We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine
Research Article

Distribution and clearance of PEG-single-walled carbon nanotube cancer drug delivery vehicles in mice

    Ashwin A Bhirde

    Department of Chemistry, University of Connecticut, Storrs, CT, USA

    ,
    Sachin Patel

    Oral & Pharyngeal Cancer Branch, National Institute of Dental & Craniofacial Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA

    ,
    Alioscka A Sousa

    Laboratory of Cellular Imaging & Macromolecular Biophysics, National Institute of Biomedical Imaging & Bioengineering, NIH, Bethesda, MD 20892, USA

    , ,
    Alfredo A Molinolo

    Oral & Pharyngeal Cancer Branch, National Institute of Dental & Craniofacial Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA

    ,
    Youngmi Ji

    Clinical & Experimental Orthopedics, National Institute of Arthritis, & Musculoskeletal & Skin Diseases, NIH, Bethesda, MD, USA

    ,
    Richard D Leapman

    Laboratory of Cellular Imaging & Macromolecular Biophysics, National Institute of Biomedical Imaging & Bioengineering, NIH, Bethesda, MD 20892, USA

    ,
    J Silvio Gutkind

    Oral & Pharyngeal Cancer Branch, National Institute of Dental & Craniofacial Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA

    &
    James F Rusling

    Department of Chemistry, University of Connecticut, Storrs, CT, USA

    Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA

    Institute of Materials Science, University of Connecticut, Storrs, CT, USA

    Published Online:https://doi.org/10.2217/nnm.10.90

    Aims: To study the distribution and clearance of polyethylene glycol (PEG)-ylated single-walled carbon nanotube (SWCNTs) as drug delivery vehicles for the anticancer drug cisplatin in mice. Materials & methods: PEG layers were attached to SWCNTs and dispersed in aqueous media and characterized using dynamic light scattering, scanning transmission electron microscopy and Raman spectroscopy. Cytotoxicity was assessed in vitro using Annexin-V assay, and the distribution and clearance pathways in mice were studied by histological staining and Raman spectroscopy. Efficacy of PEG-SWCNT–cisplatin for tumor growth inhibition was studied in mice. Results & discussion: PEG-SWCNTs were efficiently dispersed in aqueous media compared with controls, and did not induce apoptosis in vitro. Hematoxylin and eosin staining, and Raman bands for SWCNTs in tissues from several vital organs from mice injected intravenously with nanotube bioconjugates revealed that control SWCNTs were lodged in lung tissue as large aggregates compared with the PEG-SWCNTs, which showed little or no accumulation. Characteristic SWCNT Raman bands in feces revealed the presence of bilary or renal excretion routes. Attachment of cisplatin on bioconjugates was visualized with Z-contrast scanning transmission electron microscopy. PEG-SWCNT–cisplatin with the attached targeting ligand EGF successfully inhibited growth of head and neck tumor xenografts in mice. Conclusions: PEG-SWCNTs, as opposed to control SWCNTs, form more highly dispersed delivery vehicles that, when loaded with both cisplatin and EGF, inhibit growth of squamous cell tumors.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • Hirsch A: Functionalization of single-walled carbon nanotubes. Angew. Chem. Int. Ed.41,1853–1859 (2002).
    • Bianco A, Kostarelos K, Prato M: Opportunities and challenges of carbon-based nanomaterials for cancer therapy. Expert Opin. Drug Deliv.5,331–342 (2008).▪▪ Describes the biomedical applications of a variety of carbon nanomaterials studied, especially nanotubes. Discusses the potential benefits and risks of carbon nanomaterials towards clinical application.
