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Abstract

Carbon nanotubes (CNTs) can be applied as versatile biopharmaceutical delivery systems due to their high drug-loading capacity, excellent cell-penetrating ability, and customizable surface chemistry. Biopharmaceuticals are potent therapeutics when applied correctly, but are challenged by significant drawbacks. The coupling of biopharmaceuticals to CNTs can mitigate these issues, thus additively or synergistically improving their performance. Improved therapeutic effects, enhanced (targeted) delivery to specific tissue types, highly controlled release profiles, and even the visualization of in-vivo biodistribution comprise just a few examples of the benefits of such complexes. Furthermore, novel complexes have been tailored to combat cancer and other difficult-to-treat diseases, with promising success. In this chapter, the application of CNTs for the delivery of biopharmaceuticals to disease sites in vitro and in vivo will be discussed.

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... The pre-clinical studies for biomedical applications began at the beginning of the 2000's. CNT can be used as a reservoir hosting a molecule, within the tube or in between the walls in the case of Multi-Walled Carbon Nanotubes (MWCNT) [62], but it is mostly functionalized by covalent or non-covalent addition of functional groups [63]. It can also be used in scaffolds for stem cells growth [64] or tissue engineering [65]. ...
Thesis
Ewing Sarcoma is a rare pediatric cancer, caused in the majority of the cases by the expression of the fusion oncogene EWS-Fli1. Current treatments have not much evolved over the past decades. We are investigating a new therapy based on siRNA specifically targeting the oncogene and inhibiting the tumor growth. During my PhD thesis, I have tested different types of synthetic nanodiamonds (ND) used to vectorize siRNA electrostatically bound at their surface: ND produced by detonation (DND) or by High Pressure-High Temperature synthesis (NDHPTH). Their surfaces have been cationized by various processes: (i) plasma or (ii) thermal hydrogenation, (ii) chemical treatment, or (iv) covalent grafting of a copolymer (COP-NDHPHT).My PhD work included two main axis: (i) in vitro study of ND:siRNA complexes (NDs physico-chemical characterization and oncogene inhibition efficacy by the complexes); (ii) tissue distribution of COP-NDHPHT, injected into mice, using fluorescent NDHPHT containing nitrogen-vacancy defects. To detect them individually in sections of mouse organs carrying a subcutaneous xenograft tumor, we developed an epifluorescence imaging system with large numerical aperture and resolved in time to reject tissue autofluorescence (of a shorter lifetime than NDs). We quantified the number, the aggregation state and the cell localization (thanks to simultaneous histopathological imaging) of these vectors 24 hours after injection. NDs have been clearly detected in different organs, including the tumor, paving the way for tumor progression control with siRNA.
... Graphene-based nanosheets, including graphenes and graphene oxides, have properties suitable for delivery of various molecules (Shim et al., 2016). CNTs are utilized as versatile biopharmaceutical delivery systems, due to the excellent cellpenetrating ability and high drug-loading capacity (Rallapalli and Smith, 2016). ...
... Graphene-based nanosheets, including graphenes and graphene oxides, have properties suitable for delivery of various molecules (Shim et al., 2016). CNTs are utilized as versatile biopharmaceutical delivery systems, due to the excellent cellpenetrating ability and high drug-loading capacity (Rallapalli and Smith, 2016). ...
Chapter
Most bacterial pathogens have evolved as extensively drug resistant against wide classes of antimicrobials and cause a high threat to pharmaceutical sectors. As a result, there is a high necessity to address the issue and screen novel antimicrobials. This chapter focuses on the therapeutic potential of nanoparticles, especially carbon nanotubes and fullerenes, towards the probable drug targets of bacterial pathogens through computational drug discovery approaches. The chapter emphases the gene network analysis to identify probable drug targets, a need for three-dimensional (3D) structures, major 3D structure depositories, and approaches for modeling and validation. It further emphasizes various approaches for screening carbon fullerenes and nanotubes, and the need for structure-based virtual screening and molecular docking studies. Furthermore, prediction of the binding potential of carbon fullerene and nanotubes against potential drug targets of multidrug resistant pathogens. This chapter integrates the use of computational biology, proteomics and pharmaceutical biotechnology for the screening of novel carbon nanoleads, especially fullerenes and nanotubes, as ideal lead molecules against extreme drug resistant bacterial pathogens.
