Carbon Nanotube as a Tool for Fighting Cancer - American Chemical

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Cite This: Bioconjugate Chem. XXXX, XXX, XXX-XXX

Carbon Nanotube as a Tool for Fighting Cancer Edson José Comparetti,† Valber de Albuquerque Pedrosa,‡ and Ramon Kaneno*,† †

Department of Microbiology and Immunology, Laboratory of Tumor Immunology and ‡Department of Chemistry and Biochemistry, Institute of Biosciences, São Paulo State University (UNESP), 18618-691 Botucatu, Sao Paulo Brazil ABSTRACT: In 2015, cancer was the cause of almost 22% of deaths worldwide. The high frequency of relapsing diseases and metastasis requires the development of new diagnostic and therapeutic approaches, and the use of nanomaterials is a promising tool for fighting cancer. Among the more extensively studied nanomaterials are carbon nanotubes (CNTs), synthesized as graphene sheets, whose spiral shape is varied in length and thickness. Their physicochemical features, such as the resistance to tension, and thermal and electrical conductivity, allow their application in several fields. In this review, we show evidence supporting the applicability of CNTs in biomedical practice as nanocarriers for drugs and immunomodulatory material, emphasizing their potential for use in cancer treatment.

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INTRODUCTION Nanomedicine explores the medical and biomedical use of nanotechnology in order to improve usual techniques or develop new approaches for diagnosis (magnetic resonance, Xray, and ultrasound) or therapy (chemotherapy, immunotherapy, and radiotherapy). The most potentially useful nanoparticles in clinics include liposomes,1 polymeric nanoparticles,2 dendrimers,3 quantum dots,4 metal,5 and carbon nanoparticles.6 In simple terms, liposomes are spherical nanometric particles formed by one or more phospholipid layers.1 Polymer nanoparticles are prepared as nanocapsules or nanospheres composed of a polymeric matrix,2 while dendrimers are composed of a nucleus and a polymer chain branched outside.3 Quantum dots are crystalline nanoparticles with semiconductor properties, able to emit a specific wavelength depending on their size.4 Inorganic and organic elements such as gold and carbon have also been synthesized as nanostructures.6 The possibility of manipulating nanostructures allows us to address their activity to cells or organs by simple surface modifications.7 The applicability of these particles is also dependent on their size that influences their traffic through tissues and blood vessels. For example, those particles smaller than 10 nm, such as certain drugs formed by small molecules, are rapidly eliminated by the kidney, while particles ranging from 10 to 100 nm travel through the bloodstream8,9 and may be laid in a specific location under appropriate addressing. Thereby, nanoparticles can be used to carry nucleic acids, proteins, and drugs to chosen cells,10 and this addressing can be made by setting unique biomarkers on the surface of nanostructures.10,11 Among the nanoparticles synthesized with organic elements, we highlight carbon nanotubes (CNTs) due to their potential for scientific and technological innovation. CNTs are formed from graphene sheets, classified as single wall carbon nanotubes © XXXX American Chemical Society

(SWCNT; formed by a single spiral graphite layer) or as multiwall carbon nanotubes (MWCNT; composed by several spiral layers).12 The diameter and length of SWCNTs ranges 0.5−3.0 nm and 20−1000 nm, respectively, while MWCNT dimensions range 1.5−100 nm and 1−50 μm.7 Their cylindrical shape results from covalent bonds (sp2)13 with an extraordinary resistance to tensionup to 100 gigapascal (GPa)and a high density (1.3 to 1.4 g/cm3).14,15 Other properties, such as good thermal and electric conductivity,16,17 enable their use in different research fields for developing new devices. Carbon nanotubes have been studied as nanocarriers in order to increase drug delivery to target cells, and reduce drug toxicity and side effects for healthy tissues.18,19 Nanotube dimensions allow the simultaneous conjugation of different molecules carrying a large amount of anti-neoplastic agents and structures responsible for increasing this capture by target cells. For example, when chemotherapeutic molecules enter into sick cells, they can be ejected by cellular pumps before taking any action.20 In contrast, if they are bound to nanoparticles they may enter into the cells by endocytosis, being protected from cellular pumps.21−23 In addition, drug release can be triggered by the pH reduction when endosomes (pH 7.4) fuses with lysosomes to form phagolysosomes (pH 4.8).24,25 In vitro, exciting results were obtained by complexing CNTs with vitamins, sugars, proteins, peptides,26−30 or even monoclonal antibodies31−33 targeting tumor cell receptors, both to increase Special Issue: Bioconjugate Materials in Vaccines and Immunotherapies Received: September 20, 2017 Revised: October 14, 2017 Published: October 26, 2017 A

