WO2007051071A2

WO2007051071A2 - Two-step method of functionalizing carbon allotropes and pegylated carbon allotropes made by such methods

Info

Publication number: WO2007051071A2
Application number: PCT/US2006/042589
Authority: WO
Inventors: W. Edward Billups; Anil Sadana; Jayanta Chattopadhyay
Original assignee: William Marsh Rice University
Priority date: 2005-10-28
Filing date: 2006-10-30
Publication date: 2007-05-03
Also published as: WO2007051071A3

Abstract

A method of functionalizing a carbon allotrope includes reacting a carbon allotrope with an alkali metal and an organohalide species to yield a first reaction product. The first reaction product reacts with a reactive species to yield a PEG-carbon allotrope conjugate. Water soluble CNTs and graphite are provided by this methods. A conjugate used in drug delivery includes at least one of a drug, an antibody, and a fluorescent tag. The conjugate further includes at least one of a PEG-CNT conjugate and a PEG-graphite conjugate.

Description

TWO-STEP METHOD OF FUNCTIONALIZING CARBON ALLOTROPES AND PEGYLATED CARBON ALLOTROPES MADE BY SUCH METHODS

[0001] This invention was made with support from the National Science Foundation, Grant No. CHE-0450085.

FIELD OF THE INVENTION

[0002] The present invention relates generally to carbon allotropes including carbon nanotubes (CNTs) and graphite. Specifically, the present invention relates to methods of functionalizing carbon allotropes, including CNTs and graphite, with polyethylene glycol (PEG) species and to the PEGylated CNTs and PEGylated graphite made by such methods.

BACKGROUND OF THE INVENTION

[0003] Carbon nanotubes (CNTs) are generally classified as either multi-wall carbon nanotubes (MWNTs), double-wall cabon nanotubes (DWNTs) or single-wall carbon nanotubes (SWNTs). The application of these materials in biological contexts has been limited mainly due to their lack of solubility in aqueous media. If CNTs could be made biocompatible through chemical modification, they may be useful in a variety of medical applications ranging from diagnostic (e.g., imaging) to therapeutic. In such applications, targeting species, such as antibodies, may be attached to the functionalized CNTs to direct them to a cellular target, for example.

[0004] Efforts to chemically modify CNTs are well documented and generally involve functionalization either at the tube ends or at the sidewalls. Functionalization at tube ends involves chemistry of a carboxylic acid moiety. The presentation of this functional group at the tube ends is an artifact of cutting the tubes into shorter lengths, with an average length of about 60 nm. Similarly, one may introduce carboxylic acid functional groups on the sidewalls, often by vigorous treatment of SWNTs with nitric acid at 90 ⁰C for extended periods of time.

[0005] CNTs are simply graphene (graphite comprising layered graphene sheets) that has been rolled into a cylindrical shape. Because of this relationship, much of the chemistry of CNTs may translate to reactions of graphite/graphene sheets. Graphite, which finds application as a lubricant and an intumescent material, for example, would benefit from similar derivitization that would confer water solubility.

[0006] Organic-soluble fragments of graphene have been prepared through chemical modification of graphite. The process typically involves treating microcrystalline graphite with a mixture of sulfuric acid and nitric acid. A series of steps involving oxidation and exfoliation result in small graphene plates with carboxyl groups at their edges. These carboxyl groups may be derivitized by conventional organic synthetic methods resulting in materials that are soluble in organic solvents such as tetrahydrofuran, tetrachloromethane, and dichloroethane, for example.

[0007] Despite the rich chemistry of functionalizing carbon nanotubes and graphite, there is a paucity of water-soluble derivatives of carbon nanotubes or graphite/graphene. PEGylated variants would be highly desirable compounds for further studies in biological systems, wherein polyethylene glycol (PEG) is generally accepted as a biocompatible water- solubilizing polymer. n

SUMMARY OF THE INVENTION

[0008] A method of functionalizing carbon allotropes includes reacting with an alkali metal and an organohalide species to yield a first reaction product. The first reaction product reacts with a reactive species to yield a PEG-allotrope conjugate.

[0009] A water-soluble PEG-CNT conjugate is made by a process that includes reacting a CNT with an alkali metal and an organohalide species to yield a first reaction product and subsequent reaction of the first reaction product with a reactive species to yield a PEG-CNT conjugate.

