models, Animal, Cell killing, Oncology, Selumetinib, Nanoparticles, Female, Signal Transduction
Abstract

Purpose: Cross-talk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is critical for tumor initiation, maintenance, and adaptive resistance to targeted therapy in a variety of solid tumors. Combined blockade of these pathways—horizontal blockade—is a promising therapeutic strategy; however, compounded dose-limiting toxicity of free small molecule inhibitor combinations is a significant barrier to its clinical application. Experimental Design: AZD6244 (selumetinib), an allosteric inhibitor of Mek1/2, and PX-866, a covalent inhibitor of PI3K, were co-encapsulated in a tumor-targeting nanoscale drug formulation—layer-by-layer (LbL) nanoparticles. Structure, size, and surface charge of the nanoscale formulations were characterized, in addition to in vitro cell entry, synergistic cell killing, and combined signal blockade. In vivo tumor targeting and therapy was investigated in breast tumor xenograft-bearing NCR nude mice by live animal fluorescence/bioluminescence imaging, Western blotting, serum cytokine analysis, and immunohistochemistry. Results: Combined MAPK and PI3K axis blockade from the nanoscale formulations (160 ± 20 nm, −40 ± 1 mV) was synergistically toxic toward triple-negative breast (MDA-MB-231) and RAS-mutant lung tumor cells (KP7B) in vitro, effects that were further enhanced upon encapsulation. In vivo, systemically administered LbL nanoparticles preferentially targeted subcutaneous MDA-MB-231 tumor xenografts, simultaneously blocked tumor-specific phosphorylation of the terminal kinases Erk and Akt, and elicited significant disease stabilization in the absence of dose-limiting hepatotoxic effects observed from the free drug combination. Mice receiving untargeted, but dual drug-loaded nanoparticles exhibited progressive disease. Conclusions: Tumor-targeting nanoscale drug formulations could provide a more safe and effective means to synergistically block MAPK and PI3K in the clinic., United States. Department of Defense (OCRP Teal Innovator Award), National Institutes of Health (U.S.) (Grant NIBIB 1F32EB017614-02), Misrock Foundation, National Science Foundation (U.S.), Swiss National Science Foundation, David H. Koch Institute for Integrative Cancer Research at MIT (Support Grant P30-CA14051), National Cancer Institute (U.S.), National Science Foundation (U.S.) (Massachusetts Institute of Technology. Materials Research Science and Engineering Center. Shared Experimental Facilities Grant DMR-0819762), Breast Cancer Alliance (Exceptional Project Grant)

Published
2015

376. Composite RNAi-Microsponges Form through Self-Assembly of the Organic and Inorganic Products of Transcription

Author

Zhou J. Deng, Stephen W. Morton, Young Hoon Roh, Kevin E. Shopsowitz, Paula T. Hammond, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Shopsowitz, Kevin, Roh, Young Hoon, Deng, Zhou J., Morton, Stephen Winford, and Hammond, Paula T.

Subjects
Materials science, Transcription, Genetic, Concatemer, Nanoparticle, Magnesium Compounds, Metal Nanoparticles, Article, Biomaterials, chemistry.chemical_compound, RNA interference, Transcription (biology), Nanotechnology, Polyethyleneimine, General Materials Science, fungi, RNA, Spectrometry, X-Ray Emission, General Chemistry, DNA, Diphosphates, chemistry, Biochemistry, Rolling circle replication, Biophysics, Nucleic acid, Microscopy, Electron, Scanning, Nucleic Acid Conformation, RNA Interference, Biotechnology
Abstract