DOI: 10.1021/acs.bioconjchem.7b00563 Bioconjugate Chem. XXXX, XXX, XXX−XXX

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Bioconjugate Chemistry

Figure 1. Carbon nanotubes can be driven to the tumor site by antibodies and aptamers to deliver chemotherapeutic or immunomodulatory agents, and nucleic acid sequences (DNA or iRNA).

CNTs properties also make it possible to apply physicochemical techniques in a less harmful way for clinical treatments. For instance, since they have thermal properties when exposed to infrared light,43 their heating could be simultaneously used for diagnosis and disease treatments. Zhang et al.44 observed that CNT can be used as a photosensitive drug carrier both in vitro and in vivo to fight tumor cells by hyperthermia. Nanoparticles delivering hematoporphyrin monomethyl ether help to potentiate the antitumor effects of photodynamic therapy against breast cancer cells (MCF-7), increasing cancer cell death and exhibiting low toxicity in healthy tissues irradiated with laser light. In order to drive CNTs to hepatocellular carcinoma, nanoparticles were conjugated with human albumin to facilitate internalization by HepG2 cells via Gp60 receptor.45 The authors demonstrated the CNTs’ affinity for specific receptors, leading to increased CNT uptake and cell death through thermal ablation after laser treatment. In vivo assays show deposition of SWCNT in tumor mass, liver, and kidney, with the effective death of cancer cells and low cytotoxic effects to healthy cells under exposure of animals to near-infrared light. Treatments with SWCNT plus laser drastically reduced tumor volume, resulting in a relapsing rate lower than control groups (SWCNT or laser) without phototherapy.46,47 Wang et al.48 used PEGylated SWCNT combined with photothermal therapy and anti-CTLA-4 treatment as a new adjuvant for immunocompetent cells, modulating an adaptive immune system against primary and metastatic tumor cells. They observed that SWCNT-PEG works as an activator of dendritic cells (DCs), increasing the expression of their maturation marker CD80/CD86, and the production of IL-1β, IL-12, IL-6, and TNF-α, while the photothermal property boosts DC response in lymph nodes of BALB/c mice.48 CNTs have also been shown to be useful for application in gene therapy against cancer. For example, they can be used to deliver genes without size limitation, being able to carry plasmid, interfering RNA (siRNA), and micro RNA (miRNA) for sick cells. Alidori et al.49 proposed the functionalization of CNTs with oligonucleotide sequences in order to stably deliver a large amount of short DNA or RNA strands under

the effectiveness of antineoplastic drugs and for use as nanosensors,34,35 as illustrated in Figure 1.

