Non-chemotoxic induction of cancer cell death using magnetic nanowires.
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ABSTRACT:
SUBMITTER: Contreras MF
PROVIDER: S-EPMC4370947 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Exploiting and combining different properties of nanomaterials is considered a potential route for next generation cancer therapies. Magnetic nanowires (NWs) have shown good biocompatibility and a high level of cellular internalization. We induced cancer cell death by combining the chemotherapeutic effect of doxorubicin (DOX)-functionalized iron NWs with the mechanical disturbance under a low frequency alternating magnetic field. (3-aminopropyl)triethoxysilane (APTES) and bovine serum albumin (BSA) were separately used for coating NWs allowing further functionalization with DOX. Internalization was assessed for both formulations by confocal reflection microscopy and inductively coupled plasma-mass spectrometry. From confocal analysis, BSA formulations demonstrated higher internalization and less agglomeration. The functionalized NWs generated a comparable cytotoxic effect in breast cancer cells in a DOX concentration-dependent manner, (~60% at the highest concentration tested) that was significantly different from the effect produced by free DOX and non-functionalized NWs formulations. A synergistic cytotoxic effect is obtained when a magnetic field (1?mT, 10?Hz) is applied to cells treated with DOX-functionalized BSA or APTES-coated NWs, (~70% at the highest concentration). In summary, a bimodal method for cancer cell destruction was developed by the conjugation of the magneto-mechanical properties of iron NWs with the effect of DOX producing better results than the individual effects.
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Project description:Endometrial tumors with non-functional p53, such as serous uterine endometrial carcinomas, are aggressive malignancies with a poor outcome, yet they have an Achilles' heel: due to loss of p53 function, these tumors may be sensitive to treatments which abrogate the G2/M checkpoint. Our objective was to exploit this weakness to induce mitotic cell death using two strategies: (1) EGFR inhibitor gefitinib combined with paclitaxel to arrest cells at mitosis, or (2) BI2536, an inhibitor of polo-like kinase 1 (PLK1), to block PLK1 activity.We examined the impact of combining gefitinib and paclitaxel or PLK1 inhibitor on expression of G2/M checkpoint controllers, cell viability, and cell cycle progression in endometrial cancer cells with mutant p53.In cells lacking normal p53 activity, each treatment activated CDC25C and inactivated Wee1, which in turn activated cdc2 and sent cells rapidly through the G2/M checkpoint and into mitosis. Live cell imaging demonstrated irreversible mitotic arrest and eventual cell death. Combinatorial therapy with paclitaxel and gefitinib was highly synergistic and resulted in a 10-fold reduction in the IC50 for paclitaxel, from 14nM as a single agent to 1.3nM in the presence of gefitinib. However, BI2536 alone at low concentrations (5nM) was the most effective treatment and resulted in massive mitotic cell death. In a xenograft mouse model with p53-deficient cells, low dose BI2536 significantly inhibited tumor growth.These findings reveal induction of mitotic cell death as a therapeutic strategy for endometrial tumors lacking functional p53.
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Project description:The need for naturally occurring constituents is driven by the rise in the cancer prevalence and the unpleasant side effects associated with chemotherapeutics. Triptolide, the primary active component of "Tripterygium Wilfordii", has exploited for biological mechanisms and therapeutic potential against various tumors. Based on the recent pre-clinical investigations, triptolide is linked to the induction of death of cancerous cells by triggering cellular apoptosis via inhibiting heat shock protein expression (HSP70), and cyclin dependent kinase (CDKs) by up regulating expression of P21. MKP1, histone methyl transferases and RNA polymerases have all recently identified as potential targets of triptolide in cells. Autophagy, AKT signaling pathway and various pathways involving targeted proteins such as A-disintegrin & metalloprotease-10 (ADAM10), Polycystin-2 (PC-2), dCTP pyro-phosphatase 1 (DCTP1), peroxiredoxin-I (Prx-I), TAK1 binding protein (TAB1), kinase subunit (DNA-PKcs) and the xeroderma-pigmentosum B (XPB or ERCC3) have been exploited. Besides that, triptolide is responsible for enhancing the effectiveness of various chemotherapeutics. In addition, several triptolide moieties, including minnelide and LLDT8, have progressed in investigations on humans for the treatment of cancer. Targeted strategies, such as triptolide conjugation with ligands or triptolide loaded nano-carriers, are efficient techniques to confront toxicities associated with triptolide. We expect and anticipate that advances in near future, regarding combination therapies of triptolide, might be beneficial against cancerous cells.
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Project description:Selective induction of apoptosis in melanoma cells is optimal for therapeutic development. To achieve this goal, a non-thermal helium plasma torch was modified for use on cultured cells in a temperature-controlled environment. Melanoma cells were targeted with this torch (1) in parallel cultures with keratinocytes, (2) in co-culture with keratinocytes and (3) in a soft agar matrix. Melanoma cells displayed high sensitivity to reactive oxygen species generated by the torch and showed a 6-fold increase in cell death compared with keratinocytes. The extent of cell death was compared between melanoma cells and normal human keratinocytes in both short-term (5 min) co-culture experiments and longer assessments of apoptotic cell death (18-24 h). Following a 10 sec plasma exposure there was a 4.9-fold increase in the cell death of melanoma vs. keratinocytes as measured after 24 h at the target site of the plasma beam. When the treatment time was increased to 30 sec, a 98% cell death was reported for melanoma cells, which was 6-fold greater than the extent of cell death in keratinocytes. Our observations further indicate that this preferential cell death is largely due to apoptosis.. In addition, we report that this non-thermal plasma torch kills melanoma cells growing in soft agar, suggesting that the plasma torch is capable of inducing melanoma cell death in 3D settings. We demonstrate that the presence of gap junctions may increase the area of cell death, likely due to the "bystander effect" of passing apoptotic signals between cells. Our findings provide a basis for further development of this non-invasive plasma torch as a potential treatment for melanoma.