    • Dillon AC, Yudasaka M, Dresselhaus MS: Employing Raman spectroscopy to qualitatively evaluate the purity of carbon single-wall nanotube materials. J. Nanosci. Nanotechnol.4,691–703 (2004).
    • Kam S, Dai H: Carbon nanotubes as intracellular protein transporters. generality and biological functionality. J. Am. Chem. Soc.127,6021–6026 (2005).
    • Yang R, Yang X, Zhang Z et al.: Single-walled carbon nanotubes-mediated in vivo and in vitrodelivery of siRNA into antigen-presenting cells. Gene Therapy13,1714–1723 (2006).
    • Singh R, Pantarotto P, McCarthy D et al.: Binding and condensation of plasmid DNA onto functionalized carbon nanotubes: toward the construction of nanotube-based gene delivery vectors. J. Am. Chem. Soc.127(12),4388–4396 (2005).
    • Liu Z, Winters M, Holodniy M, Dai H: siRNA delivery into human T cells and primary cells with carbon-nanotube transporters. Angew. Chem. Int. Ed.46,2023–2027 (2007).
    • Kam NWS, Liu Z, Dai HJ: Functionalization of carbon nanotubes via cleavable disulfide bonds for efficient intracellular delivery of siRNA and potent gene silencing. Am. Chem. Soc.127,6021–6026 (2005).
    • Liu Z, Chen K, Davis C et al.: Drug delivery with carbon nanotubes for in vivo cancer treatment. Cancer Res.68,6652–6660 (2008).
    • 10  Kostarelos K, Bianco A, Prato M: Promises, facts and challenges for carbon nanotubes in imaging and therapeutics. Nat. Nanotechnol.4,627–633 (2009).▪▪ Provides the most recent advances in carbon nanotube-based imaging and therapeutics. Highlights the current trends and what needs to be addressed next towards carbon nanotubes as delivery vectors.
    • 11  Kim DK, Dobson J: Nanomedicine for targeted drug delivery. J. Mater. Chem.19,6294–6307 (2009).
    • 12  Wang H, Chen XY: Applications for site-directed molecular imaging agents coupled with drug delivery potential. Expert Opin. Drug Deliv.6,745–768 (2009).
    • 13  Pietronave S, Iafisco M, Locarno D, Rimondini L, Prat M: Functionalized nanomaterials for diagnosis and therapy of cancer. J. Appl. Biomater. Biomech.7,77–89 (2009).
    • 14  Lison D, Muller J: Lung and systemic responses to carbon nanotubes (CNT) in mice. Toxicol. Sci.101,179–180 (2008).
    • 15  Quintana M, Prato M: Supramolecular aggregation of functionalized carbon nanotubes. Chem. Commun.40,6005–6007 (2009).
    • 16  Kostarelos K: The long and short of carbon nanotube toxicity. Nat. Biotechnol.26,774–776 (2008).
    • 17  Lam CW, James JT, McCluskey R, Hunter RL: Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation. Toxicol. Sci.77,126–134 (2004).
    • 18  Carrero-Sanchez JC, Elías AL, Mancilla R et al.: Biocompatibility and toxicological studies of carbon nanotubes doped with nitrogen. Nano Lett.6,1609 (2006).
    • 19  Donaldson K, Poland C: Nanotoxicology: new insights into nanotubes. Nat. Nanotechnol.4,708–710 (2009).
    • 20  Mitchell LA, Lauer FT, Burchiel SW, McDonald JD: Mechanisms for how inhaled multiwalled carbon nanotubes suppress systemic immune function in mice. Nat. Nanotechnol.4,451–456 (2009).
    • 21  Poland C, Duffin R, Kinloch I et al.: Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat. Nanotechnol.3,423–428 (2008).
    • 22  Schipper ML, Nakayama-Ratchford N, Davis CR: A pilot toxicology study of single-walled carbon nanotubes in a small sample of mice. Nat. Nanotechnol.3,216–221 (2008).
    • 23  Simeonova P: Update on carbon nanotube toxicity. Nanomedicine4,373–375 (2009).▪ This short update highlights the main toxicity issues involving carbon nanotubes.
    • 24  Veronese F, Pasut G: PEGylation, successful approach to drug delivery. Drug Discov. Today10,1451–1458 (2005).
