WO2008048272A2 - Procédé de délivrance de médicament par des nanotube de carbone-nanocomplexes de chitosane - Google Patents

Procédé de délivrance de médicament par des nanotube de carbone-nanocomplexes de chitosane Download PDF

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Publication number
WO2008048272A2
WO2008048272A2 PCT/US2006/041570 US2006041570W WO2008048272A2 WO 2008048272 A2 WO2008048272 A2 WO 2008048272A2 US 2006041570 W US2006041570 W US 2006041570W WO 2008048272 A2 WO2008048272 A2 WO 2008048272A2
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Prior art keywords
chitosan
carbon nanotube
functionalized
dna
carbon nanotubes
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PCT/US2006/041570
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English (en)
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WO2008048272A3 (fr
WO2008048272A9 (fr
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Shyam S. Mohapatra
Arun Kumar
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University Of South Florida
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Priority to US12/105,884 priority Critical patent/US8536324B2/en
Publication of WO2008048272A2 publication Critical patent/WO2008048272A2/fr
Publication of WO2008048272A9 publication Critical patent/WO2008048272A9/fr
Publication of WO2008048272A3 publication Critical patent/WO2008048272A3/fr
Priority to US13/965,527 priority patent/US20140023588A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
    • A61K48/0041—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being polymeric