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Project description:Isolating and analyzing tumor-derived exosomes (TEX) can provide important information about the state of a tumor, facilitating early diagnosis and prognosis. Since current isolation methods are mostly laborious and expensive, we propose herein a fast and cost-effective method based on a magnetic nanoplatform to isolate TEX. In this work, we have tested our method using three magnetic nanostructures: (i) Ni magnetic nanowires (MNWs) (1500 × 40 nm), (ii) Fe3O4 nanorods (NRs) (41 × 7 nm), and (iii) Fe3O4 cube-octahedral magnetosomes (MGs) (45 nm) obtained from magnetotactic bacteria. The magnetic response of these nanostructures has been characterized, and we have followed their internalization inside canine osteosarcoma OSCA-8 cells. An overall depiction has been obtained using a combination of Fluorescence and Scanning Electron Microscopies. In addition, Transmission Electron Microscopy images have shown that the nanostructures, with different signs of degradation, ended up being incorporated in endosomal compartments inside the cells. Small intra-endosomal vesicles that could be precursors for TEX have also been identified. Finally, TEX have been isolated using our magnetic isolation method and analyzed with a Nanoparticle tracking analyzer (NanoSight). We observed that the amount and purity of TEX isolated magnetically with MNWs was higher than with NRs and MGs, and they were close to the results obtained using conventional non-magnetic isolation methods.
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Project description:There is a significant need for in vitro methods to study drug-induced liver injury that are rapid, reproducible, and scalable for existing high-throughput systems. However, traditional monolayer and suspension cultures of hepatocytes are difficult to handle and risk the loss of phenotype. Generally, three-dimensional (3D) cell culture platforms help recapitulate native liver tissue phenotype, but suffer from technical limitations for high-throughput screening, including scalability, speed, and handling. Here, we developed a novel assay for cytochrome P450 (CYP450) induction/inhibition using magnetic 3D cell culture that overcomes the limitations of other platforms by aggregating magnetized cells with magnetic forces. With this platform, spheroids can be rapidly assembled and easily handled, while replicating native liver function. We assembled spheroids of primary human hepatocytes in a 384-well format and maintained this culture over five days, including a 72 h induction period with known CYP450 inducers/inhibitors. CYP450 activity and viability in the spheroids were assessed and compared in parallel with monolayers. CYP450 activity was induced/inhibited in spheroids as expected, separate from any toxic response. Spheroids showed a significantly higher baseline level of CYP450 activity and induction over monolayers. Positive staining in spheroids for albumin and multidrug resistance-associated protein (MRP2) indicates the preservation of hepatocyte function within spheroids. The study presents a proof-of-concept for the use of magnetic 3D cell culture for the assembly and handling of novel hepatic tissue models.
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Project description:BACKGROUND:Identifying the precise location of cells and their migration dynamics is of utmost importance for achieving the therapeutic potential of cells after implantation into a host. Magnetic resonance imaging is a suitable, non-invasive technique for cell monitoring when used in combination with contrast agents. RESULTS:This work shows that nanowires with an iron core and an iron oxide shell are excellent materials for this application, due to their customizable magnetic properties and biocompatibility. The longitudinal and transverse magnetic relaxivities of the core-shell nanowires were evaluated at 1.5 T, revealing a high performance as T2 contrast agents. Different levels of oxidation and various surface coatings were tested at 7 T. Their effects on the T2 contrast were reflected in the tailored transverse relaxivities. Finally, the detection of nanowire-labeled breast cancer cells was demonstrated in T2-weighted images of cells implanted in both, in vitro in tissue-mimicking phantoms and in vivo in mouse brain. Labeling the cells with a nanowire concentration of 0.8 ?g of Fe/mL allowed the detection of 25 cells/µL in vitro, diminishing the possibility of side effects. This performance enabled an efficient labelling for high-resolution cell detection after in vivo implantation (~?10 nanowire-labeled cells) over a minimum of 40 days. CONCLUSIONS:Iron-iron oxide core-shell nanowires enabled the efficient and longitudinal cellular detection through magnetic resonance imaging acting as T2 contrast agents. Combined with the possibility of magnetic guidance as well as triggering of cellular responses, for instance by the recently discovered strong photothermal response, opens the door to new horizons in cell therapy and make iron-iron oxide core-shell nanowires a promising theranostic platform.
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Project description:The emergent interest in artificial nanostructures that can be remotely navigated a specific location in a fluidic environment is motivated by the enormous potential this technology offers to biomedical applications. Originally, bio-inspired micro-/nanohelices driven by a rotating magnetic field were proposed. However, fabrication of 3D helical nanostructures is complicated. One idea to circumvent complex microfabrication is to use 1D soft magnetic nanowires that acquire chiral shape when actuated by a rotating field. The paper describes the comprehensive numerical approach for modeling propulsion of externally actuated soft magnetic nanowires. The proposed bead-spring model allows for arbitrary filament geometry and flexibility and takes rigorous account of intra-filament hydrodynamic interactions. The comparison of the numerical predictions with the previous experimental results on propulsion of composite two-segment (Ni-Ag) nanowires shows an excellent agreement. Using our model we could substantiate and rationalize important and previously unexplained details, such as bidirectional propulsion of three-segment (Ni-Ag-Au) nanowires.
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