[0010] A water-soluble PEG-graphite conjugate is made by a process that includes reacting graphite with an alkali metal and an organohalide species to yield a first reaction product and subsequent reaction of the first reaction product with a reactive species to yield a PEG-graphite conjugate.

[0011] A conjugate used in drug delivery includes at least one of a drug, an antibody, and a fluorescent tag. The conjugate further includes at least one of a PEG-CNT conjugate and a PEG-graphite conjugate. DESCRIPTION OF THE INVENTION

[0012] In the following description, specific details are set forth such as specific quantities, sizes, etc. so as to provide a thorough understanding of embodiments of the present invention. However, it will be obvious to those skilled in the art that the present invention may be practiced without such specific details. In many cases, details concerning such considerations and the like have been omitted inasmuch as such details are not necessary to obtain a complete understanding of the present invention and are within the skills of persons of ordinary skill in the relevant art.

[0013] Referring to the drawings in general, it will be understood that the illustrations are for the purpose of describing a particular embodiment of the invention and are not intended to limit the invention thereto.

[0014] While most of the terms used herein will be recognizable to those of skill in the art, the following definitions are nevertheless put forth to aid in the understanding of the present invention. It should be understood, however, that when not explicitly defined, terms should be interpreted as adopting a meaning presently accepted by those of skill in the art.

[0015] "Organohalide" as used herein refers to any organic molecule possessing a halogen atom as a substituent. Among the halogen substituents, chloride, bromide, fluoride and iodide are contemplated herein. By "halogen substituent", it is meant that an halogen atom, chlorine, bromine, fluorine or iodine, is bonded to carbon in lieu of an hydrogen atom. Organohalides may also possess other substituents within the carbon backbone structure, as known in the art, for example, esters, amides, carboxylic acids, alcohols, and combinations thereof.

[0016] "Carbon nanotubes or CNTs" as used herein refers to both single wall nano tubes (SWNTs-both crude and purified), double-wall nanotubes (DWNTs), "cut tubes" and multi- wall nanotubes (MWNTs).

[0017] "Cut tubes" as used herein refers to SWNTs (crude or purified) that have been chemically degraded to decrease their average length relative to those that are synthesized by the HiPCO process.

[0018] "Polyethylene glycol or PEG" as used herein refers to the family of biocompatible water-solubilizing linear polymers based on the ethylene glycol monomer unit. It may include oligomeric PEGs of average molecular weight of 200 Da through high molecular polymers of average molecular weight 20,000 Da. [0019] "Terminated PEG" as used herein refers to any PEG described above in which one end of the linear polymer chain is functionalized with a leaving group, alcohol or amine functionality, while the other end is capped rendering it relatively unreactive.

[0020] "Leaving group" as used herein refers to any organic functional group suitable to participate in a bimolecular nucleophilic substitution reaction and may include halogens, mesylates, tosylates, triflates, nosylates, and other common leaving groups recognized by one skilled in the art.

[0021] In some embodiments, a first method builds upon a Birch-type reductive alkylation (Birch reductive alkylation) method for functionalizing a carbon allotrope, which may include carbon nanotubes (CNTs), as described in PCT/US2005/008303, filed March 11, 2005, which is incorporated by reference herein in its entirety. The Birch reductive alkylation, shown in Scheme 1, may include treatment of a carbon allotrope, such as a CNT, with an alkali metal and a substituted organohalide, generally in ammonia solvent to provide a first reaction product. As shown in Scheme 1 a halogen is represented by X. Y represents another functional group which will server to connect the CNT to tihe PEG polymer. Thus, the difunctional organohalide serves as a linker molecule.

alkali metal NH₃

Scheme 1

[0022] In a second step, the first reaction product (crude or purified) is treated with a reactive species to yield a PEG-alltrope conjugate (PEG-CNT conjugate, as shown in the example of Scheme 2). The reactive species may be any reactive terminated PEG as described herein.

Scheme 2

[0023] As shown in Scheme 2, the Y functional group of the first reaction product and the reactive group R of a terminated PEG (end capped with as a methyl ether, OMe) react to form a new functional group G, which establishes a covalent link between the PEG polymer and the CNT. G may be any functional group and may include, for example, an ester, an amide, or an. ether. One skilled in the art would recognize that a coupling agent may be desirable in order to establish functional group G. The exact coupling agent depends on the nature of moieties R and Y.

