WO2008130180A1

WO2008130180A1 - Preparation of drug delivery systems using ph-sensitive block copolymer and their application

Info

Publication number: WO2008130180A1
Application number: PCT/KR2008/002282
Authority: WO
Inventors: Ick-Chan Kwon; Doo-Sung Lee; Kwang-Meyung Kim; Bong-Sup Kim; Kyeong-Soon Park; Min-Sang Kim; Jong-Kwon Han; Jin-Young Ko
Original assignee: Korea Institute Of Science And Technology
Priority date: 2007-04-23
Filing date: 2008-04-23
Publication date: 2008-10-30
Also published as: KR20080095130A

Abstract

Disclosed is a drug delivery system, which encapsulates a hydrophobic drug and consists of a pH-sensitive block copolymer having both hydrophilic segments and hydrophobic segments. Due to its high pH-sensitivity, the drug delivery system selectively delivers a great amount of a drug to a diseased region within a short period of time by being easily degraded at a locally low ph in a variety of cancerous or inflammatory disease regions, thereby enhancing therapeutic effectiveness of the drug as well as remarkably reducing toxicity of the drug itself, thus to be useful for treatment against a variety of cancers or inflammatory diseases.

Description

PREPARATION OF DRUG DELIVERY SYSTEMS USING PH-SENSITIVE BLOCK COPOLYMER AND THEIR APPLICATION

TECHNICAL FIELD The present invention relates to a drug delivery system comprised of a pH-sensitive block copolymer encapsulating a hydrophobic drug, and more particularly, to a pH-sensitive drug delivery system which can increase the efficacy of a drug as well as remarkably reduce the toxicity of the drug itself, by delivering a drug having a specifically high concentration to a disease region while being easily degraded due to a low pH in cancerous and inflammatory disease regions, and to the use thereof.

BACKGROUND ART

Drugs that are pharmacologically efficacious (e.g., an anticancer medicine) have not shown dramatic achievements, contrary to expectations, in their actual clinical application due to serious toxicity and low solubility of the drugs. Accordingly, development of new drug formulations has been actively progressing in order to minimize the side effects of drugs used for disease treatment. Drug delivery systems, such as nano-particles, micelles, microspheres, which can enhance the therapeutic efficacy of drugs and minimize drug toxicity have been developed. For instance, a micelle has a spherical structure that is thermodynamically stable and uniform in a chemical compound having both hydrophilic segments and hydrophobic segments. Since a compound having such a micelle structure has hydrophobic properties in a central portion thereof, a variety of hydrophobic drugs may be encapsulated therein. In addition, the hydrophobic drugs have a low solubility in solution. However, once the hydrophobic drugs are included in the micelle particle, the drug solubility in solution can be enhanced. That is, the nano-sized micelles comprised of the hydrophobic and hydrophilic segments have a high possibility to be applied as a drug delivery system.

Nano-particles are designed such that a surface thereof is surrounded with hydrophilic substances so as to be protected from a variety of immune mechanisms within a human body, and an inner central portion thereof encapsulates hydrophobic drugs. These nano-particles can be selectively targeted for tissue regions of cancer or inflammatory diseases. Since blood vessels of cancerous or inflammatory disease tissues are generally loose, compared to those of other normal tissues, nano-particles having an appropriate size may easily be accumulated around the cancerous or inflammatory disease tissues due to the EPR (Enhanced Permeability and Retention) effect. In addition, these nano-particles induce an extension of residence time within a human body of an anti-cancer medicine as well as an increase in a targeting efficiency, thereby reducing the side effects of the anti-cancer medicine and increasing biological utility. However, a release rate of the encapsulated anti-cancer medicine cannot be controlled, thereby making it difficult to expect more enhanced anti-cancer effects.

Meanwhile, the pH environment in normal tissue and a human body is generally maintained at pH 7.2 ~ pH 7.4. However, cancerous or inflammatory disease tissues have a locally low pH. The pH around cancer cells is shown to have a lower level than that in normal tissue due to organic acids generated by active metabolism of the cancer cells, and it is reported to have a pH of approximately 6.8 on the average. Further, when particles are absorbed within a cell, endosome which is known to have a pH of less than approximately 6.0 is formed.