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Chapter
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Carbon nanotubes (CNTs) have the potential to overcome significant challenges related to vaccine development and immunotherapy. Central to these applications is an improved understanding of CNT interactions with the immune system. Unique properties such as high aspect ratio, flexible surface chemistry, and control over structure and morphology may allow for enhanced target specificity and transport of antigens across cell membranes. Although recent work has demonstrated the potential of CNTs to amplify the immune response as adjuvants, other results have also linked their proinflammatory properties to harmful health effects. Here, we review the recent advances of CNT-based immunological research, focusing on current understandings of therapeutic efficacy and mechanisms of immunotoxicology.
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With large current interest in nanomedicine, there has been rapid progress during the last couple of years in the understanding of opportunities offered by advanced materials in diagnostics, drug delivery, functional biomaterials, and biosensors, as well as combinations of these, e.g., theranostics. In the present overview, focus is placed on drug delivery aspects of inorganic nanomaterials, notably as carriers for proteins, peptides, DNA, and siRNA. Throughout, an attempt is made to illustrate how structure and interactions affect loading and release of such biomacromolecular drugs in various inorganic delivery systems, and how this translates into functional advantages.
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Single-walled carbon nanotubes (SWCNTs) are known to have great potential for biomedical applications such as photothermal ablation of tumor cells in combination with near-infrared (NIR) irradiation. In this study, the photothermal activity of a novel SWCNTs composite with a designed peptide having a repeated structure of H-(-Lys-Phe-Lys-Ala-)7-OH [(KFKA)7] against tumor cells was evaluated in vitro and in vivo. The SWCNTs-(KFKA)7 composite demonstrated high aqueous dispersibility that enabled SWCNTs to be used in tumor ablation. The NIR irradiation of SWCNTs-(KFKA)7 solution resulted in a rapid temperature increase dependent on the SWCNTs concentration up to 50μg/ml. Three minutes of NIR irradiation of a colon26 or HepG2 cell culture incubated with SWCNTs-(KFKA)7 resulted in remarkable cell damage, while that by single treatment with SWCNTs-(KFKA)7 or NIR irradiation alone was moderate. Intratumoral injection of SWCNTs-(KFKA)7 solution followed by NIR irradiation resulted in a rapid increase of the temperature to 43°C in the subcutaneously inoculated colon26 tumor based on thermographic observation and remarkable suppression of tumor growth compared with treatment with only SWCNTs-(KFKA)7 injection alone or NIR irradiation alone. These results suggest the great potential of a SWCNTs-peptide composite for use in photothermal cancer therapy.
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Promising therapeutic and prophylactic effects have been achieved following impressive advances in the gene therapy research arena, giving birth to the new generation of disease-modifying therapeutics. The greatest challenge that gene therapy vectors still face is the ability to deliver sufficient genetic payloads in order to enable efficient gene transfer into target cells. A whole host of viral and non-viral gene therapy vectors have been explored over the past 10years, including carbon nanotubes. In this review we will address the application of carbon nanotubes in gene therapy with the aim to give a perspective on the past achievements, present challenges and future goals. A series of important topics concerning carbon nanotubes as gene therapy vectors will be addressed, including the benefits that carbon nanotubes offer over other non-viral delivery systems, furthermore, a perspective is given on what the ideal genetic cargo to deliver with carbon nanotubes is and finally the geno-pharmacological impact of carbon nanotube-mediated gene therapy is discussed.