Inorganic nanostructures have been used extensively to package nucleic acids into forms useful for therapeutic applications. Here we report that the two products of transcription, RNA and inorganic pyrophosphate, can self-assemble to form composite microsponge structures composed of nanocrystalline magnesium pyrophosphate sheets (Mg[subscript 2]P[subscript 2]O[subscript 7]•3.5H[subscript 2]O) with RNA adsorbed to their surfaces. The microsponge particles contain high loadings of RNA (15–21 wt.%) that are protected from degradation and can be obtained through a rolling circle mechanism as large concatemers capable of mediating RNAi. The morphology of the RNAi microsponges is influenced by the time-course of the transcription reaction and interactions between RNA and the inorganic phase. Previous work demonstrated that polycations can be used to condense RNAi microsponges into nanoparticles capable of efficient transfection with low toxicity. Our new findings suggest that the formation of these nanoparticles is mediated by the gradual dissolution of magnesium pyrophosphate that occurs in the presence of polycations. The simple one-pot approach for assembling RNAi microsponges along with their unique properties could make them useful for RNA-based therapeutics., National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051), National Cancer Institute (U.S.) (Center for Cancer Nanotechnology Excellence Grant 5 U54 CA151884-02), Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship), National Health and Medical Research Council (Australia) (CJ Martin Fellowship), National Science Foundation (U.S.). Graduate Research Fellowship

Published
2014

377. A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways

Author

Paula T. Hammond, Nisarg J. Shah, Kevin E. Shopsowitz, Michael J. Lee, Elise Siouve, Michael B. Yaffe, Stephen W. Morton, Erik C. Dreaden, Zhou J. Deng, Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Morton, Stephen Winford, Lee, Michael J., Deng, Zhou J., Dreaden, Erik Christopher, Siouve, Elise, Shopsowitz, Kevin, Shah, Nisarg J., Yaffe, Michael B., and Hammond, Paula T.

Subjects
Pharmacology, Biochemistry, Erlotinib Hydrochloride, Mice, Antineoplastic Combined Chemotherapy Protocols, medicine, Animals, Doxorubicin, Epidermal growth factor receptor, Molecular Biology, Liposome, Drug Carriers, Mice, Inbred BALB C, biology, Chemistry, Combination chemotherapy, Cell Biology, Neoplasms, Experimental, Drug delivery, Liposomes, Cancer research, biology.protein, Quinazolines, Nanoparticles, Female, Erlotinib, Drug carrier, medicine.drug
Abstract

Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network rewiring into clinical practice is the design of optimal drug delivery systems. We report the generation of a nanoparticle delivery vehicle that contained more than one therapeutic agent and produced a controlled sequence of drug release. Liposomes, representing the first clinically approved nanomedicine systems, are well-characterized, simple, and versatile platforms for the manufacture of functional and tunable drug carriers. Using the hydrophobic and hydrophilic compartments of liposomes, we effectively incorporated both hydrophobic (erlotinib) and hydrophilic (doxorubicin) small molecules, through which we achieved the desired time sequence of drug release. We also coated the liposomes with folate to facilitate targeting to cancer cells. When compared to the time-staggered application of individual drugs, staggered release from tumor-targeted single liposomal particles enhanced dynamic rewiring of apoptotic signaling pathways, resulting in improved tumor cell killing in culture and tumor shrinkage in animal models., National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. P30-CA14051), National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. U54-CA151884), National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. U54-CA112967), National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. R01-ES015339), National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. R21-ES020466), Breast Cancer Alliance (Exceptional Project Grant), National Science Foundation (U.S.) (Graduate Research Fellowship), National Health and Medical Research Council (Australia) (CJ Martin Fellowship), National Institutes of Health (U.S.) (Kirschstein NRSA 1F32EB017614-01), Natural Sciences and Engineering Research Council of Canada (post-doctoral fellowship), Kathy and Curt Marble Cancer Research Fund, David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Frontier Research Program)

Published
2014

378. Redox-responsive branched-bottlebrush polymers for in vivo MRI and fluorescence imaging

Author

Ying Wang, Jessica R. McCombs, Paula T. Hammond, Erik C. Dreaden, Stephen W. Morton, Michael D. Boska, Jeremiah A. Johnson, M. Francesca Ottaviani, Andrzej Rajca, Molly A. Sowers, Joseph T. Paletta, Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Chemistry, Koch Institute for Integrative Cancer Research at MIT, Sowers, Molly A., McCombs, Jessica R., Morton, Stephen Winford, Dreaden, Erik Christopher, Hammond, Paula T., and Johnson, Jeremiah A.

