CN1511861A

CN1511861A - Polyglycol fatty acid derivative and its medicinal combination

Info

Publication number: CN1511861A
Application number: CNA021587671A
Authority: CN
Inventors: 嵇世山; 朱德权
Original assignee: BEIJING JIANKAI SCIENCE AND TECHNOLOGY Co Ltd
Current assignee: BEIJING JIANKAI SCIENCE AND TECHNOLOGY Co Ltd
Priority date: 2002-12-26
Filing date: 2002-12-26
Publication date: 2004-07-14

Abstract

The present invention relates to novel polyglycol fatty acid derivative, which is hydrolysis stable and connected via ether bond. The present invention also relates to its combination to medicine molecule and medicinal use.

Description

Polyethylene glycol-fatty acid derivatives and drug conjugates thereof

Technical Field

The invention relates to novel, hydrolytically stable polyethylene glycol-fatty acid derivatives linked by ether bonds, to a process for their preparation, to binding products of these derivatives with drugs, and to their medical use.

Background

The protein, polypeptide, terpenoid, steroid, alkaloid, flavone, anthraquinone, phenylpropanoid phenol, etc. in the active ingredients of the natural medicine show various effective performances in physiological activity, and are widely applied in medicine. Their glycosides, nucleosides, and polypeptide derivatives also have considerable application. As natural active ingredients, the compounds have the advantages of quick biodegradation, no residue, small toxic and side effects and the like. But also has the disadvantages of low bioavailability, short physiological half-life, poor water solubility, body immunity initiation and the like.

To solve this problem, polyethylene glycol (PEG) derivatives have been widely used to conjugate proteins, peptides or other therapeutic drugs to reduce biodegradation, prolong the physiological half-life of the drug, and reduce immunogenicity and toxicity thereof. In clinical use, PEG and its derivatives have been widely used in many commercial pharmaceutical products as carriers for the manufacture of pharmaceutical preparations. Attempts to bond PEG to drug molecules have also been well developed in the last decade. Such as PEG-intron^_The α -PEG conjugate has long circulation half-life and high curative effect, and the said conjugate has reduced toxicity and prolonged bioactivity.

Polyethylene glycol can be used in conjunction with many drugs. When combined with a drug, a process known as PEGylation (PEGylation) is commonly used, in which one or both of the terminal groups of the two ends of the polyethylene glycol are chemically activated to have a suitable functional group that is reactive with at least one functional group of the drug to be combined and is capable of forming a chemical bond therewith. The resulting bond can release the active ingredient under appropriate conditions in vivo.

Active polyethylene glycol (PEG) derivatives have been reported in many documents. U.S. patent No. 5672662 describes the preparation of propionic and butyric acids and their NHS esters of linear PEG. U.S. patent No. 5643575 describes a PEG derivative having a U-shaped structure in which two linear PEG structures are attached to the same molecule through the same group. The hydrophobicity of the linking group between these acidic groups and PEG has never been seriously considered and studied.

PEG fatty acids are widely used as a surfactant. However, the carboxylic acid group of the fatty acid is mostly connected with the hydroxyl or amino group in the PEG during the connection process of the fatty acid part and the PEG, and the formed ester bond or amido bond lacks certain stability. In these structures, the carboxylic acid group of the fatty acid is absent and cannot be bonded to the drug molecule.

The polyethylene glycol (PEG) -fatty acid derivative connected by ether bond has higher hydrolytic stability, and provides a stable connection mode between PEG skeleton and fatty acid acidic group, which is favorable for ensuring that the fatty acid keeps enough characteristics in the subsequent drug connection process. The PEG derivative obtained by the connection mode is connected with the drug to form a microsphere structure in aqueous solution, and the drug molecules and the hydrophobic fatty acid skeleton are wrapped by the PEG to be protected. Can effectively reduce the degradation of enzyme, improve the half-life period in the organism and change the distribution in the organism. A better effect would be obtained if the object to which it is attached is itself also a hydrophobic prodrug. The current commercial carboxylic acid derivatives of PEG, such as carboxymethylated PEG, PEG propionic acid, PEG butyric acid, do not have sufficiently strong hydrophobic groups, and therefore they do not form microsphere structures with drug conjugates, such as paclitaxel, and are rapidly hydrolyzed in water to release the PEG component.

