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Night Quotes. Unique Quotes. Target protein, Trx KD was observed at 48 h increasing at 72 h. Tumors were excised at 96 h after i. In vivo antitumor activity is robust with biweekly administration. The siRNA control weekly is shown with the biweekly data since only one animal was evaluable for the siRNA control biweekly ; c Hematology and blood chemistry showed no difference when performed 24 h after final injection following weekly administration for 4 weeks.

Subset of data is shown; d No weight loss was observed in animals treated weekly or biweekly not shown. There was a trend for reduced tumor growth rate when mice were treated weekly, but there was significant growth delay observed when they were treated with the same preparations on a biweekly schedule. Hematology and blood chemistry revealed no toxicity 24 h following the last i. No weight loss was observed in any of the treatment groups whether treated weekly or biweekly not shown.

Tumor localization for systemically delivered nanoparticles of siRNA relies mainly on the enhanced permeability and retention EPR effect and extravasation through leaky blood vessels in the tumor. However, most uptake of naked nanoparticles occurs by the RES of the liver and spleen, a process that is very rapid [ 54 ]. Attempts have also been made to prolong blood circulation time of the complexes as a more prolonged circulation of the nanoparticle is likely to favor accumulation in tumor by increasing the total number of passes made by the particle through the tumor vasculature [ 55 ].

Tissue elimination has been measured and was found to occur over time. Size and length of complexes were analyzed by atomic force microscopy and dynamic light scattering. The samples were processed as described and the lengths were determined using AFM as described below. SWCNT length distributions in the samples of various compositions were assessed using AFM and compared to those measured by dynamic light scattering. Hydrodynamic dimensions of SWCNT in suspension were determined by automatic software analysis of dynamic light scattering autocorrelation curves from 32 consecutive measurements.

Up to five such measurement sets were averaged and the distribution of hydrodynamic dimensions was created for each sample. Zeta potentials were measured in Malvern Instruments Folded Capillary Cells with embedded electrodes. Each measurement consisted of up to runs from which the average Zeta potential value was calculated.

Electrophoresis was performed at V for 20 min. Cells were washed and examined by bright field and fluorescence microscopy. NIR fluorescence microscopy was performed using a custom-built apparatus containing diode laser excitation sources emitting at and nm [ 57 ]. Cy-3 was excited with metal halide lamp and fluorescence was collected using a visible CCD camera CoolSnap, Princeton Instruments coupled to the microscope.

MiaCaPa-2 human pancreatic carcinoma cells were exposed to solutions of 0. Mice were sacrificed by CO 2 euthanasia at 24 h and 1 week post injection. Mice were sacrificed by CO 2 and blood was drawn by cardiac puncture at 3, 5, 10, 20, 60 min, 1, 4, and 24 h following injection. Blood samples were centrifuged at g for 15 min to separate optically transparent plasma from strongly absorbing red blood cells.

Fluorescence signals were acquired at nm laser excitation. The fluorescence spectra in PK samples comprised independent and distinct overlapping spectra of plasma autofluorescence and SWCNT fluorescence that were fit with linear combination of plasma background and SWCNT emission profile, measured independently. Mice were sacrificed by CO 2 euthanasia at 24, 48, 72 and 96 h pi. Mice were sacrificed by CO 2 euthanasia at 5 min, 1, 6 and 24 h and 1 week post injection.

For i. After the last injection animals 2 per group were sacrificed by CO 2 euthanasia at 24, 48, 72, 96 h post injection. Blood samples were collected by cardiac puncture and tissues including tumor, liver, spleen, heart, kidneys, lungs, brain, muscle, bone were flash frozen for protein knockdown and SWCNT biodistribution analyses.

Western blotting: Tissues were homogenized using a Polytron PT drive unit and a 5—7. Tissue homogenate, 0. Fluorescence signals were acquired using nm laser excitation. Fluorescence microscopy of tumor tissues : Tumor tissue slices 24, 48, 72 and 96 h post injection were analyzed using custom-built NIR fluorescence microscopy setup mentioned above. There is also no apparent cell line dependency for transfection, cellular uptake in vitro occurs rapidly and uniformly and the siRNA appears to be released from the SWCNT intracellularly.

There is concentration and time dependent KD of target proteins. Multiple siRNA payloads can be delivered in one sample preparation and the complexes can be delivered systemically to produce target KD in tumors in vivo. Importantly, antitumor activity has been demonstrated accompanied by target KD with single and dual siRNA payloads, and the pharmacokinetic half-life can be altered by modifying payload composition.

Finally, the complexes are well tolerated even with multi-day dosing for a 4 weeks period with no apparent toxicity from SWCNT in animal models bearing human tumor xenografts. Work is continuing to optimize the complex preparation and future studies will evaluate the antitumor activity of the optimized payloads.