Subjects
Nitroxide mediated radical polymerization, Fluorescence-lifetime imaging microscopy, Polymers, Contrast Media, General Physics and Astronomy, Ascorbic Acid, Article, Fluorescence, General Biochemistry, Genetics and Molecular Biology, Mice, In vivo, medicine, Native state, Animals, Humans, Mice, Inbred BALB C, Multidisciplinary, medicine.diagnostic_test, Chemistry, Magnetic resonance imaging, General Chemistry, Ascorbic acid, Magnetic Resonance Imaging, Molecular Imaging, Biochemistry, Biophysics, Female, Nitrogen Oxides, Molecular imaging, Oxidation-Reduction, HeLa Cells
Abstract

Stimuli-responsive multimodality imaging agents have broad potential in medical diagnostics. Herein, we report the development of a new class of branched-bottlebrush polymer dual-modality organic radical contrast agents—ORCAFluors—for combined magnetic resonance and near-infrared fluorescence imaging in vivo. These nitroxide radical-based nanostructures have longitudinal and transverse relaxation times that are on par with commonly used heavy-metal-based magnetic resonance imaging (MRI) contrast agents. Furthermore, these materials display a unique compensatory redox response: fluorescence is partially quenched by surrounding nitroxides in the native state; exposure to ​ascorbate or ​ascorbate/​glutathione leads to nitroxide reduction and a concomitant 2- to 3.5-fold increase in fluorescence emission. This behaviour enables correlation of MRI contrast, fluorescence intensity and spin concentration with tissues known to possess high concentrations of ​ascorbate in mice. Our in vitro and in vivo results, along with our modular synthetic approach, make ORCAFluors a promising new platform for multimodality molecular imaging., Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Research Support Committee, Lincoln Laboratory, National Institutes of Health (U.S.) (NIBIB 1R21EB018529-01A1), National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F32EB017614-01), United States. Dept. of Defense. Ovarian Cancer Research Program (Teal Innovator Award), National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)

Published
2014

379. FRET-enabled biological characterization of polymeric micelles

Author

Paula T. Hammond, Stephen W. Morton, Xiaoyong Zhao, Mohiuddin A. Quadir, Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Morton, Stephen Winford, Zhao, Xiaoyong, Quadir, Mohiuddin Abdul, and Hammond, Paula T

Subjects
Materials science, Light, Polymers, Biophysics, Mice, Nude, Bioengineering, Nanotechnology, Micelle, Article, Biomaterials, Mice, In vivo, Scattering radiation, Fluorescence Resonance Energy Transfer, Animals, Scattering, Radiation, Tissue Distribution, Micelles, Mice nude, Fluorescent Dyes, Mice, Inbred BALB C, Polymeric micelles, Material system, Characterization (materials science), Förster resonance energy transfer, Mechanics of Materials, Ceramics and Composites, Female
Abstract

Translation of micelles from the laboratory to the clinic is limited by a poor understanding of their in vivo fate following administration. In this paper, we establish a robust approach to real-time monitoring of the in vivo stability of micelles using Förster Resonance Energy Transfer (FRET). This characterization method allows for exquisite insight into the fate of micellar constituents, affording the capabilities to rapidly and efficiently evaluate a library of synthetically derived micellar systems as new therapeutic platforms in vivo. FRET-enabled biological characterization further holds potential to tailor material systems being uniquely investigated across the delivery community towards the next generation of stable therapeutics for disease management., National Cancer Institute (U.S.) (P30-CA14051), National Institutes of Health (U.S.) (5 U54 CA151884-02)

Published
2013

380. Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER)

Author

Douglas J. Francis, Colin N. Chesterman, Paula T. Hammond, Jason Z. Deng, Levon M. Khachigian, Diona L. Damian, Ross StC Barnetson, Carlos China, Fergal J. Moloney, Benafsha Yosufi, Eun-Ae Cho, Stephen W. Morton, Gary M. Halliday, Mark J. Raftery, Hendrik-Tobias Arkenau, Annie Au-Yeung, Richard A. Scolyer, Hong Cai, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Deng, Jason Z., Morton, Stephen Winford, and Hammond, Paula T.