    • 25  Jiang W, Mardyani S, Fischer H, Chan WCW: Design and characterization of lysine cross-linked mercapto-acid biocompatible quantum dots. Chem. Mater.4,872–878 (2006).
    • 26  Mulder WJM, Koole R, Brandwijk RJ et al.: Surfactant-assisted synthesis of water-soluble and biocompatible semiconductor quantum dot micelles. Nano Lett.6,1–6 (2006).
    • 27  Adams M, Lavasanifar A, Kwon G: Amphiphilic block copolymers for drug delivery. J. Pharm. Sci.92,1343–1355 (2003).
    • 28  Kwon GS, Suwa S, Yokoyama M, Okano T, Sakurai Y, Kataoka K: Enhanced tumor accumulation and prolonged circulation times of micelle-forming poly(ethylene oxide-aspartate) block copolymer–adriamycin conjugates. J. Control. Release29,17–23 (1994).
    • 29  Li Y, Kwon GS: Methotrexate esters of poly(ethylene oxide)-block-poly(2-hydroxyethyl-L-aspartamide). I. Effects of the level of methotrexate conjugation on the stability of micelles and on drug release. Pharm. Res.17,607–611 (2000).
    • 30  Nishiyama N, Kataoka K: Preparation and characterization of size-controlled polymeric micelle containing cis-dichlorodiammineplatinum (II) in the core. J. Control. Release74,83–94 (2001).
    • 31  Burt HM, Zhang X, Toleikis P, Embree L, Hunter WL: Development of copolymers of poly(d,l-lactide) and methoxypolyethylene glycol as micellar carriers of paclitaxel. Colloids Surf. B Biointerfaces16,161–171 (1999).
    • 32  Nish A, Nicholas J: Temperature induced restoration of fluorescence from oxidised single-walled carbon nanotubes in aqueous sodium dodecylsulfate solution. Phys. Chem. Chem. Phys.8,3547–3551 (2006).
    • 33  Matarredona O, Rhoads H, Zhongrui L, Harwell J, Balzano L, Resasco D: Dispersion of single-walled carbon nanotubes in aqueous solutions of the anionic surfactant NaDDBS. J. Phys. Chem. B107,13357–13367 (2003).
    • 34  Zheng M, Jagota A, Semke E et al.: DNA-assisted dispersion and separation of carbon nanotubes. Nat. Mater.2,338–342 (2003).
    • 35  Ju S, Doll J, Sharma I, Papadimitrakopoulos F: Selection of carbon nanotubes with specific chiralities using helical assemblies of flavin mononucleotide. Nat. Nanotechnol.3,356–362 (2008).
    • 36  Yang M, Koutsos V, Zaiser M: Interactions between polymers and carbon nanotubes: a molecular dynamics study. J. Phys. Chem. B109,10009–10014 (2005).
    • 37  Nish A, Hwang J, Doig J, Nicholas R: Highly selective dispersion of single-walled carbon nanotubes using aromatic polymers. Nat. Nanotechnol.2,640–646 (2007).
    • 38  Liu Z, Sun X, Ratchford N, Dai H: Supramolecular chemistry on water-soluble carbon nanotubes for drug loading and delivery. ACS Nano.1,50–56 (2007).
    • 39  Liu Y, Wu D, Zhang W et al.: Polyethylenimine-grafted multiwalled carbon nanotubes for secure noncovalent immobilization and efficient delivery of DNA. Angew. Chem. Int. Ed.44,4782–4785 (2005).
    • 40  Owens D, Peppas N: Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. J.Pharm.307,93–102 (2006).
    • 41  Yang S, Fernando K, Liu J et al.: Covalently PEGylated carbon nanotubes with stealth character in vivo.Small4,940–944 (2008).
    • 42  Ryan SM, Mantovani G, Wang X, Haddleton DM, Brayden DJ: Advances in PEGylation of important biotech molecules: delivery aspects. Expert Opin. Drug Deliv.5,371–383 (2008).
    • 43  Wang A, Gu F, Zhang L et al.: Biofunctionalized targeted nanoparticles for therapeutic applications. Expert Opin. Biol. Ther.8,1063–1070 (2008).
    • 44  Liu Z, Davis C, Cai W, He L, Chen X, Dai H: Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy. Proc. Natl Acad. Sci. USA105,1410–1415 (2008).
    • 45  Zeineldin R, Al-Haik M, Hudson L: Role of polyethylene glycol integrity in specific receptor targeting of carbon nanotubes to cancer cells. Nano Lett.9,751–757 (2009).