Definitions

  • This invention relates to drug delivery systems. More specifically, this invention relates to methods of preparing carbon nanotube-chitosan complexes nanocomplexes and their use in diagnostic and drug delivery systems. BACKGROUND OF THE INVENTION
  • Nanoparticles have been employed for a number of applications such as enzyme immobilization and drug delivery systems to solve various health problems. Nanomaterials are expected to have further impact on biomedicine, biosensors, diagnostics, and drug delivery systems [7-9].
  • Carbon nanotubes (CNTs) and their compatibility with aqueous environments have made it possible to interact with biological components including mammalian cells.
  • Chemical functional ization of CNT surface allows the functionalized CNT molecules (f-CNT) to be explored in advanced biotechnological applications. Functionalization is one of the most commonly used strategies to make CNT soluble in aqueous media. It makes f-CNT useful for biomedical applications.
  • Carbon nanotubes can be functionalized either by covalent or noncovalent methodologies.
  • Various biological applications of functionalized carbon nanotubes (f-CNTs) include their use as substrates for neuronal cell growth, as bioseparators and biocatalysts [10-14].
  • FET field-effective-transistors
  • ssDNAs single-strand DNA chains
  • the hybridization is detected by using redox method [15-18].
  • Carbon nanotubes can be used as stores for DNA or peptide molecules which have high . potential in gene delivery system and molecular therapy of diseases [19-20].
  • Carbon nanotubes can also be used to fabricate nanomotors, which can enter inside the cells to treat diseases. So far, the influence of carbon nanotubes and the associated nanomaterials or nanodevices on human health and environment has been a focus of current investigation. Carbon nanotubes can be functionalized to achieve improved0 properties and functions such as biocompatibility and biomolecular recognition capabilities [21-22]. The potential with which carbon nanotubes can be applied in biomedical engineering and medicinal chemistry is highly dependent upon their biocompatibility. Carbon nanotubes exhibit cytotoxicity to human keratinocyte cells [23-24], can inhibit the growth of embryonic rat-brain neuron cells [25] and induce5 the formation of mouse-lung granulomas [26-28].
  • CNT fits snugly into the major groove of double standard DNA, since the diameter of single-walled CNT is compatible with the size of the DNA major groove. Moreover, CNT is a semi conducting material which offers the possibility of being used as switching device.
  • the geometry of the combined DNA and CNT system was0 modeled using the CHARMM computational package with a properly adapted graphitic carbon force field for treating CNTs. Hybridization of electronic orbital between the CNT and the DNA is also included in this model [29-31].
  • streptavidin-functionalized SWCNT was directed to the right location on the scaffold dsDNA molecule. SWNTs were solubilized in water by micellization in5 SDS.
  • SWNTs were functionalized with streptavidin by nonspecific adsorption [32-33]. Fluorescence microscopy of SWNTs with fluorescently labeled streptavidin indicated homogeneous coverage of the nanotubes with streptavidin [34].
  • Carbon nanotubes have several advantages for drug delivery: i) size in the range of 10-40nm, ii) ability to provide a rod-like scaffold, iii) increased capacity to carry drugs, iv) ability to deliver drugs to the nucleus and v) inert and non-toxic nature.
  • researchers have obtained evidence showing the potential of carbon nanotubes in directed and targeted delivery of peptides and nucleic acids [35-36].
  • modification of nanotubes by adding certain functional groups enabled delivery of small peptides into the nuclei of fibroblast cells [37].
  • Chitosan has been shown to deliver genes into cells, but delivery of peptides by chitosan is limited. We reasoned that CNT coated with chitosan may facilitate peptide delivery and chitosan may reduce the toxicity of CNT to cells.
  • SWCNT single wall carbon nanotubes
  • the present invention provides a functionalized carbon nanotube comprising a chitosan or a derivative thereof attached thereto wherein the chitosan species is operable to bind one or more biomolecules.
  • the functionalized carbon nanotube further comprises one or more bioactive substances including peptides, proteins, nucleic acids and drugs.
  • the present invention provides a method for preparing a chitosan single-walled carbon nanotubes comprising the steps of providing a functionalized carbon nanotube, providing a chitosan solution and contacting the functionalized carbon nanotube with the chitosan solution.
  • the method can further include, within the step of providing a chitosan solution, the steps of dissolving chitosan or a derivative thereof in an about 0.05M HCl solution at a temperature of about 80° to about 90° to a concentration of about 0.5% by weight, reducing the temperature of the solution to room temperature and adjusting the pH of the solution to about 4.5 with concentrated potassium hydroxide.
  • the method can further include the step of complexing the chitosan single-walled carbon nanotubes with one or more nucleic acids or one or more peptides.
  • the present invention provides a method for delivering a desired
  • biomolecule to a subject comprising the steps of providing a carbon nanotube chitosan complexed to a desired biomolecule and contacting a subject with the complexed carbon nanotube chitosan preparation.
  • the desired biomolecule can be peptides, proteins, nucleic acids and drugs.
  • the complexed carbon nanotube chitosan can delivered to effect drug delivery to the subject, effect diagnostics in the subject or it j - can be delivered as a biosensor for the subject.