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APPLICABILITY OF CNTS IN CANCER DIAGNOSIS AND TREATMENT In order to ensure the activity of nanoparticles on tumor cells, monoclonal antibodies (mAb) and aptamers36 have been used as the main components engaged to CNTs. Carbon nanotubes complexed with mAb show increased affinity and specificity to breast cancer cells after functionalization with anti-HER2 antibodies.31 In colorectal cancer cells, nanotubes conjugated with anti-EGFR and chemotherapeutics show a high cytotoxic effect, following capture by endocytic pathway via EGFR.32 CNTs loaded with paclitaxel and antibodies specific to human breast cancer cell receptors were demonstrated to be more effective in vitro37 and in vivo38 than treatment with chemotherapy alone. Similar results were observed with CNT loaded with doxorubicin and functionalized with anti-PSCA antibodies that prevent proliferation of PC-3 human prostate cancer cells more effectively than pure chemotherapeutic. Since it facilitates the capture of a particle by PSCA+ cells, there are reduced side effects in the body.33 In vitro and in vivo studies show that human serum albumin (HSA) and peptides with rich asparagine-glycine-arginine sequences can be loaded on a CNT surface to carry paclitaxel to breast cancer cells MCF-7.39,40 Thereby, drug delivery by CNT yields a higher drug concentration inside the cell than treatment with the drug alone.41 Wu et al.34 investigated the ability of MWCNT to carry doxorubicin for cancer cells and detect them by magnetic resonance images (MRI). By coupling cobalt ferrite on CNTs, they were able to improve the MRI technique, since the MWCNT/CoFe2O4 complexes simultaneously generated MRI in cervical cancer cells (HeLa), and improved the toxicity of the doxorubicin carried by them. The potential of carbon nanotubes in magnetic resonance and radio/phototherapy in cancer was also studied in vivo,42 coupling polydopamine on the CNT surface, enhancing the quality of the MRI due to its affinity with Mn2+. Nanoparticles were also coupled with the radionuclide 131I making the cancer cells more sensitive to the effects of phototherapy. B


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with the cytoskeleton rearrangement of the main antigenpresenting cellsdendritic cells, inhibiting the distribution of factin and preventing the formation of DC dendrites.64 Studies on the toxicity of CNT are intense yet still inconclusive. Toxicity produced by nanoparticles depends on the materials used in their synthesis, their structural characteristics (size, surface area, and purity) and the experimental conditions (such as the type of cell line evaluated and the time of exposition).65−67 The smallest nanotubes can penetrate through the cell membrane without causing tissue damage.68 There is evidence that cell enzymes make their biodegradation to avoid toxic and inflammatory effects in the body,69,70 and studies with murine models show they are gradually excreted through the bile duct.71 There are no general toxic effects, but chronic exposure may lead to biochemical changes and lung injury, representing a threat to human health.72 Studies performed in mice show lung inflammatory response induced by exposure to CNTs that affects the permeability of the blood-brain barrier and increases the activity of glial cells around cerebral arterioles, triggering inflammation in the cerebral cortex.73 In vitro interaction between pristine-CNTs and astrocytes in porcine brain endothelial cells shows the low toxicity of CNTs.74 Murine models reveal that CNTs can remain in the bloodstream for long periods, within the liver, spleen, kidneys, and lungs.75,76 Albini et al.77 exposed mice to nanoparticles for portions of the material being eliminated through urine, while a part is trapped in organs for weeks, observing the formation of CNT aggregates in the main organs, increased frequency of macrophage at sites of inflammation, and deposition of amyloid proteins in the tissues. High doses of CNTs may increase the mass of organs such as the liver, spleen, and lung.78 Accumulation of CNTs in the lungs causes TNF-α expression, producing an inflammatory response, fibrosis, and formation of collagen in the lesions.79 In 2016, CNTs were tested in monkeys for the first time, and Alidori et al.80 observed that most of the nanoparticles administered intravenously were rapidly eliminated in the urine while the remainder was deposited in the liver, with no pathological changes observed in the tissues. The coating of CNTs with polymers improves their ability to circulate in the blood, preventing retention in organs, facilitating their excretion, and decreasing the in vivo toxicity.81 DNA damage and programmed cell death are the main toxic effects of a high dose of CNTs.82 This nanomaterial may induce intracellular formation of reactive oxygen species (ROS), damaging the genetic material and disturbing mitochondrial function.83 Differential genotoxicity is observed if nanotubes are internalized individually or in a cluster of particles. Mice exposed to CNT can suffer damage to the genetic material in healthy cells of the respiratory system while tangled nanoparticles reduce this harmful process by decreasing ROS production, as well as by reducing the infiltration of eosinophils and activated macrophages in tissue.84−86 Sasaki et al.87 observed that pure CNTs induce chromosomal aberrations like polyploidy in murine CHL/IU cells, and Jackson et al.88 demonstrated that hydroxylated MWCNT have reduced cytotoxicity and genotoxicity in murine lung epithelial cells when compared with controls. Human lung adenocarcinoma cells and hamster lung fibroblast show that carboxylated CNTs inhibit the fixation of genetic damage produced by reactive oxygen species.89 Therefore, the greatest challenge in nanomedicine is to develop particles capable of remaining for a long time in the