[0024] In other embodiments, a second method may include the step of a Birch reductive alkylation of graphite. The Birch reductive alkylation may include treatment of graphite (or graphene sheets) with an alkali metal and a substituted organohalide, generally in ammonia solvent to provide a first reaction product, as shown in Scheme 3. The nature of the organohalide may be the same as discussed above.

graphite graphite alkali metal NH₃

Scheme 3

[0025] In a second step, shown in Scheme 4, the first reaction product is treated with a reactive species to yield a PEG-graphite conjugate. The reactive species may be any terminated PEG derivative as described herein. Again, the newly formed functional group G may be an ester, amide or ether, for example.

Scheme 4 Reaction components

[0026] In one or more embodiments, CNTs may include SWNTs, DWNTs and MWNTs, any of which may be used in crude or purified form. SWNTs, which are used in preferred embodiments, may be prepared by, but not limited to, methods known in art such as the High-Pressure CO Conversion (HiPco) process, for example, which is a gas phase synthesis from carbon monoxide feedstock with an iron pentacarbonyl catalyst. The SWNTs purified from the HiPco process may have an average length of 300 nm and may contain less than 2% residual metal. The purified SWNTs may be treated with 4:1 vol/vol 96% H₂SO₄/30% H₂O₂ to generate "cut tubes" with an average length of 60 nm. The "cut tubes" may vary in length from about 20 to 100 nm, in one embodiment. However, one skilled in the art will recognize that some "cut tubes" may fall outside this range. [0027] In one or more embodiments, graphite may be used as a starting material. Graphite, typically composed of layered graphene sheets, is commercially available (Aldrich) in flake, rod, nanofiber, and powder form and can be used without further preparation or purification. In other embodiments, other carbon allotropes may be functionalize by the methods disclosed herein. Carbon allotropes may include, but are not limited to, C60, C70, large fullerenes (sometimes called "raw MER"), mixtures of C60 and C70, and C540.

[0028] In one or more embodiments, an organohalide may be a reactive partner in the Birch reductive alkylation. The organohalide may be a difunctional molecule, in one embodiment, and may include a linear carbon chain with an halogen X at one end and at least one selected from a protected alcohol group, an ester, an amide, and a carboxylic acid Y at the opposing end as indicated in the structure below:

[0029] The chain length of the alkyl chain n may vary from n = 0 to n = 12 in one embodiment. One skilled in the art will recognize that for applications where water solubility is desirable, carbon chains longer than 14 carbons may be deleterious to said solubility. In some embodiments, Y is a carboxylic acid. From this functional group, a variety of PEG attachment schemes may be viable.

[0030] In some embodiments, the Birch reductive alkylation may include a zero valent alkali metal which may include any of Li, Na, K, and combinations thereof.

[0031] In one or more embodiments, the reactive species is a terminated PEG. This species may be selected to react with the first reaction product to form the covalent linkage between the CNT and the PEG polymer. In one embodiment the PEG polymer may have a molecular weight of about 200 Da, and about 20,000 Da in another embodiment. In a particular embodiment the PEG polymer has an average molecular weight of 5,000 Da. One skilled in the art would recognize that a PEG polymer that is less than 200 Da may not confer appreciable water solubility to the CNT. Likewise, a PEG polymer that more than 20,000 Da may completely wrap itself about the CNT and may obscure the biological utility of the solubilized CNT.

[0032] In some embodiments, the PEG may have one end capped as an ether for example, which renders that end of the linear PEG polymer unreactive. The opposing end of a linear PEG may include a reactive functional group such as an alcohol or amine for example. Finally, although embodiments disclosed herein use linear PEG polrners, other PEG polymers that are branched, dendritic, and the like may also be used.

Reactions

[0033] The Birch reductive alkylation reaction may be performed as described in PCT/US2005/008303, filed March 11, 2005, as previously mentioned. Thus, the focus here will be on reaction of the first reaction product with the terminated PEG species.

[0034] In one or more embodiments, the first reaction product and terminated PEG species may react to form an amide bond, as shown in Scheme 5 below.