The series of acidicPEG derivatives provided by the invention have longer hydrophobic groups, so that better half-life protection and treatment effect improvement can be provided. Hydrophobic groups with different lengths can be selected according to the characteristics of different medicines, so that the stability and the biodegradation characteristics of the corresponding medicines can be effectively improved.

Meanwhile, the polyethylene glycol (PEG) -fatty acid derivative can be further derivatized into other active forms, such as NHS ester or maleic amide, and the active forms can directly react with protein drugs in aqueous solution to obtain active bonding substances.

Disclosure of Invention

Accordingly, it is an object of the present invention to provide a polyethylene glycol (PEG) -fatty acid derivative of the formula:

or

B′-(CH₂)_l-O-PEG-O-(CH₂)_l-B

(II)

Wherein PEG is a polyethylene glycol polymer;

l is an integer from 4 to 18;

and is

A is C_1-12Alkoxy, cycloalkoxy or alkoxyaryl, or an ester group;

b and B' are carboxyl groups or functional groups selected from one of ester groups, acid chlorides, acid traps, maleimides and pyridodisulfides.

In a preferred embodiment of the present invention, there is provided a polyethylene glycol (PEG) -fatty acid derivative of the formula:

CH₃O-PEG-O-(CH₂)_l-COOH

(Ia)

or

HOOC-(CH₂)_l-O-PEG-O-(CH₂)_l-COOH

(IIa)

Wherein:

PEG is a polyethylene glycol polymer, including branched, straight, star, and tree;

l is an integer from 4 to 18.

The invention also includes polyethylene glycol (PEG) -fatty acid reactive derivatives of the formula:

or

Wherein:

l is an integer from 4 to 18;

f is a functional group which, together with the acidic group, forms a reactive functional group, including ester groups (such as NHS esters or HOBT esters), acid chlorides, acid traps, maleimides, pyridodisulfides. Can react with amino, hydroxyl, sulfhydryl and the like in the drug molecule.

The present invention also provides polyethylene glycol (PEG) -fatty acid derivatives of the general formula:

wherein,

f is a functional group which, together with the acidic group, forms a reactive functional group, including ester groups (such as NHS esters or HOBT esters), acid chlorides, acid traps, maleimides, pyridodisulfides. Can react with amino, hydroxyl, sulfydryl and the like in a drug molecule;

y is a reactive functional group including an ester group (such as NHS ester or HOBT ester);

and, the ester group as F and the ester group as Y may be the same or different.

The invention also provides a method for preparing the compound shown in the formula (Ia), which comprises the steps of reacting PEG with bromocyanide, and hydrolyzing a cyano group to obtain a corresponding acid group.

The invention further provides conjugates of polyethylene glycol (PEG) -fatty acid derivatives and drug conjugates of the following general formula:

or

Wherein:

a is a group as described above;

x and X', which are identical or different, are O, NH or S;

drug is a Drug molecule.

The present invention preferably provides conjugates of polyethylene glycol (PEG) -fatty acid derivatives and drug conjugates of the general formula:

wherein:

PEG is a polyethylene glycol polymer;

l is an integer from 4 to 18;

x is a linking group, including O, NH, S, etc.;

drug is a Drug molecule.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the above polyethylene glycol (PEG) -fatty acid active derivative as an active ingredient.

According to a further aspect of the present invention there is provided the use of said polyethylene glycol (PEG) -fatty acid active derivative for the manufacture of a medicament and a pharmaceutical composition.

The drug combination of the invention can improve drug absorption, prolong action time, enhance curative effect, reduce administration dosage and avoid certain toxic and side effects.

Detailed Description

The polyethylene glycol used in the polyethylene glycol (PEG) -fatty acid derivative of the present invention is a hydrophilic polymer, and the hydrophilic polymer may also be a copolymer of polyethylene glycol and polypropylene glycol, polyvinyl alcohol, or polypropylene morpholine, with polyethylene glycol being particularly preferred. Such hydrophilic polymers are linked to free amino groups, hydroxyl groups, etc. in proteins, polypeptides or other natural pharmaceutical active ingredients by modifying the free terminal hydroxyl groups to bind acid groups such as fatty acids to the parent of the polymer, allowing the polymer to provide a point of attachment to the drug molecule.