    • 46  Podesta J, Al-Jamal K, Herrero M et al.: Antitumor activity and prolonged survival by carbon-nanotube-mediated therapeutic siRNA silencing in a human lung xenograft model. Small5,1176–1185 (2009).
    • 47  Kelland L: The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer7,573–584 (2007).
    • 48  Bhirde A, Patel V, Gavard J et al.: Targeting killing of cancer cells in vivo and in vitro with EGF-directed carbon nanotube-based drug delivery. ACSNano3,307–316 (2009).▪ Describes the site-specific targeting capabilities of carbon nanotubes for chemotherapeutic drug targeting both in vitro and in vivo.
    • 49  Gabano E, Ravera M, Cassino C, Bonetti S, Palmisano G, Osella D: Stepwise assembly of platinum–folic acid conjugates. Inorganica Chimica Acta361,1447–1455 (2008).
    • 50  Cardinali M, Pietraszkiewicz H, Ensley J, Robbins K: Tyrosine phosphorylation as a marker for aberrantly regulated growth-promoting pathways in cell lines derived from head and neck malignancies. Int. J. Cancer61,98–103 (1995).
    • 51  Prencipe G, Tabakman S, Welsher K et al.: PEG branched polymer for functionalization of nanomaterials with ultralong blood circulation. J. Am. Chem. Soc.131,4783–4787 (2009).
    • 52  Lee J, Kim J, An K et al.: Electrophoretic and dynamic light scattering in evaluating dispersion and size distribution of single-walled carbon nanotubes. J. Nanosci. Nanotech.5,1045–1049 (2005).
    • 53  Isobe H, Tanaka T, Maeda R et al.: Preparation, purification, characterization, and cytotoxicity assessment of water-soluble, transition-metal-free carbon nanotube aggregates. Angew. Chem. Int. Ed.45,6676–6680 (2006).
    • 54  Hong S, Tobias G, Ballesteros B et al. Atomic scale detection of organic molecules coupled to single-wall carbon nanotubes. J. Am. Chem. Soc.129,10966–10967 (2007).
    • 55  Porter A, Gass M, Bendall J et al.: Uptake of noncytotoxic acid-treated single-walled carbon nanotubes into the cytoplasm of human macrophage cells. ACS Nano.3,1485–1492 (2009).
    • 56  Bhirde A, Sousa A, Patel V et al.: Imaging the distribution of individual platinum-based anticancer drug molecules attached to single-wall carbon nanotubes. Nanomedicine4,763–772 (2009).▪ Describes the distribution of chemotherapeutic drug cisplatin onto single-walled carbon nanotubes using electron microscopy.
    • 57  Liu Z, Cai W, He L et al.: In vivo biodistribution and highly efficient tumor targeting of carbon manotubes in mice. Nat. Nanotechnol.2,47–52 (2007).
    • 58  Graupner R: Raman spectroscopy of covalently functionalized single-wall carbon nanotubes. J. Raman Spectrosc.38,673–683 (2007).
    • 59  Schipper M, Ratchford N, Davis C et al.: A Pilot toxicology study of single-walled carbon nanotubes in a small sample of mice. Nat. Nanotechnol.3,216–221 (2008).
    • 60  Shen Y, Tang H, Radosz M, Van Kirk E, Murdoch WJ: pH-responsive nanoparticles for cancer drug delivery. Methods Mol. Biol.437,183–216 (2008).
    • 61  Liu Z, Cai W, He L et al.: In vivo biodistribution and highly efficient tumor targeting of carbon nanotubes in mice. Nat. Nanotechnol.2,47–52 (2007).
    • 62  Zeineldin R, Al-Haik M, Hudson L: Role of polyethylene glycol integrity in specific receptor targeting of carbon nanotubes to cancer cells. Nano Lett.9,751–757 (2009).
    • 63  Yang S, Fernando K, Liu J et al.: Covalently PEGylated carbon nanotubes with stealth character in vivo.Small4,940–944 (2008).
    • 64  Jung H, Ko K, Jung T: Aggregation behavior of chemically attached poly(ethylene glycol) to single-walled carbon nanotubes (SWNTs) ropes. Mater. Sci. Eng. C24,117–121 (2004).