Scheme 5

[0035] The first reaction product carboxylic acid may be coupled to an amine terminated PEG through the use of carbodiimide coupling chemistry. Such reagents to carry out the coupling reaction may include dicyclohexylcarbodiirnide (DCC), diisopropylcarbodiimide (DIC), N-(3-Drmethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), and (Benzotriazol-l-yloxy)tripyrrolidinophosρhonium hexafluorophosphate (PyBOP), for example. Reactions may be carried out in aqueous solvent, organic solvents, and combinations thereof. One skilled in the art will recognize that other reagents to facilitate the coupling may also be present, such as hydroxybenzotriazole (HOBt) for example.

[0036] Under similar reaction conditions, in other embodiments, the amine terminated PEG may be replaced by a reactive alcohol functional group to provide ester products, as shown in Scheme 6 below.

Scheme 6

[0037] One of ordinary skill in the art will recognize that amides and esters may be formed by means other than carbodiimide-based coupling chemistry. For example, one may generate a reactive acid chloride from the first reaction product by treatment of the carboxylic acid with oxalyl chloride in the presence of catalytic DMF, or with thionyl chloride. Other reactive species suitable for forming amides or esters may include acyl fluorides, pentafluorophenyl esters, and similar reactive carboxylic acid derivatives known by those skilled in the art. In one embodiment, esters may be formed by bimolecular nucleophilic substitution, as shown in Scheme 7.

Scheme 7

[0038] Using this strategy, a salt of the carboxylic acid is reacted with a substituted PEG polymer. The carboxylate salt may be formed with an alkali metal cation M, for example, lithium, sodium, and potassium. The PEG coupling partner may include a leaving group (as defined above) X at one end of the linear polymer.

[0039] Although embodiments disclosed above involve carboxylic acids in the first reaction product and a reactive species PEG, such as an amine, alcohol, or leaving group, one skilled in the art would recognize that the functional groups may be interchanged on the reacting partners. That is to say the PEG may incorporate the carboxylic acid functional group and the first reaction product incorporate the amine, alcohol, or leaving group.

[0040] In one or more embodiments, an ether linkage may be established by the Williamson-type ether synthesis as shown in Scheme 8.

Scheme 8

[0041] The carboxylic acid of the first reaction product may be replaced by the alcohol functional group, accessible by reduction of the corresponding carboxylic acid with borane- THF, for example. Alternatively, the alcohol may have been introduced in a protected form in the Birch reductive alkylation. Li this embodiment, the PEG partner incorporates a leaving group X so that reaction with the CNT-alcohol (or it's corresponding alkoxide salt) provides the ether linked CNT-PEG conjugate.

[0042] In embodiments encompassing CNTs, it may also be possible to react carboxylic acid functional groups that are present on the ends of "cut tubes" and at the site of sidewall defects under substantially the same reaction conditions. These functional moieties attached directly to the tube, without the intervening methylene units of a difunctional linker, may provide a secondary site for PEG attachment. Such sites may be used for PEG conjugation in lieu of those installed by the Birch reductive alkylation with an ω-halocarboxylic acid.. In other embodiments such sites may be used in conjunction with carboxylic acid moieties introduced by the Birch reductive alkylation.

[0043] Scheme 5-8 show embodiments in which CNTs couple to PEGs by way of a difiinctional linker molecule. One skilled in the art would recognize that identical chemistry may be carried out on the Birch reductive alkylation products of graphite, in nominally the same manner, as shown in Schemes 9-12 below.

NH₂-PEG-OMe H N. graphite ^>Y^CO₂H graphite PEG-OMe carbodiimide O

Scheme 9

HO-PEG-OMe graphite ACCO₂H graphite °" PEG-OMe carbodiimide O

Scheme 10

X-PEG-OMe graphite ^^VT^COaM graphite PEG-OMe

O

Scheme 11 X-PEG-OMe O._P graphite graphite ⁷X^ "PEG- O" Me

Scheme 12

[0044] Embodiments of the present invention provide PEG-CNT conjugates and PEG- graphite conjugates synthesized by methods disclosed above. In particular embodiments, the PEG conjugates may be substantially water-soluble. Such compounds may include conjugates in which the difunctional linker has about 10 carbons (n = 7 in Schemes 5-12) and a PEG partner having an average molecular weight of 5,000 Da. In a particular embodiment, PEG-CNT conjugates with purified, cut SWNTs (20-100 run in length, with average length 60 run) may exhibit improved water solubility compared to the uncut SWNTs (with average length 300 nm). One skilled in the art would recognize that other biocompatible polymers may be used in place of PEG polymer, utilizing the synthetic methods disclosed herein.

