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

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 FundDavid H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Frontier Research Program

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

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 FoundationNational Science Foundation (U.S.)Swiss National Science FoundationDavid 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

Evidence for insertional codemixing: mixed compounds and French nominal groups in Brussels Dutch

In this paper we analyse mixed compounds, such as legume+winkel ‘vegetable shop, greengrocery’ and winter+paletot ‘winter coat’ which contain a French and a Dutch element, and French nominal groups, such as carte d’identité ‘identity card’, and journal parlé ‘radio news’, which bilingual speakers from Brussels frequently insert into Brussels Dutch utterances. Using Muysken’s (2000) typology of bilingual speech, we claim that the mixed compounds and the nominal groups display the characteristics of insertional code-mixing. In addition, some evidence for the existence of a continuum between borrowing and code-switching can be obtained from these examples. As the multimorphemic units that are inserted into Dutch are neither single words, nor full constituents, their status in the lexicon raises interesting issues for researchers interested in the interface between syntax and the lexicon (see also Backus 2003). We try to argue that nominal groups such as carte d’identité and journal parlé are probably best seen as lexical templates or constructional idioms (Booij, 2002b). The insertion of French constructional idioms in Brussels Dutch represents an innovation in the lexical patterns that are available to speakers of this language, which is highly relevant for theories of language change

Implementing OPCAT through prison monitoring: the relevance of rehabilitation

The purposes of imprisonment are always debated but it is expected that people leaving prison are changed such that they do not reoffend: that they are rehabilitated. Indeed the United Nations International Covenant on Civil and Political Rights spells out rehabilitation as the 'essential aim' of imprisonment. Rehabilitation in the prison context may involve (for example) provision of education, training, work experience, addressing offending behaviours, and maintaining family contacts. Yet Australian prison statistics show that our prisons are not proving rehabilitative, and specifically are not preventing reoffending. Ratification of the Optional Protocol to the Convention Against Torture and other Cruel, Inhuman or Degrading Treatment or Punishment (OPCAT) requires establishment of comprehensive monitoring frameworks to prevent 'torture and cruel, inhuman and degrading treatment' in places of detention. This article examines the scope for the inclusion of rehabilitation in prison monitoring under OPCAT. It makes the argument that the rehabilitative orientation of a prison is linked to the risk of cruel, inhuman and degrading treatment, and that prevention of such treatment requires attention to whether the prison is 'rehabilitative'. It concludes that Australian jurisdictions should ensure the widest scope for OPCAT monitoring to support the rehabilitative goal of Australian prisons

Health system dynamics analysis of eyecare services in Trinidad and Tobago and progress towards Vision 2020 Goals

Avoidable blindness is an important global public health concern. This study aimed to assess Trinidad and Tobago's progress towards achieving the Pan American Health Organization, 'Strategic Framework for Vision 2020: The Right to Sight-Caribbean Region,' indicators through comprehensive review of the eyecare system, in order to facilitate health system priority setting. We administered structured surveys to six stakeholder groups, including eyecare providers, patients and older adult participants in the National Eye Survey of Trinidad and Tobago. We reviewed reports, registers and policy documents, and used a health system dynamics framework to synthesize data. In 2014, the population of 1.3 million were served by a pluralistic eyecare system, which had achieved 14 out of 27 Strategic Framework indicators. The Government provided free primary, secondary and emergency eyecare services, through 108 health centres and 5 hospitals (0.26 ophthalmologists and 1.32 ophthalmologists-in-training per 50 000 population). Private sector optometrists (4.37 per 50 000 population), and ophthalmologists (0.93 per 50 000 population) provided 80% of all eyecare. Only 19.3% of the adult population had private health insurance, revealing significant out-of-pocket expenditure. We identified potential weaknesses in the eyecare system where investment might reduce avoidable blindness. These included a need for more ophthalmic equipment and maintenance in the public sector, national screening programmes for diabetic retinopathy, retinopathy of prematurity and neonatal eye defects, and pathways to ensure timely and equitable access to subspecialized surgery. Eyecare for older adults was responsible for an estimated 9.5% (US$22.6 million) of annual health expenditure. This study used the health system dynamics framework and new data to identify priorities for eyecare system strengthening. We recommend this approach for exploring potential health system barriers to addressing avoidable blindness, and other important public health problems

Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles

Effective treatment for glioblastoma (GBM) is limited by the presence of the blood–brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 leads to increased DNA damage and apoptosis that correlates with a 1.5- to 2-fold decrease in tumor burden and corresponding increase in survival compared to equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also show protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this nanoscale platform to deliver novel combination therapies to gliomas and other central nervous system tumors