physiological conditions in vivo. Unlike free oligonucleotides, DNA carried by CNTs are protected from the enzymatic cleavage and interference from nucleic acid binding proteins, providing higher stability and maintenance of their function for a longer period in the cytoplasm.50 Silencing specific genes responsible for the differentiation and migration of tumor cells with iRNA or siRNA inhibits the synthesis of proteins required for cell survival. For instance, CNTs conjugated to siRNA of human telomerase reverse transcriptase (hTERT), a protein upregulated in human cancers, inhibited the expression of this enzyme as well as the growth of human prostate cancer cells, that became more sensitive to treatments.51 In vitro and in vivo studies show that CNTs directly arrest the growth of Calu6 tumor cells by impairing the expression of a protein kinase responsible for the regulation of mitotic spindle formation (PLK1). Conjugation of a PLK1 siRNA to CNT improves the ability to block PLK expression, increasing the effectiveness of the treatment.52 In order to drive the activity of these synthetic molecules, a nanoparticle can be modified to target and speed up the delivery of siRNA molecules to the cells and tumor sites. Complexation of CNT with BCL91 siRNA (a protein expressed by colorectal and breast cancer) and aptamers drive them to the epithelial cell adhesion molecule (EpCAM), increasing the efficiency of transfection and the cytotoxic effects due to the inhibition of BCL91 expression in breast adenocarcinoma cells (MCF-7).53 Therefore, addressing the delivery of therapeutic agents adopts and renews Paul Ehrlich’s seminal concept of “magic bullets”.

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INTERACTIONS AND TOXICITY OF CNTS The internalization of nanoparticles is distinct among cell lines; for instance, immunocompetent cells recognize nanoparticles and capture them by phagocytosis, while tumor cells do so by diffusion or endocytosis.54 Materials absorbed to the CNT surface influence the hydrophilicity of the particles and their interaction with the cell membrane.55 Therefore, changes to increase the solubility in aqueous solution facilitates CNTs transpassing into the cytoplasm, while their capture by low functional chemical groups is considerably reduced.55 Internalization of CNTs may occur by endocytic pathway mediated by clathrin proteins, that actively transport them across the cell membrane, followed by the formation of endosomal vesicles for further degradation and release into the cytoplasm.56 Normal bronchial epithelial cells also endocyte CNT preferentially by clathrin, but other pathways such as macropinocytosis also contribute to their internalization.57 Whether energy supply is blocked in tumor cells, CNTs are internalized by plasma membrane translocation, a pathway that does not consume energy and confirms the various possibilities of CNT uptake.58 After this process, CNTs may interact with the mitochondrial membrane and with proteins involved in microtubule assembly.59,60 CNTs may also enter the cell nucleus either by targeting structures found on the membrane or by interaction, in the cytoplasm, with proteins involved in nuclear transportation.61,62 CNTs do not damage mitochondria of tumor cells, but can change their membrane potential and effectively delivery anti-neoplastic molecules, decreasing the cell growth.59,63 The shape of CNTs is very similar to microtubules and other structures involved in the cytoskeleton rearrangement, and they interact with tubulin during the microtubule assembly and are incorporated into microfilaments of cancer cells.60 Other studies show that MWCNT can also interfere C


