Multifunctional Polymer‐Coated Carbon Nanotubes for Safe Drug Delivery

Though progress in the use carbon nanotubes in medicine has been most encouraging for therapeutic and diagnostic applications, any translational success must involve overcoming the toxicological and surface functionalization challenges inherent in the use of such nanotubes. Ideally, a carbon nanotube-based drug delivery system would exhibit low toxicity, sustained drug release, and persist in circulation without aggregation. We report a carbon nanotube (CNT) coated with a biocompatible block-co-polymer composed of poly(lactide)-poly(ethylene glycol) (PLA-PEG) to reduce short-term and long-term toxicity, sustain drug release of paclitaxel (PTX), and prevent aggregation. The copolymer coating on the surface of CNTs significantly reduces in vitro toxicity in human umbilical vein endothelial cells (HUVEC) and U-87 glioblastoma cells. Moreover, coating reduces in vitro inflammatory response in rat lung epithelial cells. Compared to non-coated CNTs, in vivo studies show no long-term inflammatory response with CNT coated with PLA-PEG (CLP) and the surface coating significantly decreases acute toxicity by doubling the maximum tolerated dose in mice. Using polymer coatings, we can encapsulate PTX and release over one week to increase the therapeutic efficacy compared to free drugs. In vivo biodistribution and histology studies suggests a lower degree of aggregation in tissues in that CLP accumulate more in the brain and less in the spleen than the CNT-PLA (CL) formulation.

[1]  H. Aoki,et al.  An in vivo study on the reaction of hydroxyapatite-sol injected into blood , 2000, Journal of materials science. Materials in medicine.

[2]  Allan S. Hoffman,et al.  Biosafety of Non-Surface Modified Carbon Nanocapsules as a Potential Alternative to Carbon Nanotubes for Drug Delivery Purposes , 2012, PloS one.

[3]  A. Rao,et al.  A carbon nanotube toxicity paradigm driven by mast cells and the IL-₃₃/ST₂ axis. , 2012, Small.

[4]  Maurizio Prato,et al.  Double functionalization of carbon nanotubes for multimodal drug delivery. , 2006, Chemical communications.

[5]  Craig A. Poland,et al.  Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. , 2008, Nature nanotechnology.

[6]  Magnus Bergkvist,et al.  Paradoxical glomerular filtration of carbon nanotubes , 2010, Proceedings of the National Academy of Sciences.

[7]  Zhuang Liu,et al.  A route to brightly fluorescent carbon nanotubes for near-infrared imaging in mice. , 2009, Nature nanotechnology.

[8]  M Laird Forrest,et al.  Effects of nanomaterial physicochemical properties on in vivo toxicity. , 2009, Advanced drug delivery reviews.

[9]  H. Dai,et al.  In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. , 2020, Nature nanotechnology.

[10]  M. Annunziato,et al.  p-maleimidophenyl isocyanate: a novel heterobifunctional linker for hydroxyl to thiol coupling. , 1993, Bioconjugate chemistry.

[11]  Eric Pridgen,et al.  Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles , 2008, Molecular pharmaceutics.

[12]  J. Hedrick,et al.  Organocatalytic ring-opening polymerization. , 2007, Chemical reviews.

[13]  H. Dai,et al.  Soluble single-walled carbon nanotubes as longboat delivery systems for platinum(IV) anticancer drug design. , 2007, Journal of the American Chemical Society.

[14]  Zhuang Liu,et al.  Drug delivery with carbon nanotubes for in vivo cancer treatment. , 2008, Cancer research.

[15]  Daniel A. Heller,et al.  Treating metastatic cancer with nanotechnology , 2011, Nature Reviews Cancer.

[16]  J. Saunders,et al.  The chemistry of the organic isocyanates. , 1948, Chemical reviews.

[17]  Hongjie Dai,et al.  Supramolecular Chemistry on Water- Soluble Carbon Nanotubes for Drug Loading and Delivery , 2007 .

[18]  R. Shukla,et al.  Functionalized radioactive gold nanoparticles in tumor therapy. , 2012, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[19]  P. G. Gemeinhardt,et al.  Catalysis of the isocyanate‐hydroxyl reaction , 1960 .

[20]  Weibo Cai,et al.  Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy , 2008, Proceedings of the National Academy of Sciences.

[21]  P. Ajayan,et al.  Long-term survival following a single treatment of kidney tumors with multiwalled carbon nanotubes and near-infrared radiation , 2009, Proceedings of the National Academy of Sciences.

[22]  Kostas Kostarelos,et al.  The long and short of carbon nanotube toxicity , 2008, Nature Biotechnology.

[23]  James F Rusling,et al.  Targeted killing of cancer cells in vivo and in vitro with EGF-directed carbon nanotube-based drug delivery. , 2009, ACS nano.

[24]  Maurizio Prato,et al.  Carbon-nanotube shape and individualization critical for renal excretion. , 2008, Small.

[25]  S. Gambhir,et al.  Noninvasive Raman spectroscopy in living mice for evaluation of tumor targeting with carbon nanotubes. , 2008, Nano letters.

[26]  Kostas Kostarelos Carbon nanotubes: Fibrillar pharmacology. , 2010, Nature materials.

[27]  P. Norris,et al.  The expression of endothelial leukocyte adhesion molecule-1 (ELAM-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in experimental cutaneous inflammation: a comparison of ultraviolet B erythema and delayed hypersensitivity. , 1991, The Journal of investigative dermatology.

[28]  Ren-Shen Lee,et al.  Polymer-grafted multi-walled carbon nanotubes through surface-initiated ring-opening polymerization and click reaction , 2011 .

[29]  H. Dai,et al.  Targeted single-wall carbon nanotube-mediated Pt(IV) prodrug delivery using folate as a homing device. , 2008, Journal of the American Chemical Society.

[30]  I. Wilson,et al.  Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. , 2000, European journal of biochemistry.

[31]  Toshiro Hirai,et al.  Amorphous nanosilica induce endocytosis-dependent ROS generation and DNA damage in human keratinocytes , 2011, Particle and Fibre Toxicology.

[32]  Zhen Zheng,et al.  A facile approach to covalently functionalized carbon nanotubes with biocompatible polymer , 2007 .

[33]  A. Gearing,et al.  Soluble forms of E-selectin, ICAM-1 and VCAM-1 are present in the supernatants of cytokine activated cultured endothelial cells. , 1992, Biochemical and biophysical research communications.

[34]  M. Prato,et al.  Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Mark E. Davis,et al.  Clinical Developments in Nanotechnology for Cancer Therapy , 2011, Pharmaceutical Research.

[36]  Sanjiv S Gambhir,et al.  A pilot toxicology study of single-walled carbon nanotubes in a small sample of mice. , 2008, Nature nanotechnology.

[37]  M. Prato,et al.  Tissue histology and physiology following intravenous administration of different types of functionalized multiwalled carbon nanotubes. , 2008, Nanomedicine.

[38]  Jamie M. Messman,et al.  Organocatalytic stereoselective ring-opening polymerization of lactide with dimeric phosphazene bases. , 2007, Journal of the American Chemical Society.

[39]  Paolo Verderio,et al.  Cytotoxicity of some catalysts commonly used in the synthesis of copolymers for biomedical use , 1994 .

[40]  J. Karp,et al.  Nanocarriers as an Emerging Platform for Cancer Therapy , 2022 .

[41]  K Kostarelos,et al.  Promises, facts and challenges for carbon nanotubes in imaging and therapeutics. , 2009, Nature nanotechnology.