Article
Single-walled carbon nanotubes (SWNTs) can deliver imaging agents or drugs to tumours and offer significant advantages over approaches based on antibodies or other nanomaterials. In particular, the nanotubes can carry a substantial amount of cargo (100 times more than a monoclonal antibody), but can still be rapidly eliminated from the circulation by renal filtration, like a small molecule, due to their high aspect ratio. Here we show that SWNTs can target tumours in a two-step approach in which nanotubes modified with morpholino oligonucleotide sequences bind to cancer cells that have been pretargeted with antibodies modified with oligonucleotide strands complementary to those on the nanotubes. The nanotubes can carry fluorophores or radioisotopes, and are shown to selectively bind to cancer cells in vitro and in tumour-bearing xenografted mice. The binding process is also found to lead to antigen capping and internalization of the antibody-nanotube complexes. The nanotube conjugates were labelled with both alpha-particle and gamma-ray emitting isotopes, at high specific activities. Conjugates labelled with alpha-particle-generating (225)Ac were found to clear rapidly, thus mitigating radioisotope toxicity, and were shown to be therapeutically effective in vivo.
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Abstract An aspargine-glycine-arginine (NGR) peptide modified single-walled carbon nanotubes (SWCNTs) system, developed by a simple non-covalent approach, could be loaded with the anticancer drug tamoxifen (TAM). This TAM-loaded NGR modified SWCNTs (TAM/NGR-SWCNTs) not only retained both optical properties of SWCNTs and cytotoxicity of TAM, but also could accumulate in tumors and enter into 4T1 cells, which facilitated combination chemotherapy with photothermal therapy in one targeting system. Enhanced cellular uptake, antitumor effect and cell apoptosis of TAM/NGR-SWCNTs on 4T1 cells were observed in vitro, compared with the TAM solution, TAM/SWCNTs and photothermal therapy alone. In vivo investigation of TAM/NGR-SWCNTs in tumor-bearing mice further confirmed that this system possessed much higher tumor targeting capacity and antitumor efficacy than the control, especially with the near-infrared-laser irradiation treatment. Moreover, it demonstrated negligible systematic toxicity through the histopathological analysis. All these results suggest TAM/NGR-SWCNTs are promising for high targeted efficiency and treatment efficacy and low side effects of future cancer therapy by synergistic effect of chemo-photothermal combination.
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In the present study, we report the design and synthesis of peptide-based-multi-walled carbon nanotubes (MWCNTs) to target mitochondria. Targeting these intracellular organelles might open the way to develop alternative systems to address diseases related to genetic mutations in mitochondrial (mt)-DNA, by delivering therapeutic oligonucleotides. The first step towards mitochondrial delivery of this type of nucleic acid was to target MWCNTs to mitochondria by covalent functionalization with a well-known endogenous mitochondrial targeting sequence (MTS). The subcellular localization of the conjugates, which were fluorescently labeled, in murine RAW 264.7 macrophages and human HeLa cells was then studied using different microscopy techniques, such as wide-field epifluorescence microscopy, confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM). The localization of the MTS-MWCNT conjugates into mitochondria was further confirmed by analyzing the isolated organelles using TEM.
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The enhancement of the conventional synthesis of carbon nanotubes by means of catalytic chemical vapor deposition (CCVD), was investigated. This synthesis route is more efficient than conventional and commercial ones employing metal oxide catalyst supports. Electron microscopy investigations were made using a Philips XL30 scanning electron microscope and a Philips transmission electron microscope. The results show that NaCl catalysts support has an inhibiting effect on the growth of carbon nanotubes.
Article
Small interfering RNA (siRNA) has the potential to influence gene expression with a high degree of target gene specificity. However, the clinical application of siRNA therapeutics has proven to be less promising as evidenced by its poor intracellular uptake, instability in vivo, and nonspecific immune stimulations. Recently, we have demonstrated that single-walled carbon nanotube (SWNT)-mediated siRNA delivery can enhance the efficiency of siRNA-mediated gastrin-releasing peptide receptor (GRP-R) gene silencing by stabilizing siRNA while selectively targeting tumor tissues. Based on our recent findings, we introduce a novel technique to silence specific gene(s) in human neuroblastoma through SWNT-mediated siRNA delivery in vitro and in vivo.