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Figure 2. Effect of CNTs, CNT-PTX, and PTX on the expression of CD86 (A) and HLA-DR (B) on the surface of immature human dendritic cells (mean fluorescence intensity - MFI). Toxicity was evaluated by flow cytometry using 7-aminoactinomycin D (7-AAD) to label dead cells (C).

and increases the activity of APCs in the tumor site.100 Thus, CNTs help to reduce MYC expression in tumor and immune cells, impairing the growth of neoplastic cells and restoring the pro-inflammatory response. In vitro and in vivo studies show that nanoparticles reduce CD44 expression and increase the activity of immune cells in the tumor microenvironment, increasing the potential of conventional chemo- and radiotherapy.101 CD44 is expressed by several cell lines and is responsible for the development of tumor metastasis and cancer cell progression.101 Conjugation of hyaluronic acid to CNTs facilitates their interaction with CD44 proteins, increasing their endocytosis by human lung carcinoma (A549) and cervical carcinoma cells (HeLa), enabling their use as an effective nanocarrier of the anticancer drug doxorubicin.102,103 In order to improve nanoparticle solubility in aqueous solution and decrease their toxicity, synthetic or natural lipids can be laid on the CNT surface.104 For instance, CNTs coated with synthetic lipids deliver paclitaxel to MCF-7 cells both in vitro and in vivo.26 Lipids and proteins from the plasma membrane of healthy or neoplastic cells can be used to coat nanoparticles, with the aim of enhancing the immune response against tumor cells.105,106 These molecules include the cell surface receptors for selectins, chemokines, and integrin, helping nanoparticles to achieve the target cells at the tumor site and to deliver tumor antigens for antigen presentation cells (APCs).105−107 The development of an immune response is strongly dependent on the activity of DCs that are the main APCs and are responsible for triggering a specific antitumor immune response.108−110 Therefore, any material able to change the features and functions of DCs can impact the intensity and quality of the immune response. There are both reports that CNTs can modulate DC activities and that they can carry antigenic material̀ for these professional APCs to potentiate an immune response.111 Studies in murine models show that CNTs carrying ovalbumin, CpG oligodeoxynucleotides, and anti-CD40 antibody improve DC activity as demonstrated by their ability to in vivo generate cytotoxic T lymphocyte and to interrupt the growth of B16F10 melanoma cells.112,113 In vitro treatment using immunostimulatory drugs and CNTs changes the expression of HLA-DR, CD86, and CD80 on DCs and enhances both Th1 and Th2 immune response in vivo.114 The applicability of CNTs as specific antigen carriers is

blood and of crossing physiological barriers without causing tissue toxicity. Coating CNTs with polymers improves their ability to circulate in the blood, preventing retention in organs, facilitating their excretion, and decreasing the in vivo toxicity.81

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IMPACT OF NANOTUBES ON THE IMMUNE SYSTEM Besides the toxicity, nanocomposites developed for clinical applications need to be deeply analyzed for their immunomodulatory properties, since mononuclear and polymorphonuclear phagocytic cells are the first host cells to directly interact with them. High concentrations of CNTs induce the production of reactive oxygen species by peripheral blood leukocytes, with consequent damage to genetic material and cell death.90 At nontoxic concentrations, nanoparticles do not impair cell viability or lymphostimulation,91 but increase the production of IFN-γ and TNF-α, interfering with the functions of immunocompetent cells.92 Studies reveal the feasibility of CNTs to carry oligonucleotides, in order to modulate immunocompetent cells. Results show that fragments of nucleic acid conjugated to nanoparticles may increase the TNF-α, IL-6, and IL-12p70 production in tumor tissue and serum. These inflammatory cytokines make tumor cells more susceptible to CNT hyperthermic properties, reducing the tumor growth after exposure to near-infrared radiation (NIR).93 Tumor microenvironment contains a number of immunocompetent cells that are directly or indirectly modulated by cancer cells. Nanoparticles can be used to carry immunomodulatory agents for both tumoral and immunocompetent cells, in order to regulate their phenotypes and functions. For instance, nanoparticles can be used to blockade or inhibit the expression of immunosuppressive proteins, increasing the susceptibility of neoplastic cells to the immune response. The transcription factor c-Myc is expressed by a wide range of human cancers, such as lung, breast, and colon to regulate the cell metabolism, proliferation, and apoptosis.94−97 In addition, c-Myc induces the production of the regulatory proteins CD44, CD47, and PD-L1, responsible for decreasing the immune response against tumor cells.95,96 c-Myc also increases the expression of anti-inflammatory cytokines in immunocompetent cells driving the immunoresponse for a suppressive profile.98,99 In contrast, inactivation of this gene through treatment with nanoparticles induces the death of cancer cells D