Accordingly, the pH-sensitive polymers have been prepared for drug delivery and disease treatment by using the locally low pH in the cancerous or inflammatory disease tissues. A pH-sensitive drug delivery system refers to a delivery system, which has almost no release of drug in normal tissue, but is accumulated in the disease regions due to the EPR effect and then the drug release is maximized when the drug is degraded.

The conventional pH-sensitive polymers have the following problems: they could not substantially be used since the pH-sensitivity according to the pH change is very low, and when hydrophobic drugs are included, high therapeutic efficacy against the disease cannot be expected.

Therefore, the present inventors have completed the present invention by developing a nano-particle pH-sensitive drug delivery system for the treatment of cancer or inflammatory diseases, which can enhance therapeutic efficacy by maximizing the release of an anti-cancer medicine while the delivery system is degraded by a locally low pH environment after the pH-sensitive drug delivery system having nano-sized particles and encapsulating a hydrophobic drug is accumulated in the cancerous or inflammatory disease tissues, and can minimize the toxicity of the drug.

DISCLOSURE OF THE INVENTION Technical Problem

The present invention is directed to providing a drug delivery system encapsulating a hydrophobic drug and comprised of a pH-sensitive block copolymer, which can be selectively accumulated in the tissues of various cancers or inflammatory diseases, thus to increase the therapeutic efficacy against the diseases by releasing the drug at a high concentration within a short period of time while nano-sized particles are degraded under the condition of a low pH in the disease regions, as well as to minimize the side effects of the drug.

Technical Solution

To achieve these and other advantages and in accordance with an aspect of the present invention, there is provided a drug delivery system, which encapsulates a hydrophobic drug and consists of a pH-sensitive block copolymer. The pH-sensitive block copolymer is an amphiphilic polymer having both hydrophilic segments and hydrophobic segments, and has a characteristic of biocompatibility or biodegradability.

The hydrophilic segments may include polyethylene glycol, poly(N-2-(hydroxypropyl)methacrylamide), poly(divinyl ether-co-maleic anhydride) or poly(styrene-co-maleic anhydride), preferably, a polyethylene glycol compound having monofunctional acrylate or methacrylate.

The hydrophobic segments may include poly( β -amino ester)(PAE), poly(amido-amine) (PAA) or mixed copolymers thereof (PAEA), preferably, poly(β -amino ester)(PAE). In addition, amine compounds or diamine compounds may exist in the hydrophobic segments. The amine compounds may include 3-methyl-4-(3-methylphenyl) piperazine, 3 methyl piperazine, 4-(bis-(fluorophenyl)methyl) piperazine, 4-(ethoxycarbonylmethyl) piperazine, 4-(phenylmethyl)piperazine, 4-(1-phenylethyl)piperazine,

4-(1 ,1-dimethoxycarbonyl)piperazine, 4-(2-(bis-(2-propenyl)amino)ethyl) piperazine, methylamine, ethylamine, butylamine, hexylamine, 2-ethylhexylamine, 2-piperidine-1 -ethylamine, C-aziridine-1-yl-methylamine, 1 -(2-aminoethyl)piperazine, 4-(aminomethyl)piperazine),

N-methylethylenediamine, N-ethylethylenediamine, N-hexylethylenediamine, pycoliamine or adenine. The diamine compounds may include piperazine, piperidine, pirrolidine, 3,3-dimethylpiperidine, 4,4'-trimethylene dipiperidine, N.N'-dimethylethylenediamine, N,N'-diethylethylenediamine, imidazolidine or diazepam.

The hydrophobic drugs of the present invention serve as an anti-cancer medicine or anti-inflammatory agent. The anti-cancer medicine may be selected from the group consisting of paclitaxel, doxorubicin, retinoic acid series, cis-platin, camptothecin, 5-FU, Docetaxel, Tamoxifen, anasterozole, carboplatin, topotecan, belotecan, irinotecan, gleevec and vincristine. The anti-inflammatory agent may be selected from the group consisting of aspirin and salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenylbutazone, methotrexate, cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib, valdecoxib, nimesulide, cortisone and corticosteroid.