  • FIG. 1 is an illustration depicting the functionalization strategy for SWCNT.
  • FIG 2 illustrates the transduction of efficiency of f-SWCNT-chitosan for delivery of peptide.
  • A Fluorescent microscopy of chitosan transduced BAL cells.
  • B Percent chitosan positive cells quantified from A.
  • FIG. 3 is a series of photographs demonstrating that CNT enabled chitosan to deliver 25 peptides into cells.
  • FIG. 4 is a scanning electron micrograph (SEM) of functionalized carbon nanotubes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
  • the disclosed invention is a system and method of drug delivery using carbon 30 nanotube chitosan nanocomplexes.
  • the organic functionalisation of carbon nanotubes can improve substantially their solubility and biocompatibility profile; as a consequence, their manipulation and integration into biological systems has become possible so that functionalised carbon nanotubes hold currently strong promise as novel systems for the delivery of drugs, antigens and genes.fBiomedical applications
  • chitosan will be understood by those skilled in the art to include all derivatives of chitin, or poly-N-aceryl-D-glucosamine (including all polyglucosamine and oligomers of glucosamine materials of different molecular weights), in which the greater proportion of the N-acetyl groups have been removed through hydrolysis.
  • chitosans are a family of cationic, binary hetero- polysaccharides composed of (l ⁇ 4)-linked 2-acetamido-2-deoxy- ⁇ -D-glucose (GIcNAc, A-unit) and 2-amino-2-deoxy- ⁇ -D-glucose, (GIcN; D-unit) (Varum K. M.
  • the chitosan has a positive charge.
  • Chitosan, chitosan derivatives or salts e.g., nitrate, phosphate, sulphate, hydrochloride, glutamate, lactate or acetate salts
  • chitosan derivatives are intended to
  • ⁇ n include ester, ether or other derivatives formed by bonding of acyl and/or alkyl groups with OH groups, but not the NH 2 groups, of chitosan.
  • Examples are O-alkyl ethers of chitosan and O-acyl esters of chitosan.
  • Modified chitosans, particularly those conjugated to polyethylene glycol, are included in this definition.
  • Low and medium viscosity chitosans for example CLl 13, G210 and CLI lO
  • SWCNT Single Wall Carbon Nanotube
  • Step 1 To prepare peroxide (succinic) 10 g of succinic anhydride fine powder was added to 20 mL of ice cold 8% hydrogen peroxide and stirred for 30 min until all of the powder dissolved and a white gel like solution formed. The solution was filtered onto a 1 -micrometer pore size PTFE membrane (Cole Palmer) to leave a deposit which was washed with a small amount of water and air-dried for 10 min. The white peroxide products were transferred from the membrane to a glass vial and vacuum- dried at room temperature for 24 h. The succinic peroxide yield was obtained about
  • Step 2 Preparation of acid-functionalized SWCNTs.
  • Purified SWCNTs 50 mg were placed in a 250-mL flask filled with 50 mL of dry o-dichlorobenzene and sonicated with 2510 Braison bath for 30 min to obtain a SWCNT suspension solution.
  • the SWCNT suspension heated with 1 gram of peroxide at 80-90 0 C for 10 days (synthesized in step 1) (Fig Ia) After the reaction was complete, the suspension was cooled and poured into a 500-mL flask containing a large amount of tetrahydroftiran and sonicated for 15 min.
  • the obtained solution was filtered using a 0.2- micrometer pore size PTFE membrane (Cole Palmer). Functionalized SWCNTs were collected on the membrane, then placed in 100 mL of ethanol, sonicated for 20 min, and then filtered again. During the filtration, a large amount of ethanol was repeatedly used to completely wash off the unreacted peroxides and the reaction byproducts. Finally, the functionalized SWCNTs were vacuum-dried at 70 0 C overnight. SWCNT (Sigma) was acid functionalized as per the reaction shown below.
  • SWNTs were then complexed with nanochitosan NG042 and further complexed with DNA encoding EGFP reporter protein.
  • SWCNTs were characterized by scanning electron micrograph of a cluster of functionalized SWCNT (left) and acid- functionalized and coated with NG042 (FIG 2). Step 1 - Solutions of Chitosan and Carbon Nanotubes
  • Chitosan is soluble in acidic aqueous solutions in which it behaves as a cationic polyelectrolyte.
  • pH 6 chitosan flocculated due to the deprotonation of its amine groups.
  • a 0.50 wt % chitosan stock solution was prepared by dissolving chitosan flakes in hot 0.05 M HCI solution (80-90 0 C). The solution was cooled to room temperature, and its pH was adjusted to 4.5 using a concentrated KOH solution. The chitosan solution was filter and stored in a refrigerator (4 0 C).
  • the appropriate volume of nanotube coupled with chitosan was diluted in 500 microliters of DI water and stored in 100 microliter aliquots.
  • the CNT concentrations in this stock solution was about 50 microgram/mL.
  • plasmid DNA was mixed with CNT-coupled chitosan solution in a ratio of 1 :5 (w/w), and stirred for 12 hrs.
  • the f-CNTchitosan-DNA complex was washed with 50 microliter DI water and centrifugation. Then the complexes were allowed to settle for 30 min at room temperature prior to use.
  • EXAMPLE 3 Preparation of Peptide-f-SWNT Samples SWNTs were obtained from Sigma USA. A FITC labeled ANP peptide solutions was prepared by dissolving 3 mg of peptide in 300 microliter Dl water and peptide concentrations were verified using UV-Vis absorption spectrometry. The 50 microgram of f-SWNTs will be dispersed in 1 mL DI water. The 1:5 ratio mixtures of peptide and f-SWCNT were vortexed for approximately 60 min and leave it over night at 4°C. Next day sonication was performed using a Branson Sonifier 2150 with the sample immersed in an ice water bath for 25 min. it yielding dense black mixtures.