[0045] In particular embodiments, PEG-CNT and PEG-graphite conjugates may be useful in biological applications. Said conjugates may be used to monitor drug delivery in one embodiment. This may be carried using a fluorescent tag, which may also be covalently attached to the CNT or graphite conjugate. In alternate embodiments, one may attach cell recognition molecules to said conjugates (in conjunction with a covalently linked drug) for site specific drug delivery. For example, any number of antibodies may be immobilized through covalent linkage to said conjugates for the purpose of drug delivery.

Examples

[0046] The following examples are included to demonstrate particular embodiments of the present invention. It should be appreciated by those of skill in the art that the methods disclosed in the examples that follow merely represent exemplary embodiments of the present invention. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments described and still obtain a like or similar result without departing from the spirit and scope of the present invention.

[0047] The following experimental examples are included to demonstrate embodiments of the preparation of CNT-PEG conjugates and graphite-PEG conjugates, in accordance with embodiments disclosed herein. They are intended to be exemplary of the present invention, and thus not limiting.

[0048] The PEG-functionalized CNTs or graphite may be characterized by Raman spectroscopy, thermogravimetric analysis (TGA), FT-IR spectroscopy with ATR accessory, X-ray photoelectron spectroscopy (XPS), atomic force spectroscopy (AFM) and transmission electron microscopy (TEM).

[0049] Example 1: Birch reductive alkylation of Purified SWNTs with 11- bromoundecanoic acid

[0050] In a 100 mL three neck round bottom flask fitted with a dry ice condenser, 40 mg of purified SWNTs was added under an atmosphere of argon. 60 mL of ammonia was then condensed into the flask followed by addition of 0.24 g of lithium metal (Aldrich). 11- bromoundecanoic acid (Aldrich) was then added. The mixture was stirred at -33 ⁰C and allowed to warm and evaporate the ammonia gradually overnight. The reaction mixture was quenched by slow addition of ethanol, followed by water. The mixture was acidified (10% HCl), filtered through a 0.2 μm PTFE membrane and washed successively with water and ethanol. The functionalized SWNTs were dried overnight at 80 ⁰C. FT-IR bands at 2950, 2840 and 1691 cm^"1 confirm attachment of the undecanoic acid moiety.

[0051] Example 2: General procedure for conjugation of SWNT to PEG polymer [0052] 3.3 mmol of the carboxylic acid functionalized SWNT was dissolved in 20 mL of dimethylfoπnamide (DMF) and sonicated for 10 minutes to achieve a homogeneous dispersion. Dimethylaminopyridine (DMAP, 3.3mmol) in 5 mL of DMF and H₂N-PEG-OMe (MW = 5000 Da, 5x 10^"5 mmol, Aldrich) in 10 mL of DMF and 15 mL of dimthyl sulfoxide (DMSO) were added dropwise to this mixture over an hour and the reaction stirred at room temperature for 48 hours. The solution was filtered through a 0.2 μm PTFE membrane and washed several times with chloroform. The product was then dried overnight in vacuo at 50 °C.

[0053] Example 3: Birch reductive alkylation of graphite with carboxylic acid functionalization

[0054] In a 100 mL three neck round bottom flask fitted with a dry ice condenser, 40 mg of purified SWNTs was added under an atmosphere of argon. 60 mL of ammonia was then condensed into the flask followed by addition of 0.24 g (10 eqv.) of lithium metal (Aldrich). 5-bromovaleric acid (1.7 eqv.) (Aldrich) was then added. The mixture was stirred at -33 ⁰C and allowed to warm and evaporate the ammonia gradually overnight. The reaction mixture was quenched by slow addition of ethanol, followed by water. The mixture was acidified (10% HCl), filtered through a 0.2 μm PTFE membrane and washed successively with water and ethanol. The functionalized SWNTs were dried overnight at 80 ⁰C.