The pH-sensitive drug delivery system encapsulating the hydrophobic drugs according to the present invention is characterized in that particles of the drug delivery system are degraded in the cancerous or inflammatory disease regions, which have a locally low pH of less than pH 7.2, thereby rapidly releasing the drugs. The cancers may include lung cancer, uterine carcinoma, uterine cervical cancer, prostatic carcinoma, head and neck cancer, pancreatic carcinoma, brain tumor, breast cancer, liver cancer, skin cancer, esophageal cancer, testicular cancer, kidney cancer, large intestine cancer or rectal cancer. The inflammatory diseases may include rheumatoid arthritis, osteoarthritis or arteriosclerosis.

Effect of the Invention As so far described, the present invention relates to a drug delivery system which encapsulates a hydrophobic drug and is comprised of a pH-sensitive block copolymer having both hydrophilic and hydrophobic segments. The drug delivery system according to the present invention increases efficacy of the drug as well as remarkably reduces toxicity of the drug itself, by delivering the drug having a specifically high concentration to a disease region while being easily degraded due to a locally low pH in cancerous and inflammatory disease regions.

The pH-sensitive drug delivery system according to the present invention has the hydrophobic segments in the central portions of the particles. Accordingly, a variety of anti-cancer treatments or anti-inflammatory drugs having hydrophobicity that are currently under development or being applied clinically are easily encapsulated therein, thereby being highly useful for the treatment against cancer or inflammatory diseases.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates a structural formula of a pH-sensitive block copolymer according to the present invention;

Figure 2 is a mimetic view showing a micelle particle obtained by encapsulating a hydrophobic drug in an amphiphilic pH-sensitive block copolymer;

Figures 3(a)-3(d) are, respectively, TEM (transmission electron microscope) images of micelles consisting of MPEG-HPAE (a) and MPEG-OPAE (c), which are pH-sensitive polymers, and micelles consisting of DOX-MPEG-HPAE (b) and OX-MEPG-OPAE (d), which encapsulate a drug; Figure 4 is a graph which shows the results, measured in hours, of the degree of drug release from a micelle consisting of a pH-sensitive block copolymer encapsulating the drug as prepared in Example 2 according to the pH value;

Figure 5 illustrates florescence images that compare the degree of absorption within a cell of pH-sensitive DOX-MPEG-HPAE micelles encapsulating doxorubicin under other pH conditions; and

Figures 6 through 8 are graphs which respectively illustrate the cancer growth inhibition (Fig. 6), the weight change (Fig. 7) and the survival rate (Fig. 8) of a pH-sensitive DOX-MPEG-HPAE encapsulating doxorubicin.

MODES FOR CARRYING OUT THE PREFERRED EMBODIMENTS Hereinafter, description of the present invention is given in detail. The drug delivery system according to the present invention is comprised of a nano-sized pH-sensitive block copolymer, and an anti-cancer medicine or anti-inflammatory agent is encapsulated therein. The drug delivery system is maintained in the form of particles under the normal condition of pH 7.4, thereby not releasing the drug. However, the drug delivery system selectively releases the drug under the condition of a low pH in cancerous or inflammatory disease regions, thereby enhancing the efficacy of the treatment for cancerous or inflammatory diseases and minimizing the toxicity of the drug. Accordingly, the present invention provides a drug delivery system which can be used to treat a variety of cancers or inflammatory diseases.

The pH-sensitive block copolymer is comprised of amphiphilic polymer nanoparticles. Here, the polymer nanoparticles may form a nano-sized self-assembly or self-aggregate through a balance between hydrophilicity and hydrophobicity, and be selectively accumulated along blood vessels in a variety of cancerous or inflammatory disease tissues. In addition, it may facilitate the encapsulation of a variety of anti-cancer medicine or anti-inflammatory agents in the pH-sensitive polymer nanoparticles as well as be applied for the treatment of cancer or inflammatory diseases.

