169 research outputs found
Nanotechnology-mediated targeting of tumor angiogenesis
No full textAbstract Angiogenesis is disregulated in many diseased states, most notably in cancer. An emerging strategy for the development of therapies targeting tumor-associated angiogenesis is to harness the potential of nanotechnology to improve the pharmacology of chemotherapeutics, including anti-angiogenic agents. Nanoparticles confer several advantages over that of free drugs, including their capability to carry high payloads of therapeutic agents, confer increased half-life and reduced toxicity to the drugs, and provide means for selective targeting of the tumor tissue and vasculature. The plethora of nanovectors available, in addition to the various methods available to combine them with anti-angiogenic drugs, allows researchers to fine-tune the pharmacological profile of the drugs ad infinitum. Use of nanovectors has also opened up novel avenues for non-invasive imaging of tumor angiogenesis. Herein, we review the types of nanovector and therapeutic/diagnostic agent combinations used in targeting tumor angiogenesis.National Institutes of Health (U.S) (1R01CA135242-01A2)United States. Dept. of Defense (BCRP Era of Hope Scholar Award W81XWH-07-1-0482)United States. Dept. of Defense (BCRP Innovator Collaborative Award
Mechanistic studies of Gemcitabine-loaded nanoplatforms in resistant pancreatic cancer cells
No full textBackground: Pancreatic cancer remains the deadliest of all cancers, with a mortality rate of 91%. Gemcitabine is considered the gold chemotherapeutic standard, but only marginally improves life-span due to its chemical instability and low cell penetrance. A new paradigm to improve Gemcitabine’s therapeutic index is to administer it in nanoparticles, which favour its delivery to cells when under 500 nm in diameter. Although promising, this approach still suffers from major limitations, as the choice of nanovector used as well as its effects on Gemcitabine intracellular trafficking inside pancreatic cancer cells remain unknown. A proper elucidation of these mechanisms would allow for the elaboration of better strategies to engineer more potent Gemcitabine nanotherapeutics against pancreatic cancer. Methods: Gemcitabine was encapsulated in two types of commonly used nanovectors, namely poly(lactic-co-glycolic acid) (PLGA) and cholesterol-based liposomes, and their physico-chemical parameters assessed in vitro. Their mechanisms of action in human pancreatic cells were compared with those of the free drug, and with each others, using cytotoxity, apoptosis and ultrastructural analyses. Results: Physico-chemical analyses of both drugs showed high loading efficiencies and sizes of less than 200 nm, as assessed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), with a drug release profile of at least one week. These profiles translated to significant cytotoxicity and apoptosis, as well as distinct intracellular trafficking mechanisms, which were most pronounced in the case of PLGem showing significant mitochondrial, cytosolic and endoplasmic reticulum stresses. Conclusions: Our study demonstrates how the choice of nanovector affects the mechanisms of drug action and is a crucial determinant of Gemcitabine intracellular trafficking and potency in pancreatic cancer settings.Canadian Institutes of Health Research (Fellowship)Breast Cancer Research Program (U.S.) (BCRP Era of Hope Scholar Award)Mary Kay Foundation (Mary Kay Ash Charitable Foundation Grant)Charles A. King Trust (Postdoctoral Research Fellowship Program
Insulin-Like Growth Factors Promote Vasculogenesis in Embryonic Stem Cells
No full textThe ability of embryonic stem cells to differentiate into endothelium and form functional blood vessels has been well established and can potentially be harnessed for therapeutic angiogenesis. However, after almost two decades of investigation in this field, limited knowledge exists for directing endothelial differentiation. A better understanding of the cellular mechanisms regulating vasculogenesis is required for the development of embryonic stem cell-based models and therapies. In this study, we elucidated the mechanistic role of insulin-like growth factors (IGF1 and 2) and IGF receptors (IGFR1 and 2) in endothelial differentiation using an embryonic stem cell embryoid body model. Both IGF1 or IGF2 predisposed embryonic stem to differentiate towards a mesodermal lineage, the endothelial precursor germ layer, as well as increased the generation of significantly more endothelial cells at later stages. Inhibition of IGFR1 signaling using neutralizing antibody or a pharmacological inhibitor, picropodophyllin, significantly reduced IGF-induced mesoderm and endothelial precursor cell formation. We confirmed that IGF-IGFR1 signaling stabilizes HIF1α and leads to up-regulation of VEGF during vasculogenesis in embryoid bodies. Understanding the mechanisms that are critical for vasculogenesis in various models will bring us one step closer to enabling cell based therapies for neovascularization.United States. Dept. of Defense. Hope Scholar Award (W81XWH-07-1-0482)American Heart Association. Scientist Development Gran
Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
No full textUnderstanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition towards a favoured transient CD44[superscript Hi]CD24[superscript Hi] chemotherapy-tolerant state. This state is associated with a clustering of CD44 and CD24 in membrane lipid rafts, leading to the activation of Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) and suppression of apoptosis. The use of pharmacological inhibitors of SFK/Hck in combination with taxanes in a temporally constrained manner, where the kinase inhibitor is administered post taxane treatment, but not when co-administered, markedly sensitizes the chemotolerant cells to the chemotherapy. This approach of harnessing chemotherapy-induced phenotypic cell state transition for improving antitumour outcome could emerge as a translational strategy for the management of cancer.United States. Dept. of Defense (Breast Cancer Research Program (U.S.) Collaborative Innovator Grant W81XWH-09-1-0700)National Institutes of Health (U.S.) (RO1 1R01CA135242)United States. Dept. of Defense (Breakthrough Award BC132168)American Lung Association (Innovation Award LCD-259932-N)Indo-US Science and Technology Forum (Indo-US Joint Center Grant)American Cancer Society (Postdoctoral Fellowship 122854-PF-12-226-01-CDD
Drug-induced reactive oxygen species (ROS) rely on cell membrane properties to exert anticancer effects
No full textPharmacological concentrations of small molecule natural products, such as ascorbic acid, have exhibited distinct cell killing outcomes between cancer and normal cells whereby cancer cells undergo apoptosis or necrosis while normal cells are not adversely affected. Here, we develop a mathematical model for ascorbic acid that can be utilized as a tool to understand the dynamics of reactive oxygen species (ROS) induced cell death. We determine that not only do endogenous antioxidants such as catalase contribute to ROS-induced cell death, but also cell membrane properties play a critical role in the efficacy of ROS as a cytotoxic mechanism against cancer cells vs. normal cells. Using in vitro assays with breast cancer cells, we have confirmed that cell membrane properties are essential for ROS, in the form of hydrogen peroxide (H[subscript 2]O[subscript 2]), to induce cell death. Interestingly, we did not observe any correlation between intracellular H[subscript 2]O[subscript 2] and cell survival, suggesting that cell death by H[subscript 2]O[subscript 2] is triggered by interaction with the cell membrane and not necessarily due to intracellular levels of H[subscript 2]O[subscript 2]. These findings provide a putative mechanistic explanation for the efficacy and selectivity of therapies such as ascorbic acid that rely on ROS-induced cell death for their anti-tumor properties.Natural Sciences and Engineering Research Council of Canada (NSERC discovery grant)Natural Sciences and Engineering Research Council of Canada (NSERC/CIHR Collaborative Health Research grant
DNA double strand break and repair: mechanisms and involvement in human cancer
No full textThe most frequent damage on a cell is the DNA double-strand break (DSB). This is sensed and repaired by normal cellular DSB response pathways. Depending on the phase of the cell at which the DSB is sensed, there are two different pathways for the repair of this lesion, the non homologous end joining (NHEJ) repair and the homologous recombination (HR) repair. Defects in these sensing and repair pathways leads to no repair or inappropriate/abnormal repair. This causes genome instability that results in different disorders among which cancer is the most significant one. We describe how cells repair DSB and the relationship between the defects in this repair system and cancer
DNA double strand break and repair: mechanisms and involvement in human cancer
No full textThe most frequent damage on a cell is the DNA double-strand break (DSB). This is sensed and repaired by normal cellular DSB response pathways. Depending on the phase of the cell at which the DSB is sensed, there are two different pathways for the repair of this lesion, the non homologous end joining (NHEJ) repair and the homologous recombination (HR) repair. Defects in these sensing and repair pathways leads to no repair or inappropriate/abnormal repair. This causes genome instability that results in different disorders among which cancer is the most significant one. We describe how cells repair DSB and the relationship between the defects in this repair system and cancer
Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity
No full textNanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O→Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC50 values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-RasLSL/+/Ptenfl/fl ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics.United States. Dept. of Defense (Breast Cancer Research Program Era of Hope Scholar Award W81XWH-07-1- 0482)United States. Dept. of Defense (Collaborative Innovator Grant)National Institutes of Health (U.S.) (Grant R01 CA135242-01A2)Medical Foundation, inc. (Charles A. King Trust Postdoctoral Research Fellowship Program)United States. Dept. of Defense (Breast Cancer Research Program Postdoctoral Fellowship Award)Dana-Farber/Harvard Cancer Center (Ovarian Cancer SPORE award)Canary FoundationMary Kay FoundationV Foundation for Cancer Researc