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Figure 3. Effect of CNTs, CNT-PTX, and PTX on the antigen presenting function of human DCs. Peripheral blood lymphocytes were labeled with carboxyfluorescein succinimidyl ester (CFSE) and cocultured for 5 days with allogeneic DCs previously exposed to CNTs, CNT-PTX, or pure PTX, in order to evaluate their ability to stimulate the lymphocyte proliferation. We first gated the proliferating cells based on their size and granularity (A); then we analyzed the proliferation of CD3+ cells (B) and CD3+/ CD4+ or CD3+/CD8+ events (C). The medium percentages of lymphocyte proliferation (n = 3) are illustrated in figures D, E, and F.

an antitumor immune response. In order to activate such a response and enhance DCs’ immunogenic potential, Colic et al.119 conjugated carbon nanotubes with the toll-like binding molecule 7-thia-8-oxo-guanosine (7-TOG) and put them on immunocompetent cells. Their results show that DCs, previously incubated with CNT-7-TOG, induce both a Th1 and Th17 response in higher intensity than CNTs or 7-TOG alone. They observed a high proliferation of CD4+ T-cells, increased expression of IFN-γ and IL-17, and a lower cytotoxic effect on APCs. In addition, another in vivo study shows that the administration of nanotubes loaded with DNA plasmids induces B cell proliferation and modulates the antibody ́ production, working as a new transfection tool against virus infection.120 High concentrations of CNTs may decrease the viability of human monocytes and induce their differentiation into macrophages.121 Recent research indicates a reduction of the pro-inflammatory profile when complement system proteins interact with the CNT surface,122 favoring their capture by monocytes and macrophages. Instead of being activated, these cells decrease the synthesis of TNF-α and IL-1β synthesis, performing an anti-inflammatory role.123 In fact, varied signals such as IL-4 and IL-13 may induce an immunosuppressive phenotype in macrophages, favoring tumor progression.124 According to their pro-inflammatory potential, macrophages can be classified as M1, following classical activation pathway; or M2, induced by an alternative activation. M1 and M2 macrophages express different cytokines and chemokines, and are responsible for distinct immune responses.124,125 In addition, M1 macrophages are involved in inflammatory response, pathogen capture, and antitumor immunity.126 In contrast, M2 macrophages exhibit an anti-inflammatory response and pro-tumorigenic properties.126 Tumor-associated macrophagesTAMpreferentially have the M2 phenotype