  • the sonicated samples were first centrifuged in an Eppendorf 5415D centrifuge for 5 min. The upper 75% of the supernatant was recovered using a small-bore piped, avoiding sediment at the bottom, and transferred to a centrifuge tube for further centrifugation. Samples were then centrifuged for 30 min. The upper 50% of the supernatant was recovered using a small-bore piped, avoiding sediment at the bottom, and transferred to a clean tube. Centrifugation of SWNTs-peptide complex formed insoluble pellet. The pellet was dissolved in DI water and used for experiments.
  • NG042-TR Texas red
  • SEM Heitachi S-800
  • f-SWCNTs Carbon nanotubes in SEM are observed as bundles of different diameter and length without functionalization. After functionalization, SWCNTs are visualized as single entities which indicated the formation of nanotube- DNA complexes.
  • the f-SWCNTs were presented in bundles of different diameters on which the plasmid DNA was condensed by forming super coiled structures. This observation was extremely encouraging for the subsequent planning of gene delivery and expression experiments.
  • EXAMPLE 6 Functionalized SWCNT as a gene carrier system.
  • BAL cells from mice given NG042-TR without CNT were used as control (-).
  • CNT facilitated chitosan incorporation into cells
  • BAL cells were observed under fluorescent microscope (FIG. 2A). The cells were counted for DAPI (nuclear) and Red staining and % chitosan positive cells was determined (FIG. 2B)
  • DAPI nuclear
  • % chitosan positive cells was determined
  • HEK293 cells were transduced with FITC-labeled NP73-102 peptide using functionalized SWCNT. The cells were transduced in well 8-chamber plates with 1 microgram of peptide. After 24 h cells were examined under fluorescent microscope after staining with DAPI. Cells given peptide without CNT were used as control (-). Results show that f-SWCNT-chitosan significantly increases peptide delivery to the cells (Fig 3)
  • Functionalized nanotubes may act as building blocks for the preparation of nylon-type cross-linked single-walled carbon nanotube-polymers. These tubes can also covalently bind to DNA and drugs and, if made soluble, might serve as nanovehicles for drug delivery.
  • Carbon nanotubes are man-made one-dimensional carbon crystals with different diameters and chiralities. Owing to their superb mechanical and electrical properties, many potential applications have been proposed for them. However, polydispersity and poor solubility in both aqueous and non-aqueous solution impose a considerable challenge for their separation and assembly, which is required for many applications.
  • Carbon nanotubes constitute a class of nanomaterials that possess characteristics suitable for a variety of possible applications. Their compatibility with 35 aqueous environments has been made possible by the chemical functionalization of their surface, allowing for exploration of their interactions with biological components including mammalian cells. Functionalized CNTs (f-CNTs) are being intensively explored in advanced biotechnological applications ranging from molecular biosensors to cellular growth substrates. f-CNTs offer great potential as delivery vehicles of biologically active molecules in view of possible biomedical applications, including vaccination and gene delivery. The capability of ammonium- functionalized single-walled CNTs to penetrate human and murine cells and facilitate the delivery of plasmid DNA leading to expression of marker genes has been shown.
  • Functionalised carbon nanotubes are emerging as new tools in the field of nanobiotechnology and nanomedicine. This is because they can be easily manipulated
  • T c and modified by encapsulation with biopolymers or by covalent linking of solubilising groups to the external walls and tips have opened the way to the exploration of their potential applications in biology and medicinal chemistry.
  • one use of CNTs is as new carrier systems for the delivery of therapeutic molecules. [Carbon nanotubes for the delivery of therapeutic molecules. Expert Opin Drug Deliv. 2004 Nov;l(l):57-65.]
  • CNT carbon nanotubes
  • Carbon nanotubes are considered as molecular wires exhibiting novel properties for diverse applications including medicinal and biotechnological purposes.
  • Surface chemistry on carbon nanotubes results on their solubilization in organic solvents5 and/or aqueous/physiological media.
  • we will present how interfacing such novel carbon-based nanomaterials with biological systems may lead to new applications in diagnostics, vaccine and drug delivery.
  • Recent developments in this rapidly growing field will be presented thus suggesting exciting opportunities for the utilization of carbon nanotubes as useful tools for biotechnological applications.0
  • Emphasis will be placed in the integration of biomaterials with carbon nanotubes, which enables the use of such hybrid systems as biosensor devices, immunosensors and DNA-sensors.
  • Carbon nanotubes materials for medicinal chemistry and biotechnological applications Curr Med Chem. 2006;13(15): 1789-98].
  • 5 Carbon nanotubes (CNTs) revealing metallic or semiconductive properties depending on the folding modes of the nanotube walls represent a novel class of nanowires.
  • Different methods to separate semiconductive CNTs from conductive CNTs have been developed, and synthetic strategies to chemically modify the side walls or tube ends by molecular or biomolecular components have been reported. Tailoring hybrid systems consisting of CNTs and biomolecules (proteins and DNA) has rapidly expanded and attracted substantial research effort.
  • biomaterials with CNTs enables the use of the hybrid systems as active field-effect transistors or biosensor devices (enzyme electrodes, immunosensors, or DNA sensors). Also, the integration of CNTs with biomolecules has allowed the generation of complex nanostructures and nanocircuitry of controlled properties and functions.