Abstract 4610: Towards understanding the cellular uptake patterns of nano-particles among different immune cell lines
No full textAbstract
Today with the privilege of being able to synthesize extremely small particles in the nano-range and make use of nanoscience and nanotechnology, we can reach superior properties than the bulk scale. Nanoparticles have their own physicochemical properties that make them promising in the field of cancer immunotherapy in form of drug delivery, diagnostic and theranostic modalities. Manipulation of the immune response by therapeutic intervention is becoming of great interest owing to the significant role of immunity in the general health and disease control. APCs like Dendritic cells and macrophages are important targets for the particulate delivery system due to their ability to trigger cascade of events on both levels cellular and humoral immune response specially DCs. Successful targeting of DCs and macrophages will have a great impact on T-cell activation and priming. The design of successful particulate system that can elicit preferential targeting towards specific immune cell in the tumor microenvironment is becoming crucial. This might represent a novel avenue for enhancing the antitumor immunity. Liposomes are made of phospholipid bilayer with a composite nature. Their properties are highly linked to their physicochemical characteristics such as size, surface charge and composition. These physicochemical properties can trigger certain immune response.The hypothesis here whether passive targeting via particulate system can offer a platform for preferential targeting for critical immune cells residing in spleen and tumor. Moreover, test whether there will be differences in uptake according to certain preference towards surface charge in specific time frame. In the current study, three sets of fluorescently labelled nano-liposomes were engineered as a model for different surface charges, the cationic DOTAP NP, anionic DOPG NP and near neutral DOPC NP with mean diameter of ~ 200 nm. Physical stability of the NPs was evaluated by monitoring the changes in size and zeta potential. B16 melanoma cancer model was induced subcutaneously in C57BL/6 black mice, divided into four groups each of five mice. CD11c Dendritic Cells (DCs), CD11b macrophages, CD90.2 T-cells and CD49b Natural Killer (NK) cells were isolated from the tumors and spleens of each group. The three sets of NPs were tested against the isolated cell lines. The cellular uptake (internalization) was assessed by normalizing the fluorescence of the cells against their protein concentration, then all samples were acquired to flow cytometry, and shifts in fluorescence histograms on horizontal axis were monitored against PE channel on the vertical axis. Results reveal the presence of preferential internalization of specific surface charge over others in some cell lines in different time frames. For the first time differences in the internalization pattern are reported in the same immune cell line isolated from two different contexts tumor and spleen.
Note: This abstract was not presented at the meeting.
Citation Format: Noha Ismail, Ashish Kulkarni, Siva Kumar, Vineeth krishna, Shiladitya Sengupta. Towards understanding the cellular uptake patterns of nano-particles among different immune cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4610. doi:10.1158/1538-7445.AM2017-4610</jats:p
Applied approach to privacy and security for the internet of things Advances in information security, privacy, and ethics (AISPE) book series./ Parag Chatterjee, Emmanuel Benoist, Asoke Nath.
No full text"Premier Reference Source" -- taken from front cover.Includes bibliographical references and index."This book examines the conceptual aspects of security and privacy in IoT. It also explores the application of IoT systems in smart transports, smart cities, and smart healthcare"--Collision avoidance methodology in internet of things & wireless ad hoc network / Arundhati Arjaria, Priyanka Dixit -- Information security management system : a case study of employee management / Manoj Srivastav -- Anomaly detection in IoT frameworks using machine learning / Phidahunlang Chyne, Parag Chatterjee, Sugata Sanyal, Debdatta Kandar -- Real-time, cross-platform detection of spectre and meltdown attack variants / Xinxing Zhao, Chandra Veerappan, Peter Loh -- Trust models in IoT / Shiladitya Sengupta -- Vulnerabilities of smart home / Suchandra Datta -- Security and privacy vulnerabilities in automated driving / Suchandra Datta -- Key vulnerabilities in IoT systems / Shiladitya Sengupta -- IoT forensic : principles, processes and activities / Eoghan Casey, Hannes Spichiger, Elénore Ryser, Francesco Servida, David-Olivier Jaquet-Chiffelle -- IoT controlled railway gate system with ML object detection approach : applied approach for secured IOT system / Megha Kamble.1 online resource (xix, 295 pages)
- …