The hydrophilic polymers may use well-known biodegradable compounds having hydrophilicity, without limit. Preferably, such may include polymers synthesized from the group of poly(N-2-(hydroxypropyl)methacrylamide), poly(divinyl ether-co-maleic anhydride)), (poly(styrene-co-maleic anhydride)), or dextran, chitosan, glycol chitosan, poly-L-lysine and poly-aspartic acid, more preferably, polyethylene glycol series compounds, and most preferably, polymers having monofunctional acrylate, metacrylate, etc. endmost among the polyethylene glycol series compounds. The hydrophobic polymers may use any polymers having biocompatibility and biodegradability. Preferably, such may include poly(amino acid) compounds having both hydrophobicity and pH-sensitivity, and as non-limiting examples thereof, poly(β -amino ester)(PAE), poly(amido-amine) (PAA) or mixed copolymers thereof (PAEA) are included. Among these, poly( β -amino ester)(PAE) is the most preferable.

The drug delivery system particles comprised of the pH-sensitive block copolymer have excellent biocompatibility and biodegradability as well as excellent stability within a living body, thereby having high biodistribution within blood, thus to be accumulated for enough time in the cancerous or inflammatory disease tissues.

The hydrophobic drug coupled to the hydrophilic polymer may include an anti-cancer medicine, such as paclitaxel, doxorubicin, retinoic acid series, cis-platin, camptothecin, 5-FU, Docetaxel, Tamoxifen, anasterozole, carboplatin, topotecan, belotecan, irinotecan, gleevec, vincristine, etc., and an anti-inflammatory agent, such as aspirin, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenylbutazone, methotrexate, cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib, valdecoxib, nimesulide, cortisone, corticosteroid, and the like. It is preferable to encapsulate a drug having hydrophobicity.

In the pH-sensitive drug delivery system encapsulating the drug, the drug is not released in a normal body condition (i.e., in the range of pH7.2 ~ pH7.4) while maintaining the form of nano-sized particles. However, the particles are degraded under an abnormal condition such as in tissues of cancer or inflammatory diseases (i.e., pH less than 7.2), and thus the drug is released. In addition, the particles are absorbed within a cell and then degraded in a pH less than 6.0 of endosome by endocytosis, thus to release the drug.

Cancers treatable with the drug delivery system according to the present invention may include lung cancer, uterine carcinoma, uterine cervical cancer, prostatic carcinoma, head and neck cancer, pancreatic carcinoma, brain tumor, breast cancer, liver cancer, skin cancer, esophageal cancer, testicular cancer, kidney cancer, large intestine cancer or rectal cancer. The inflammatory diseases may include rheumatoid arthritis, osteoarthritis or arteriosclerosis.

Further, the present invention may be applied to another field, other than cancer and inflammatory diseases, by appropriately changing the constituting elements, molar ratio, molecular weight and functional groups within a block of the block copolymer, and also be utilized by designing a target-oriented micelle by marking folic acid, RGD series protein or aptamer.

In addition, the present invention may variously control formation conditions, functional groups and the like of the pH-sensitive block copolymer, thereby easily controlling the rate of drug degradation of the pH-sensitive block copolymer particles within the living body, thus to selectively deliver the drug to a proper target position needing the drug delivery.

As a preferred embodiment of the present invention, the pH-sensitive block copolymer consists of polyethylene glycol as hydrophilic segments and poly(β -amino ester)(PAE) as hydrophobic segments, and a hydrophobic anti-cancer treatment or anti-inflammatory agent is encapsulated in the nano-sized particle of the pH-sensitive block copolymer. The pH-sensitive block copolymer in which such hydrophobic drug can be encapsulated may be indicated by general formula (1) as below:

(hydrophlllc segment) (hydrophobic segment

R- alkyl chain

General formula (1 ) In general formula (1), the pH-sensitive block copolymer refers to a repeating structure of polyethylene glycol (i.e., hydrophilic segments) and poly(β -amino ester), and R in the composition of poly( J3 -amino ester) (i.e., hydrophobic segments) refers to a variety of alkyl chain structures.