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Abstract

Nanotube de carbone à paroi unique fonctionnalisé (SWCNT) complexé à un nanochitosane à des fins de délivrance de substances bioactives et d'applications diagnostiques. Des SWCNT fonctionnalisés complexés au chitosane NG042 ont été utilisés pour la délivrance de protéines rapporteurs EGFP codantes pour l'ADN et de peptides. Les résultats démontrent que les nanoparticules hybrides de chitosane CNT représentées présentent une efficacité de transfection nettement supérieure in vivo à celle du chitosane seul. En outre, les nanotubes fonctionnalisés ont été testés pour le transfert peptidique dans les cellules HEK293. Les résultats ont montrés que les nanoparticules hybrides ont assurés efficacement le transfert des peptides. Conjointement, ces résultats montrent que les particules de chitosane SWCNT hybrides augmentent le transfert peptidique et de l'ADN dans les cellules.
PCT/US2006/041570 2005-10-21 2006-10-23 Procédé de délivrance de médicament par des nanotube de carbone-nanocomplexes de chitosane WO2008048272A2 (fr)

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US13/965,527 US20140023588A1 (en) 2005-10-21 2013-08-13 Method of drug delivery by carbon nanotube chitosan nanocomplexes

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010086406A1 (fr) * 2009-01-29 2010-08-05 Philipps-Universität Marburg Vecteur de transfection non viral
CN101726521B (zh) * 2009-12-01 2012-07-04 暨南大学 用于快速检测杂色曲霉素的生物传感器及其组装方法
CN106633128A (zh) * 2016-10-21 2017-05-10 皖西学院 壳聚糖薄膜的制备方法及壳聚糖薄膜

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050037374A1 (en) * 1999-11-08 2005-02-17 Melker Richard J. Combined nanotechnology and sensor technologies for simultaneous diagnosis and treatment
US20060134220A1 (en) * 2002-06-20 2006-06-22 Bioalliance Pharma Vectorization system comprising nanoparticles of homogenous size of at least one polymer and at least one positively charged polysaccharide and method for the preparation thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050037374A1 (en) * 1999-11-08 2005-02-17 Melker Richard J. Combined nanotechnology and sensor technologies for simultaneous diagnosis and treatment
US20060134220A1 (en) * 2002-06-20 2006-06-22 Bioalliance Pharma Vectorization system comprising nanoparticles of homogenous size of at least one polymer and at least one positively charged polysaccharide and method for the preparation thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010086406A1 (fr) * 2009-01-29 2010-08-05 Philipps-Universität Marburg Vecteur de transfection non viral
CN101726521B (zh) * 2009-12-01 2012-07-04 暨南大学 用于快速检测杂色曲霉素的生物传感器及其组装方法
CN106633128A (zh) * 2016-10-21 2017-05-10 皖西学院 壳聚糖薄膜的制备方法及壳聚糖薄膜
CN106633128B (zh) * 2016-10-21 2022-04-01 皖西学院 壳聚糖薄膜的制备方法及壳聚糖薄膜

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WO2008048272A9 (fr) 2008-06-26

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