The difference between the polyethylene glycol (PEG) -fatty acid derivative and the common PEG fatty acid surfactant is that the ether bond is adopted to connect the fatty acid and the PEG, and the hydrolytic stability of the structure is obviously higher than that of the common ester bond and amido bond; also, in the conjugates of the present invention, the carboxyl group of the free fatty acid provides a binding site for a protein, polypeptide, or other natural pharmaceutical active ingredient. Thus, this structure will significantly improve the hydrolytic stability of the prodrug in body fluids. Due to the non-hydrophilic groups contained in fatty acid, for example, the combination of the fatty acid and some non-hydrophilic drug molecules, such as some natural drug active ingredients, is more favorable, so that the combination forms a microsphere structure with a plurality of molecules assembled to form a molecular group in aqueous solution. The structure keeps the excellent characteristics of good hydrophilicity, flexibility, macrophage phagocytosis resistance and the like of a hydrophilic polymer, provides slow release and controlled release of drug molecules, and can greatly prolong the retention period of the drugs, especially natural drug molecules, in vivo.

One advantage of the present invention is that in addition to retaining the usual solubility, non-immunogenicity, and non-toxicity characteristics of hydrophilic polymers such as polyethylene glycol, the ether linkage structure will help maintain the stability of the drug molecule and reduce abnormal loss upon reaching the target organ. Meanwhile, the microsphere structure is also beneficial to improving the distribution in the body, and the effective blood concentration and the stepwise release of the drug molecules are ensured.

The attachment of the hydrophilic polymer to the fatty acid in the present invention will now be described by taking a polyethylene glycol derivative as an example.

The structure of the polyethylene glycol derivative includes a polymer branch portion and a terminal functional group portion, which are respectively described below.

Polyethylene glycol (PEG) with a general structural formula shown as I:

wherein:

r is H or C_1-12An alkyl group, a carboxyl group,

n is any integer representing the degree of polymerization.

When R is lower alkyl, R may be any lower alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or n-hexyl. When R is cycloalkyl, R is preferably cycloalkyl having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl and cyclohexyl. A preferred cycloalkyl group is cyclohexyl. A typical compound is methoxypolyethylene glycol (mPEG). Other polyethylene glycol analogs or polyethylene glycol copolymers may also be used in the present invention, such as polypropylene glycol, polyvinyl alcohol, polypropylene morpholine, and the like.

For polyethylene glycol, molecular weights are generally used, so long as the polyethylene glycol forming the conjugate has a molecular weight of 300 to 60000 daltons, which corresponds to n being about 6 to 1300. More preferably, n is 28, 112 and 450, which correspond to molecular weights of 1325, 5000 and 20000, respectively. Because of the potential heterogeneity of the starting PEG compound, which is generally defined by its average molecular weight rather than by its self-repeating units, it is preferred to characterize the polyethylene glycol polymer by molecular weight rather than representing the self-repeating units in the PEG polymer by the integer n. Starting PEG compounds of various molecular weights can be prepared by methods known in the art or can be obtained from commercial sources.

The preparation method of the polyethylene glycol (PEG) -fatty acid adopts a method of reacting PEG with bromocyanide and then hydrolyzing cyano to obtain corresponding acid groups. In practice, it is necessary to activate the terminal portion of the hydrophilic polymer to ensure that it reacts with the bromocyanide compound to bind the two. The commonly used method is toactivate the hydroxyl group of the end group of PEG to sodium alkoxide or potassium alkoxide by hydride to improve the reaction property of the PEG and bromide. A typical reaction is as follows:

if there is a free hydroxyl group on the hydrophilic polymer, the free hydroxyl group may be C_1-12Alkoxy, cycloalkoxy or aralkoxy endcapping, preferably methoxy, ethoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclohexyloxy and benzyloxy.

In addition, targeting molecules, such as antibodies and the like, can be attached to the hydrophilic polymer to direct the delivery of the conjugate of the invention.