This work has been in part supported through funding by the Emerging Technology Fund from the State of Texas. Special thanks to Sergi M. Materials Basel. Published online Feb Bruce Weisman , 3 and Olga Gliko 1. Lynn Kirkpatrick 1 Ensysce Biosciences Inc. Find articles by D. Lynn Kirkpatrick. Michelle Weiss 1 Ensysce Biosciences Inc. Find articles by Michelle Weiss. Anton Naumov 1 Ensysce Biosciences Inc.

Find articles by Anton Naumov. Bruce Weisman. Olga Gliko 1 Ensysce Biosciences Inc. Find articles by Olga Gliko. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC.

Abstract Carbon nanotubes have many unique physical and chemical properties that are being widely explored for potential applications in biomedicine especially as transporters of drugs, proteins, DNA and RNA into cells. Keywords: single-walled carbon nanotube, short interfering RNA, therapeutic delivery. Introduction Carbon nanotubes CNT have many unique physical and chemical properties that are being widely explored for potential applications in biomedicine including drug delivery systems DDS , sensors, imaging agents and composites [ 1 , 2 , 3 , 4 , 5 , 6 ].

Toxicity Pristine CNT lack solubility [ 31 ], have a tendency for the formation of thick and inhomogeneous bundles, have short circulation half-lives, bio-incompatibility and immunogenicity. Results and Discussion 2. Open in a separate window. Scheme 1. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7.

Figure 8. Figure 9. Figure Experimental Section 3. Acknowledgments This work has been in part supported through funding by the Emerging Technology Fund from the State of Texas. References 1. Liu Z. Drug delivery with carbon nanotubes for in vivo cancer treatment. Cancer Res. Carbon nanotubes in biology and medicine: In vitro and in vivo detection, imaging and drug delivery.

Nano Res. Supramolecular stacking of doxorubicin on carbon nanotubes for in vivo cancer therapy. Kostarelos K. Promises, facts and challenges for carbon nanotubes in imaging and therapeutics. Ruggiero A. Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes. Han Z. Effect of hydrophilicity of carbon nanotube arrays on the release rate and activity of recombinant human bone morphogenetic protein Beg S. Advancement in carbon nanotubes: Basics, biomedical applications and toxicity.

Pantarotto D. Functionalized carbon nanotubes for plasmid DNA gene delivery. Bartholomeusz G. Pastorin G. Crucial functionalizations of carbon nanotubes for improved drug delivery: A valuable option? Carbon nanomaterials in biological systems. Yang R. Single-walled carbon nanotubes-mediated in vivo and in vitro delivery of siRNA into antigen-presenting cells.

Gene Ther. Kam N. Functionalization of carbon nanotubes via cleavable disulfide bonds for efficient intracellular delivery of siRNA and potent gene silencing. Podesta J. Antitumor activity and prolonged survival by carbon-nanotube-mediated therapeutic siRNA silencing in a human lung xenograft model.

Al-Jamal K. Functional motor recovery from brain ischemic insult by carbon nanotube-mediated siRNA silencing. Bhirde A. Targeted killing of cancer cells in vivo and in vitro with EGF-directed carbon nanotube-based drug delivery. ACS Nano. Targeted therapy of SMMC liver cancer in vitro and in vivo with carbon nanotubes based drug delivery system. Interface Sci. Guven A. Cisplatin US-tube carbon nanocapsules for enhanced chemotherapeutic delivery.

Carbon nanotubes protect DNA strands during cellular delivery. Welsher K. A route to brightly fluorescent carbon nanotubes for near-infrared imaging in mice. Deep-tissue anatomical imaging of mice using carbon nanotube fluorophores in the second near-infrared window.

Peng G. Detection of nonpolar molecules by means of carrier scattering in random networks of carbon nanotubes: Toward diagnosis of diseases via breath samples. Nano Lett. Jin H. Detection of single-molecule H2O2 signalling from epidermal growth factor receptor using fluorescent single-walled carbon nanotubes. Heller D. Multimodal optical sensing and analyte specificity using single-walled carbon nanotubes.

Barone P. Reversible control of carbon nanotube aggregation for a glucose affinity sensor. Lin Y. Glucose biosensors based on carbon nanotube nanoelectrode ensembles. Ghosh S. Increased heating efficiency and selective thermal ablation of malignant tissue with DNA-encased multiwalled carbon nanotubes. Zhou F. Cancer photothermal therapy in the near-infrared region by using single-walled carbon nanotubes.

Robinson J. Tasis D. Soluble carbon nanotubes.

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