Subjects
Male, medicine.medical_specialty, Pathology, Skin Neoplasms, Maximum Tolerated Dose, Angiogenesis, Antineoplastic Agents, Injections, Intralesional, medicine.disease_cause, Gastroenterology, Immune system, Internal medicine, Biopsy, Carcinoma, Medicine, Humans, Adverse effect, medicine.diagnostic_test, business.industry, General Medicine, DNA, Catalytic, Middle Aged, medicine.disease, Treatment Outcome, Tolerability, Carcinoma, Basal Cell, Female, business, Carcinogenesis, Dz13
Abstract

Background The nuclear transcription factor c-Jun is preferentially expressed in basal-cell carcinoma. Dz13 is a deoxyribozyme that targets JUN messenger RNA and has inhibited the growth of a range of tumours in mice. We did a phase 1 study to assess safety and tolerability in human beings. Methods Adults with nodular basal-cell carcinoma were recruited from Royal Prince Alfred Hospital, Sydney, Australia, between September, 2010, and October, 2011. Patients were assigned to receive one intratumoral injected dose of 10, 30, or 100 μg Dz13, in a 50 μL volume of lipid carrier, and were assessed for adverse effects in the first 24 h then at 7, 14, and 28 days after injection. Treated tumours were surgically excised 14 days after injection and compared with the baseline biopsy samples for expression of c-Jun and tumorigenesis markers. Findings Nine patients were recruited, of whom three received each dose of Dz13. All patients completed the study with no drug-related serious adverse events. No systemic Dz13 exposure was detected. c-Jun expression was reduced in the excised tumours of all nine (100%) patients, compared with baseline, and histological tumour depth had decreased in five (56%) of nine. Proportions of cells positive for caspases 3, 8, and 9 and P53 were increased, but those of cells positive for Bcl-2 and MMP-9 were decreased. Infiltration by inflammatory and immune cells was stimulated. Interpretation Dz13 was safe and well tolerated after single intratumoral injections at all doses., Cancer Institute NSW, Cancer Council Australia, National Health and Medical Research Council (Australia)

Published
2013

381. Inhibition of vein graft stenosis with a c-jun targeting DNAzyme in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)

Author

Paula T. Hammond, Ravinay Bhindi, Zhou J. Deng, Levon M. Khachigian, Yue Li, Stephen W. Morton, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Deng, Zhou J., Morton, Stephen Winford, and Hammond, Paula T.

Subjects
Graft Rejection, Male, Neointima, medicine.medical_specialty, Intimal hyperplasia, Chemistry, Pharmaceutical, Constriction, Pathologic, Pharmacology, Article, Fatty Acids, Monounsaturated, Cations, Jugular vein, Animals, Medicine, Cells, Cultured, Liposome, business.industry, Phosphatidylethanolamines, JNK Mitogen-Activated Protein Kinases, technology, industry, and agriculture, DNA, Catalytic, Hyperplasia, medicine.disease, Surgery, Quaternary Ammonium Compounds, Transplantation, Stenosis, Liposomes, Vascular Grafting, Rabbits, Jugular Veins, Cardiology and Cardiovascular Medicine, business, Dz13
Abstract

Background/objectives Coronary artery bypass grafting (CABG) is among the most commonly performed heart surgical procedures. Saphenous vein graft failure due to stenosis impedes the longer-term success of CABG. A key cellular event in the process of vein graft stenosis is smooth muscle cell hyperplasia. In this study, we evaluated the effect of a DNAzyme (Dz13) targeting the transcription factor c-Jun in a rabbit model of vein graft stenosis in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Dz13 in DOTAP/DOPE has undergone preclinical toxicological testing, and a Phase I clinical trial we recently conducted in basal cell carcinoma cancer patients demonstrates that it is safe and well tolerated after local administration. Methods Effects of Dz13 in a formulation containing DOTAP/DOPE on smooth muscle cell (SMC) growth and c-Jun expression were assessed. Dz13 transfection was determined by cellular uptake of carboxyfluorescein-labeled Dz13. Autologous jugular vein to carotid artery transplantation was performed in New Zealand White rabbits to investigate the effect of the Dz13 in DOTAP/DOPE formulation on intimal hyperplasia. Results Dz13/DOTAP/DOPE reduced SMC proliferation and c-Jun protein expression in vitro compared with an impotent form of Dz13 bearing a point mutation in its catalytic domain (Dz13.G > C). The Dz13(500 μg)/DOTAP/DOPE formed lipoplexes that were colloidally stable for up to 1 h on ice (0 °C) and 30 min at 37 °C, allowing sufficient uptake by the veins. Dz13 (500 μg) inhibited neointima formation 28 d after end-to-side transplantation. Conclusions This formulation applied to veins prior to transplantation may potentially be useful in efforts to reduce graft failure., National Health and Medical Research Council (Australia), National Heart Foundation (Australia), Heart Research Australia