Many drugs currently in use, particularly natural drugs, contain functional groups such as amino groups and hydroxyl groups. The carboxylic acid groups of the hydrophilic polymer and the drug molecule can be bound together, for example, by an ester-based synthesis reaction, which can be simply as follows:

the ester group can be removed in the organism by means of biodegradation, with the active ingredient being released.

Suitable drug molecules may be used in the drug conjugates of the present invention to form the drug moiety therein, which include amino acids, proteins, enzymes, nucleosides, sugars, organic acids, glycosides, flavonoids, quinones, terpenes, phenylpropanoid phenols, steroids and their glycosides, alkaloids, and the like.

The above-mentioned protein which can be conjugated with the polyethylene glycol (PEG) -fatty acid derivative of the present invention is selected from one of erythropoietin (GCSF), Erythropoietin (EPO), Interleukin (IL), interferon, hirudin,and antibody.

In the drug conjugate of the present invention, the drug molecule part is preferably a pharmaceutically active ingredient isolated from natural plants, such as cinobufagin, glycyrrhetinic acid, and scopoletin. The drug molecule part is particularly preferable to natural drugs for treating tumors, such as paclitaxel, camptothecin, etoposide and derivatives thereof.

The drug conjugates of the present invention may be administered as pure compounds or as suitable pharmaceutical compositions, and may be administered by any acceptable mode of administration. The combination dosage forms comprise conventional pharmaceutical carriers or excipients and the combination of the invention as active ingredient(s), and may additionally comprise other pharmaceutical agents, carriers, adjuvants and the like.

Generally, a pharmaceutically acceptable combination dosage form will comprise from about 1 to about 99% by weight of a drug conjugate of the invention, and from 99 to 1% by weight of a suitable pharmaceutical excipient, depending on the desired mode of administration. Preferably, the composition comprises about 5 to 75% by weight of a drug conjugate of the invention, the remainder being suitable pharmaceutical excipients.

The preferred route of administration is by injection, using a conventional daily dosage regimen which may be adjusted depending on the severity of the disease. The conjugates of the invention, or pharmaceutically acceptable salts thereof, may also be formulated as an injectable preparation, for example, using from about 0.5 to about 50% of the active ingredient dispersed in a pharmaceutically acceptable adjuvant which may be administered in liquid form, such as water, saline, aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension.

If desired, the pharmaceutical combination dosage forms of the present invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants and the like, for example: citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, and the like.

The actual preparation of such dosage forms is well known or obvious to those skilled in the art, for example, see Remington's Pharmaceutical Sciences, 18 th edition (MackPublishing Company, Easton, Pennsylvania, 1990). In any event, the dosage form of the compositions used will contain a therapeutically effective amount of a conjugate of the invention for the treatment of the corresponding disease, in accordance with the techniques of the present invention.

Examples

The polyethylene glycol-fatty acid derivatives, the conjugates thereof and the preparation method thereof according to the present invention will be described below with reference to examples, which do not limit the present invention, the scope of which is defined by the claims.

Example 1

Preparation of methoxypolyethylene glycol caproic acid

10 g methoxy polyethylene glycol (molecular weight 10000) is dissolved in 100ml toluene, 70 ml is heated and distilled off, the solution is cooled to 35 ℃, 30 ml anhydrous tetrahydrofuran is added, 0.1 g sodium hydride is added, and the mixture is stirred for 30 minutes. To the solution was added 1 g of 6-bromohexanenitrile, which was stirred overnight at 35 ℃. The solution was concentrated under reduced pressure and 100ml of isopropanol were added. The precipitate was collected by filtration and dried under vacuum, yield: 9.5 g (95%).

9g methoxy polyethylene glycol hexanenitrile (mPEG-O-CH)₂CH₂O-CH₂CH₂CH₂CH₂CH₂CN, molecular weight 10000, from the above) was dissolved in 50 ml of 37% concentrated hydrochloric acid, stirred at room temperature for three days, diluted with 150 ml of 8% sodium chloride solution, and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The intermediate product was dissolved in 50 ml of 10% potassium hydroxide solution, stirred at room temperature for one day, adjusted to pH 2.6 with hydrochloric acid and added with 8 g of sodium chloride. Extracted three times with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. Concentrated in vacuo and precipitated by addition of 100ml of isopropanol. The precipitate was collected by filtration and dried under vacuum, yield: 6.5 g (72%).