In general formula (1), there is no specific limit in the molecular weight of compounds in the polyethylene glycol series (i.e., hydrophilic segments), but preferably, it is in the range of 500 ~ 5,000. Diamine compounds existing within the composition of the poly(β -amino ester) (i.e., hydrophobic segments) may include piperazine, piperidine, pirrolidine,

3,3-dimethylpiperidine, 4,4'-tri methylene(dipiperidine), N,N'-dimethyl ethylenediamine, N,N'-diethyl ethylenediamine, imidazoline or diazepam.

In general formula (1 ), R refers to an alkyl chain including 1 - 20 carbon atoms.

The drug delivery system having the pH-sensitive block copolymer structured according to general formula (1) is prepared as nano-sized particles in the form of a self-assembly or self-aggregate in solution, and has a size of a few tens of ran to a few hundreds of run. For the drugs which can be encapsulated in the pH-sensitive polymer drug delivery system comprised of nano-sized particles, a variety of anti-cancer medicines or anti-inflammatory agents are currently under clinical trials or use. The anti-cancer medicines may include paclitaxel, doxorubicin, retinoic acid series, cis-platin, camptothecin, 5-FU, Docetaxel, Tamoxifen, anasterozole, carboplatin, topotecan, belotecan, irinotecan, gleevec, vincristine, and the like. The anti-inflammatory agents may include aspirin, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenylbutazone, methotrexate, cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib, valdecoxib, nimesulide, cortisone, corticosteroid, and the like. These drugs are hydrophobic, thereby facilitating the drug encapsulation, thus to be capable of treating cancers or inflammatory diseases.

Particles in the pH-sensitive drug delivery system encapsulating the drug are easily degraded under acidic conditions of pH less than 7.2, thereby releasing the drug. In addition, the pH-sensitive drug delivery system encapsulating the drug has a high selectivity for diseased tissue due to the EPR effect of cancerous or inflammatory tissues compared to drugs having a low molecular weight, thereby having excellent accumulation efficiency at the diseased regions. Further, the drug delivery system greatly increases the residence time within the human body when compared to drugs having a low molecular weight, thereby enhancing the therapeutic effectiveness against cancer or inflammatory diseases as well as reducing the toxicity of the drug.

Hereinafter, the present invention will be described in more detail with reference to the below examples and experiments. The below examples and experiments are only exemplary, and are not limitative of the claims of the present application.

Example 1. Preparation of a pH-sensitive drug delivery system encapsulating doxorubicin

100mg of MPEG-HPAE, which is a pH-sensitive polymer, was dissolved in 20ml of chloroform/methanol (1 :1 , v/v) co-solvent. 10mg of doxorubicin was dissolved into 5ml of chloroform/methanol (1 :1 , v/v) co-solvent containing triethyleneamine, added into the solution having the dissolved pH-sensitive polymer, and then stirred for 10 minutes. The mixed solution was placed into a spherical flask of 100ml, and the solvent was completely evaporated by using a stirred retort. Here, the polymer and doxorubicin were uniformly spread out onto an inner wall of the flask, thereby forming a thin film. 10ml of distilled water was added into the flask and stirred. Then, the unencapsulated drug was removed by using a filter, and was yielded through freeze-drying.

2mg of the pH-sensitive drug delivery system encapsulating doxorubicin, which was thusly yielded after freeze-drying, was dissolved in chloroform/methanol (1 :1 , v/v) co-solvent. Then, encapsulation efficiency of the doxorubicin into the pH-sensitive polymer was measured using an UV-vis spectrometer. In addition, the sizes and shapes of the particles before and after doxorubicin was encapsulated were analyzed using dynamic light scattering and a transmission electron microscopy (TEM).