Article
Carbon nanotubes (CNTs) are nanomaterials with interesting emerging applications. Their properties makes CNTs excellent candidates for use as new nanovehicles in drug delivery, immunization and diagnostics. In the current study, we assessed the immune-response-amplifying properties of CNTs to haptens by using azoxystrobin, the first developed strobilurin fungicide, as a model analyte. An azoxystrobin derivative bearing a carboxylated spacer arm (hapten AZc6) was covalently coupled to bovine serum albumin (BSA), and the resulting BSA-AZc6 conjugate was covalently linked to four functionalized CNTs of different shapes and sizes, varying in diameter and length. These four types of CNT-based constructs were obtained using efficient, fast, and easy functionalization procedures based on microwave-assisted chemistry. New Zealand rabbits and BALB/c mice were immunized with BSA-AZc6 alone and with the four CNT-BSA-AZc6 constructs, both with and without Freund's adjuvant. The IgG-type antibody responses were assessed in terms of the titer and affinity, paying special attention to the relationship between the immune response and the size and shape of the employed CNTs. Immunization with CNT-BSA-AZc6 resulted in enhanced titers and excellent affinities for azoxystrobin. More important, remarkable IgG responses were obtained even in the absence of an adjuvant, thus proving the self-adjuvanting capability of CNTs. Immunogens were able to produce strong anti-azoxystrobin immune responses in rabbits even when administered at a BSA-AZc6 conjugate dose as low as 0.05 μg. The short and thick CNT-BSA-AZc6 construct produced the best antibody response under all tested conditions.
Article
Sometimes shorter is better: The apparent similarity between multi-walled carbon nanotubes (MWNTs) and asbestos fibers has generated serious concerns about their safety profile. The asbestos-like pathogenicity observed for long, pristine nanotubes (NTlong, see scheme) can be completely alleviated if their effective length is decreased as a result of chemical functionalization, such as with tri(ethylene glycol) (TEG).
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INTEREST in carbon fibres1,2 has been stimulated greatly by the recent discovery of hollow graphitic tubules of nanometre dimensions3. There has been much speculation about the properties and potential application of these nanotubes4–8. Theoretical studies predict that their electronic properties will depend on their diameter and degree of helicity4,5. Experimental tests of these ideas has been hampered, however, by the lack of macroscopic quantities of the material. Here we report the synthesis of graphitic nanotubes in gram quantities. We use a variant of the standard arc-discharge technique for fullerene synthesis under a helium atmosphere. Under certain conditions, a carbonaceous deposit forms on one of the graphite rods, consisting of a macroscopic (diameter of about 5 mm) cylinder in which the core comprises pure nanotubes and nanoscale particles in high yield. The purity and yield depend sensitively on the gas pressure in the reaction vessel. Preliminary measurements of the conductivity of the bulk nanotube material indicate a conductivity of about 100 S cm–1 1.
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Single-walled carbon nanotubes (SWNTs) are special nano-materials which exhibit interesting physical and chemical properties, presenting new opportunities for biomedical research and applications. In this study, we have successfully adopted a novel strategy to chemically functionalize SWNTs with polyethylenimine (PEI) through purification, oxidation, amination and polymerization, which were then bound by DSPE-PEG2000-Maleimide for further conjugation with the tumor targeting NGR (Cys-Asn-Gly-Arg-Cys-) peptide via the maleimide group and sulfhydryl group of cysteine, and finally hTERT siRNA was loaded to obtain a novel tumor targeting siRNA delivery system, designated as SWNT-PEI/siRNA/NGR. The results showed that SWNT-PEI/siRNA/NGR could efficiently cross cell membrane, induced more severe apoptosis and stronger suppression in proliferation of PC-3 cells in vitro. Furthermore, in tumor-bearing mice model the delivery system exhibited higher antitumor activity due to more accumulation in tumor without obvious toxicity in main organs. The combination of RNAi and near-infrared (NIR) photothermal therapy significantly enhanced the therapeutic efficacy. In conclusion, SWNT-PEI/siRNA/NGR is a novel and promising anticancer system by combining gene therapy and photothermal therapy.