Published
2013

382. The Architecture and Biological Performance of Drug-Loaded LbL Nanoparticles

Author

Paula T. Hammond, Stephen W. Morton, Zhiyong Poon, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Morton, Stephen Winford, Poon, Zhiyong, and Hammond, Paula T.

Subjects
Drug, Biodistribution, Materials science, media_common.quotation_subject, Biophysics, Nanoparticle, Bioengineering, Nanotechnology, Article, Biomaterials, chemistry.chemical_compound, Mice, Drug Delivery Systems, Pharmacokinetics, Animals, media_common, Drug Carriers, Mice, Inbred BALB C, PLGA, Kinetics, chemistry, Targeted drug delivery, Mechanics of Materials, Doxorubicin, Drug delivery, Ceramics and Composites, Nanoparticles, Female, Drug carrier, Biomedical engineering
Abstract

Layer-by-Layer (LbL) nanoparticles are an emerging class of therapeutic carriers that afford precise control over key design parameters that facilitate improved drug and carrier pharmacokinetics, and enhanced molecular-targeting capabilities. This paper advances the development of these systems by establishing them as drug carriers, with the means to control drug release in a systemic environment and retard particle clearance from circulation, promoting improved biodistribution of the drug-containing system. Using dual-fluorescent tracking in vivo, this work establishes a robust means of screening libraries of LbL systems generated, affording simultaneous resolution over persistence and biodistribution of both the drug and carrier following systemic administration of a single particle formulation. Employing a PLGA drug-containing core as a substrate for LbL deposition, a range of coated systems were fabricated to investigate the abilities of these films to stabilize drug for delivery as well as to improve the pharmacokinetics of both the drug and carrier. Significant reductions in liver accumulation were observed for different formulations of the layered architectures within the first 30 min of systemic circulation. LbL architectures diminished liver localization of the surrogate drug, cardiogreen, by 10–25% ID/g relative to native PLGA nanoparticles and modulated carrier accumulation in the liver >50% ID/g. Further, enhanced persistence of the drug was observed with the coated systems, significantly increasing the drug half-life from 2 to 3 min for free drug and 1.87 h for the uncoated core to 4.17 h and 4.54 h for the coated systems. These systems provide an exciting, modular platform that improves the pharmacokinetic properties of the therapeutic, reduces bolus release of drug from nanoparticles, and enhances the safety and circulation half-life of the drug in vivo, proving them to be highly clinically-relevant and a promising approach for future development of molecularly-targeted and combination therapeutics., Janssen Pharmaceutical Ltd. (TRANSCEND Partnership), National Science Foundation (U.S.). Graduate Research Fellowship

Published
2013

383. Beyond building back better: imagining a future for human and planetary health.

Author

de León EA, Shriwise A, Tomson G, Morton S, Lemos DS, Menne B, and Dooris M

Subjects
Forecasting, Humans, Sustainable Development, COVID-19 epidemiology, Global Health trends, Pandemics
Abstract