[0055] Example 4: PEGylation of valeric acid substituted graphite

[0056] 2.5 mmol of valeric acid substituted graphite was dissolved in 14 mL of dimethylformamide (DMF) and sonicated for 15 minutes to achieve a homogeneous dispersion. Drops of dimethylaminopyridine (DMAP) (2.5 mmol ) in 3.5 mL of DMF and NH₂-PEG-OMe (4xlO^'5 mmol) in 7.5 mL of DMF were added slowly to the reaction mixture followed by stirring. Dicyclohexylcarbodiimide (DCC) (2.7 mmol) dissolved in a mixture of 7.5 mL DMF and 10 mL of dimethylsulfoxide (DMSO) was added dropwise to the reaction mixture over one hour and the reaction allowed to stir at room temperature for 72 hours. The solution was filtered through a 0.2 μm PTFE membrane and washed several times with chloroform. The product was dried overnight in vacuo at 50 °C. XPS spectra between 0 and 1000 eV indicated the presence of carbon, nitrogen, and oxygen in the PEGylated graphite. The C Is, Ols, and N Is XPS spectra (SI-2) show distinct peaks at 284.5, 532.7 and 401 eV, respectively. That N lS peak is indicative of the amide bond in the PEGylated graphite. FT- IR shows carbonyl absorption at 1624 cm^"1 and an NH stretch at 3738 cm^"1. [0057] Advantageously, the present invention provides methods for preparing water- soluble carbon nanotubes and water-soluble graphite. These synthetic methods may be applicable to other carbon allotropes as well. The solubilizing agent PEG polymer is well recognized as a biocompatible polymer, which augers well for biological applications. Other advantages may become apparent by those skilled in the art.

[0058] All patents and publications referenced herein are hereby incorporated by reference. It will be understood that certain of the above-described structures, functions, and operations of the above-described embodiments are not necessary to practice the present invention and are included in the description simply for completeness of an exemplary embodiment or embodiments. In addition, it will be understood that specific structures, functions, and operations set forth in the above-described referenced patents and publications can be practiced in conjunction with the present invention, but they are not essential to its practice. It is therefore to be understood that the invention may be practiced otherwise than as specifically described without actually departing from the spirit and scope of the present invention as defined by the appended claims.

Claims

WHAT IS CLAIMED:

1. A method of functionalizing a carbon allotrope comprising: reacting carbon allotrope with an alkali metal and an organohalide species to yield a first reaction product; and reacting the first reaction product with a reactive species to yield a PEG-carbon allotrope conjugate.

2. The method of claim 1, wherein the carbon alltrope is at least one selected from a carbon nanotube (CNT), graphite, C60, C70, large fullerenes and C540, and mixtures thereof.

3. The method of claim 2, wherein the carbon allotrope is a CNT.

4. The method of claim 2, wherein the carbon allotrope is graphite.

5. The method of claim 3, wherein the CNT is a single wall nanotube (SWNT).

6. The method of claim 1, wherein the organohalide is a difunctional species comprising an alkyl chain terminating in at least one selected from a protected alcohol group and a carboxylic acid.

7. The method of claim 1, wherein the reactive species comprises terminated PEG.

8. A water-soluble PEG-CNT conjugate made by a process comprising: reacting a CNT with an alkali metal and an organohalide species to yield a first reaction product; and reacting the first reaction product with a reactive species to yield a PEG-CNT conjugate.

9. The PEG-CNT conjugate of claim 8, wherein the CNT ranges in length from about 20 to 100 nm and has an average length of about 60 nm.

10. The PEG-CNT conjugate of claim 8, wherein the CNT is at least one selected from a single-wall nanotube, double-wall nanotube, and a multi-wall nanotube.

11. The PEG-CNT conjugate of claim 8, wherein the organohalide is a difunctional species comprising an alkyl chain terminating in at least one selected from a protected alcohol group and a carboxylic acid.

12. The PEG-CNT conjugate of claim 8, wherein the reactive species comprises terminated PEG.

13. A water soluble PEG-graphite conjugate made by a process comprising: reacting graphite with an alkali metal and an organohalide species to yield a first reaction product; and reacting the first reaction product with a reactive species to yield a PEG-graphite conjugate.

14. The PEG-graphite conjugate of claim 13, wherein the organohalide is a difunctional species comprising an alkyl chain terminating in at least one selected from a protected alcohol and a carboxylic acid.

15. The PEG-graphite conjugate of claim 15, wherein the reactive species comprises terminated PEG.

16. A conjugate used in drug delivery comprising at least one selected from a drug, an antibody, and a fluorescent tag; wherein the conjugate further comprises at least one of a PEG-CNT conjugate and a PEG- graphite conjugate.