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Two distinct proteins, streptavidin and HupR, bind and form regular helical arrays on the surface of multiwalled carbon nanotubes under appropriate conditions (see picture). The decoration of the outer surface of these nanostructures with biological macromolecules was investigated by electron microscopy.
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Multi-walled carbon nanotubes functionalized with diethylentriaminepentaacetic dianhydride (DTPA-MWNT) and radiolabeled with Indium-111, having therapeutic and diagnostic applications, were tracked in the systemic blood circulation and the excretory system using a microSingle Photon Emission Tomography (microSPECT) scanner. Quantitative Kaiser test was used to determine the number of free amino groups on the DTPA-MWNT. A suspension of PBS and DTPA-MWNT was intravenously injected by tail vein in the Wistar rats and the urine production, water consumption and body weight were observed for 24 hours. The rat was necropised and tissues of various organs were fixed and observed with a Nikon Microphot-FXA microscope coupled with digital camera. The Length of DTPA-MWNT used in the study is larger than the dimensions of the glomerular capillary wall, so it was excreted through urine after 24 hours post-administration.
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Delivery is one of the most critical obstacles confronting nanoparticle use in cancer diagnosis and therapy. For most oncological applications, nanoparticles must extravasate in order to reach tumor cells and perform their designated task. However, little understanding exists regarding the effect of nanoparticle shape on extravasation. Herein we use real-time intravital microscopic imaging to meticulously examine how two different nanoparticles behave across three different murine tumor models. The study quantitatively demonstrates that high-aspect ratio single-walled carbon nanotubes (SWNTs) display extravasational behavior surprisingly different from, and counterintuitive to, spherical nanoparticles although the nanoparticles have similar surface coatings, area, and charge. This work quantitatively indicates that nanoscale extravasational competence is highly dependent on nanoparticle geometry and is heterogeneous.
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Since their first observation nearly a decade ago by Iijima (Iijima S. Helical microtubules of graphitic carbon Nature. 1991; 354:56–8), carbon nanotubes have been the focus of considerable research. Numerous investigators have since reported remarkable physical and mechanical properties for this new form of carbon. From unique electronic properties and a thermal conductivity higher than diamond to mechanical properties where the stiffness, strength and resilience exceeds any current material, carbon nanotubes offer tremendous opportunities for the development of fundamentally new material systems. In particular, the exceptional mechanical properties of carbon nanotubes, combined with their low density, offer scope for the development of nanotube-reinforced composite materials. The potential for nanocomposites reinforced with carbon tubes having extraordinary specific stiffness and strength represent tremendous opportunity for application in the 21st century. This paper provides a concise review of recent advances in carbon nanotubes and their composites. We examine the research work reported in the literature on the structure and processing of carbon nanotubes, as well as characterization and property modeling of carbon nanotubes and their composites.
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Direct laser vaporization of transition-metal/graphite composite rods produced single-walled carbon nanotubes (SWT) in the condensing vapor in a heated flow tube. A much higher yield of nanotubes was found, with little of the amorphous overcoating on those produced by the metal-catalyzed arc-discharge method. A mixture of Co with Ni catalyzed about 50% of all the carbon vaporized to SWT. A model for SWT growth is presented for both the present case and the arc in which the metal particle size is limited due to the concurrent carbon condensation.
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Mammalian cell expression has become the dominant recombinant protein production system for clinical applications because of its capacity for post-translational modification and human protein-like molecular structure assembly. While expression and production have been fully developed and Chinese hamster ovary cells are used for the majority of products both on the market and in clinical development, significant progresses in developing and engineering new cell lines, introducing novel genetic mechanisms in expression, gene silencing, and gene targeting, have been reported in the last several years. With the latest analytical methods development, more attention is being devoted towards product quality including glycol profiling, which leads to better understanding the impact of culture condition during production. Additionally, transient gene expression technology platform plays more important role in biopharmaceutical early development stages. This review focused on the latest advancements in the field, especially in active areas such as expression systems, glycosylation impact factors, and transient gene expression.