COVID-19 is disrupting and transforming the world. We argue that transformations catalysed by this pandemic should be used to improve human and planetary health and wellbeing. This paradigm shift requires decision makers and policy makers to go beyond building back better, by nesting the economic domain of sustainable development within social and environmental domains. Drawing on the engage, assess, align, accelerate, and account (E4As) approach to implementing the 2030 Agenda for Sustainable Development, we explore the implications of this kind of radical transformative change, focusing particularly on the role of the health sector. We conclude that a recovery and transition from the COVID-19 pandemic that delivers the future humanity wants and needs requires more than a technical understanding of the transformation at hand. It also requires commitment and courage from leaders and policy makers to challenge dominant constructs and to work towards a truly thriving, equitable, and sustainable future to create a world where economic development is not an end goal itself, but a means to secure the health and wellbeing of people and the planet., Competing Interests: Declaration of interests EAdL reports grants from Bundesgesundheitsministeriums fur Gesundheit, Germany, outside the submitted work. AS reports grants from the European Research Council, during the conduct of the study; personal fees from the Sustainable Development and Health Programme, WHO Regional Office for Europe, and the Office for Investment for Health and Development, WHO Regional Office for Europe, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Published
2021
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384. Sustainable Development Goals (SDGs), and their implementation: A national global framework for health, development and equity needs a systems approach at every level.

Author

Morton S, Pencheon D, and Squires N

Subjects
Goals, Health Equity, Humans, Program Development, Quality of Life, Social Responsibility, Systems Analysis, United Nations, Conservation of Natural Resources, Global Health
Abstract

Introduction: The Sustainable Development Goals (SDGs) are a set of global goals for fair and sustainable health at every level: from planetary biosphere to local community. The aim is to end poverty, protect the planet and ensure that all people enjoy peace and prosperity, now and in the future., Sources of Data: The UN has established web-sites to inform the implementation of the SDGs and an Inter-Agency and Expert Group on an Indicator Framework. We have searched for independent commentaries and analysis., Areas of Agreement: The goals represent a framework that is scientifically robust, and widely intuitive intended to build upon the progress established by the Millennium Development Goals (MDGs). There is a need for system wide strategic planning to integrate the economic, social and environmental dimensions into policy and actions., Areas of Controversy: Many countries have yet to understand the difference between the MDGs and the SDGs, particularly their universality, the huge potential of new data methods to help with their implementation, and the systems thinking that is needed to deliver the vision. The danger is that individual goals may be prioritized without an understanding of the potential positive interactions between goals., Growing Points: There is an increasing understanding that sustainable development needs a paradigm shift in our understanding of the interaction between the real economy and quality of life. There would be many social, environmental and economic benefits in changing our current model., Areas Timely for Developing Research: We need to develop systems wide understanding of what supports a healthy environment and the art and science of making change., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Published
2017
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385. Ligand-decorated click polypeptide derived nanoparticles for targeted drug delivery applications.

Author

Quadir MA, Morton SW, Mensah LB, Shopsowitz K, Dobbelaar J, Effenberger N, and Hammond PT

Subjects
Animals, Cell Line, Tumor, Drug Carriers, Folic Acid, Humans, Mice, Polymers, Antibiotics, Antineoplastic administration & dosage, Doxorubicin administration & dosage, Drug Delivery Systems, Nanoparticles, Peptides
Abstract

A ligand decorated, synthetic polypeptide block copolymer platform with environment-responsive capabilities was designed. We evaluated the potential of this system to function as a polymersome for targeted-delivery of a systemic chemotherapy to tumors. Our system employed click chemistry to provide a pH-responsive polypeptide block that drives nanoparticle assembly, and a ligand (folic acid) conjugated PEG block that targets folate-receptor over-expressing cancer cells. These nanocarriers were found to encapsulate a high loading of conventional chemotherapeutics (e.g. doxorubicin at physiological pH) and release the active therapeutic at lysosomal pH upon cellular uptake. The presence of folic acid on the nanoparticle surface facilitated their active accumulation in folate-receptor-overexpressing cancer cells (KB), compared to untargeted carriers. Folate-targeted nanoparticles loaded with doxorubicin also showed enhanced tumor accumulation in folate-receptor positive KB xenografts, resulting in the suppression of tumor growth in an in vivo hind flank xenograft mouse model., (Copyright © 2017. Published by Elsevier Inc.)

Published
2017
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