Example 2

Preparation of methoxypolyethylene glycol heptanoic acid

10 g methoxy polyethylene glycol (molecular weight 10000) is dissolved in 100ml toluene, 70 ml is heated and distilled off, the solution is cooled to 35 ℃, 30 ml anhydrous tetrahydrofuran is added, 0.1 g sodium hydride is added, and the mixture is stirred for 30 minutes. To the solution was added 1 g of 6-bromoheptanitrile, and the mixture was stirred overnight at 35 ℃. The solution was concentrated under reduced pressure and 100ml of isopropanol were added. The precipitate was collected by filtration and dried under vacuum, yield: 9.5 g (95%).

9 g methoxy polyethylene glycol heptanenitrile (molecular weight 10000, mPEG-O-CH)₂CH₂O-CH₂CH₂CH₂CH₂CH₂CN, prepared from the above) was dissolved in 50 ml of 37% concentrated hydrochloric acid, stirred at room temperature for three days, diluted with 150 ml of 8% sodium chloride solution, and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The intermediate product was dissolved in 50 ml of 10% potassium hydroxide solution, stirred at room temperature for one day, adjusted to pH 2.6 with hydrochloric acid and added with 8 g of sodium chloride. Extracted three times with dichloromethane.The organic phases were combined and dried over anhydrous sodium sulfate. Concentrated in vacuo and precipitated by addition of 100ml of isopropanol. The precipitate was collected by filtration and dried under vacuum, yield: 6.1 g (68%).

Example 3

Preparation of polyethylene glycol diheptanoic acid

10 g of polyethylene glycol (molecular weight: 10000) is dissolved in 100ml of toluene, 70 ml is distilled out by heating, the solution is cooled to 35 ℃, 30 ml of anhydrous tetrahydrofuran is added, 0.2 g of sodium hydride is added, and the mixture is stirred for 30 minutes. To the solution was added 2g of 6-bromoheptanitrile, and the mixture was stirred overnight at 35 ℃. The solution was concentrated under reduced pressure and 100ml of isopropanol were added. The precipitate was collected by filtration and dried under vacuum, yield: 9.5 g (95%).

9 g of polyethylene glycol-diheptonitrile (molecular weight 10000, obtained from the above) was dissolved in 50 ml of 37% concentrated hydrochloric acid, stirred at room temperature for three days, diluted with 150 ml of 8% sodium chloride solution, and extracted three times with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. And (4) concentrating in vacuum. The intermediate product was dissolved in 60 ml of 10% potassium hydroxide solution, stirred at room temperature for one day, adjusted to pH 2.6 with hydrochloric acid, and 8 g of sodium chloride was added. Extracted three times with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. Concentrated in vacuo and precipitated by addition of 100ml of isopropanol. The precipitate was collected by filtration and dried under vacuum, yield: 6.3 g (70%).

Example 4

Preparation of methoxy polyethylene glycol heptanoic acid N-hydroxysuccinimide ester

1 g of methoxypolyethylene glycol heptanoic acid (molecular weight 10000, prepared according to example 2) was dissolved in 200 ml of anhydrous dichloromethane, 14.7 mg of N-hydroxysuccinimide and 23 mg of DCC were added, and stirring was carried out overnight at 35 ℃. The solution was concentrated under reduced pressure and 20 ml of isopropanol were added. The precipitate was collected by filtration and dried under vacuum, yield: 0.9 g (90%).

Example 5

Preparation of methoxypolyethylene glycol heptanoic acid and paclitaxel conjugate

mPEG-O-CH₂CH₂-OCH₂CH₂CH₂CH₂CH₂COOH

Paclitaxel

Wherein, Paclitaxel: paclitaxel

0.6 g of methoxypolyethyleneglycol heptanoic acid (molecular weight: 10000, prepared according to example 2) was dissolved in 10 ml of dichloromethane, 60 mg of paclitaxel, 8 mg of DMAP and 18 mg of DCC were added dropwise to the solution, and the solution was stirred for 6 hours. The solvent was distilled off under reduced pressure. To the residue was added 20 ml of isopropyl alcohol (IPA). Filtering, collecting precipitate, washing with diethyl ether, draining, and vacuum drying. Yield: 0.54 g (90%).