reinforced by the observation that they enhance the DC activation and antigen presenting property, boosting the lymphoproliferative responses of CD4+ and CD8+ T cells, as well as their ability to produce IFN-γ.115 Low concentrations of CNTs cause only a slight cytotoxic effect in DCs and neither pure SWCNTs or MWCNTs induce phenotypic changes in the expression of CD80, CD86, and HLA-DR.64,116 However, SWCNTs reduce the stimulatory ability of DCs and suppress the proliferative response of lymphocytes.116 Exposure of peripheral blood monocytes to CNTs during their in vitro differentiation into DCs decreases the expression of CD1a, CD209, and MHC-II by immature DCs. As a consequence, phenotypic and functional changes are also observed in mature DCs.117 These changes include changes in the decreased expression of CD80, with reduced expression of cytokine genes (IL-12p35, IL-23p19, IL-6, and IL10) impairing the ability to induce T cell proliferation, and cytoskeleton rearrangement.64 In our own studies, we observed that immature DCs generated in vitro from peripheral blood monocytesincrease their expression of MHC class II and CD86 following a challenge with CNTs (Figure 2). We further observed that despite the direct toxicity of CNTs and paclitaxel-loaded CNTs (CNT-PTX) on DCs (Figure 2), these composites did not interfere with the ability of DCs to in vitro stimulate the lymphocytes (Figure 3). Similar results were reported by Shvedova116 and Ballerini64 who observed no phenotypic changes in DCs exposed to CNTs. However, exposure of these cells to high concentrations of CNTs suppresses their ability to stimulate T lymphocytes. Lymphocytes are cells with a high plasticity, and depending on the stimuli, naive CD4+ cells can be induced to mature into Th1, Th2, Th17, Th22, or even inducible Treg cells.118 Among them, Th1 lymphocytes are considered essential for stabilizing E


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effects on immune cells, requiring a detailed characterization of each material associated with CNTs.

and promote tissue remodeling and angiogenesis, thus providing a favorable microenvironment for tumor development and progression in vivo.126,127 Macrophages capturing CNTs can exhibit both M1 and M2 profiles.128 For instance, in vitro studies show that macrophages do not secrete large amounts of IL-6 and TNF-α after exposure to CNTs, but increase the production of other pro-inflammatory cytokines such as MIP-1α and MIP-2, which contributes to the recruitment of naive cells.128 There is an increased expression of CD206 (characteristic for M2 cells line) with no change in MHC class II expression.128 CD206+ cells exposed to CNTs secrete a large amount of the main mediators of tumor angiogenesis MMP-9 (matrix metallopeptidase 9) and VEGF (vascular endothelial growth factor).128 In a murine system, classical activation of macrophage is improved by incubation with MWCNT-OVA, stimulating the proliferation of CD4+ T cells. In this system, the production of cytokines is associated with the M1 profile (TNF-α and IL-6), and with increased expression of MHC class II,129 as well as with the development of inflammatory symptoms. For instance, secretion of proinflammatory cytokines IL-1β and TNF-α130 in the knee joint and IL-23, IL-12, and TNF -α in the liver131 leads to severe tissue damage, while pure CNTs induce the production of reactive oxygen species that damage the genetic material and eventually kill the cells.132 A model of the interactions of immunocompetent cells with tumor cells is illustrated in Figure 4.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +55 14 3880 0432. ORCID

Ramon Kaneno: 0000-0002-4292-3298 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Comparetti EJ was a recipient of a fellowship from São Paulo Research Foundation − FAPESP, proc.: 2014/26032-9.

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REFERENCES

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Figure 4. Cancer microenvironment is populated by immunosuppressive macrophages, dendritic cells, and lymphocytes that produce regulatory cytokines to decrease the antitumor response. CNTs can be used to carry modulatory agents to the host defense cells, and restore the pro-inflammatory activity in tumor sites, attenuating the growth of cancer cells.

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CONCLUSION The increasing incidence of several types of cancer worldwide requires the development of new therapeutic and diagnostic approaches. CNTs are efficient chemotherapeutic carriers for neoplastic cells, able to produce cytotoxic effects similarly or more efficiently than pure anti-neoplastic drugs. Conjugation with antibodies allows the internalization and increases their action on target cells. Although highly phagocytosed by immunocompetent cells, CNTs are an innocuous material, exhibiting low toxicity and causing only a few phenotypic changes. However, surface modifications produce adverse F


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