Example 6

Methoxypolyethylene glycol heptanoic acid N-hydroxysuccinimide ester and

preparation of erythropoietin (GCSF) conjugates

6 mg of methoxypolyethylene glycol heptanoic acid N-hydroxysuccinimide ester (molecular weight 10000, prepared in example 4) was dissolved in 5 ml (pH7.4) of PBS buffered saline containing 1 mg/ml of erythropoietin. The reaction system was shaken for one hour at 4 ℃ and then for 8 hours at room temperature at a ratio of polyethylene glycol to erythropoietin (GCSF) of 3: 1. Diluting to 0.5mg/ml of erythropoietin, purifying with ion exchange resin, and collecting mono-substituted and di-substituted components. SDS-PAGE showed no free erythropoietin.

Example 7

This example illustrates the preparation of a representative parenteral dosage form of a pharmaceutical combination of the invention, which is the conjugate of the invention of example 5.

Composition (I)

Drug conjugate of example 5 2g

0.9% saline solution to 100mL

The drug conjugate of the present invention was dissolved in 0.9% saline solution to obtain 100mL of solution for intravenous injection, which was filtered through a 0.2 μmembrane filter and packaged under aseptic conditions.

Claims

1. A compound of the formula:

or

B′-(CH₂)_l-O-PEG-O-(CH₂)_l-B

(II)

Wherein PEG is a polyethylene glycol polymer;

l is an integer from 4 to 18;

and is

A is C_1-12Alkoxy, cycloalkoxy or alkoxyaryl, or an ester group;

b and B' are the same or different and are each a functional group selected from one of a carboxyl group, an ester group, an acid chloride, a hydrazide, a maleimide and a pyridodisulfide.

2. The compound according to claim 1, wherein the compound is of the general formula (I) and a is methoxy, ethoxy, isopropoxy, cyclobutoxy, cyclohexyloxy or benzyloxy.

3. The compound of claim 2, wherein a is methoxy and B is carboxy.

4. The compound of claim 1, wherein the compound is of formula (I) and a is an ester group selected from N-hydroxysuccinamide ester or 1-hydroxybenzotriazole ester and B is different from a.

5. The compound of claim 1, wherein said compound is of formula (II), and said B and B' are the same.

6. The compound of claim 5, wherein said compound is of formula (II), and said B and B' are both carboxy.

7. The compound according to claim 1, wherein the polyethylene glycol has a molecular weight of 150 to 60,000, and the polyethylene glycol may have a linear, branched, star-shaped or tree-shaped structure.

8. The compound of claim 1, wherein l is equal to 5 or 6.

9. A process for the preparation of a compound as claimed in claim 3, which comprises the steps of reacting PEG with a bromocyanide and then hydrolysing the cyano group to give the corresponding acidic group.

10. A pharmaceutical combination of a compound according to any one of claims 1 to 8 and a drug according to the formula:

or

Wherein:

x and X', which are identical or different, are O, NH or S;

drug is a Drug molecule.

11. The drug conjugate of claim 10, wherein the drug molecule is selected from one of the following classes: protein, enzyme, polypeptide, nucleoside, saccharide, organic acid, glycoside, flavone, quinone, terpenoid, phenylpropanoid phenol, steroid and its glycoside, alkaloid, cardiovascular drug, antineoplastic agent, anti-infection drug, antifungal agent, anxiolytic agent, gastrointestinal drug, central nervous system drug, analgesic, progestational drug, contraceptive, and lipid.

12. The drug conjugate of claim 11, wherein said protein is selected from the group consisting of an erythropoietin, an interleukin, an interferon, a hirudin, and an antibody.

13. The drug conjugate of claim 11, wherein the anti-tumor drug is selected from the group consisting of paclitaxel, camptothecin, etoposide, and derivatives thereof.