The pH-sensitive drug delivery system encapsulating doxorubicin was prepared by encapsulating doxorubicin into the drug delivery system due to the hydrophobic interaction of the pH-sensitive polymer block copolymer comprised of hydrophilic segments and hydrophobic segments. The principle of preparing the same is shown in reaction equation 1 below: [Reaction Equation 1]

pH-sensitive hydrophobic pH-sensitive dru^g delivery system encapsulating polymer drug hydrophobic drug

hydrophilic segment hydrophobic segment hydrophobic drug

Experimental Example 1. Analysis of particle size of drug delivery system

The size of the drug delivery system micelle particles before and after the doxorubicin was encapsulated into the micelle particles composed of the pH-sensitive polymer was analyzed using dynamic light scattering and transmission electron microscopy (TEM).

According to the experimental results, as shown in Figs. 2a to 2d, the size of the micelle particles consisting of MPEG-HPAE (referring to Fig. 2a) and MPEG-OPAE (referring to Fig. 2c) as pH-sensitive polymers without doxorubicin was respectively measured at 42iini and 53nm. In addition,

DOX-MPEG-HPAE (referring to Fig. 2b) and DOX-MPEG-OPAE (referring to Fig. 2d) encapsulating doxorubicin were respectively shown to have a size of

62nm and 94nm. Also, according to an analysis result using transmission electron microscopy (TEM), all particles were shown to have a spherical particle shape.

Experiment Example 2. Drug release of pH-sensitive drug delivery system encapsulating doxorubicin

The drug release experiments on DOX-MPEG-HPAE and DOX-MPEG-OPAE, which were the pH-sensitive drug delivery systems encapsulating doxorubicin prepared in Example 1 , were respectively performed in PBS solution at pH7.4 and PBS solution at pH6.4. As a result of the experiments, as shown in Fig. 3, it was shown that doxorubicin of approximately 20% was released from the micelle particles under a physiological condition of pH7.4. However, it was observed that doxorubicin of more than 65% was released within 6 hours under low pH conditions such as at pH6.4 and pH5.8. That is, under the condition of pH7.4, the drug delivery system encapsulating doxorubicin was stable, thereby exhibiting a slow release rate. Under the condition of the low pH, a hydrogen ion H+ was coupled to the amine of dipiperidine at the hydrophobic segments of the polymer to be thereby hydrogenated. Accordingly, the drug delivery system was degraded due to the repulsive power of a positive charge, thus to release doxorubicin at a rapid rate. That is, it was confirmed that the pH-sensitive drug delivery system encapsulating doxorubicin released quickly under acidic conditions.

Experimental Example 3. Absorption of doxorubicin within a cell by pH-sensitive drug delivery system encapsulating doxorubicin A phenomenon that DOX-M PEG-H PAE particles, as the pH-sensitive drug delivery system encapsulating doxorubicin, were degraded under the physiological condition of pH7.4 and acidic extracellular pH and thereby doxorubicin was absorbed within the cell was observed through a florescent microscope.

As a result of the experiment, as shown in Fig. 5, it was confirmed that absorption of doxorubicin within the cell was low at pH7.4, but absorption of doxorubicin within the cell was high at pH6.4. Therefore, it could be confirmed that the drug delivery system was degraded under acidic conditions and the drug was absorbed at a high concentration within a short period of time.

Experimental Example 4. Absorption of doxorubicin within a cell by pH-sensitive drug delivery system encapsulating doxorubicin

Anti-cancer efficacy of the pH-sensitive drug delivery system encapsulating doxorubicin, which was repeatedly injected into the tail vessels of C57/BL6 mice having B16F10 cancer cells transplanted, was measured.

According to the experiment, as shown in Figs. 6 to 8, it was shown that a DOX-MPEG-HPAE drug delivery system encapsulating doxorubicin had more enhanced efficacy of cancer growth inhibition when compared to the group injected with doxorubicin only (Fig. 6). The rate of weight reduction of the mice in a group to which the DOX-MPEG-HPAE drug delivery system was injected was shown to be low compared to those in a group to which doxorubicin only was injected (Fig. 7). In addition, it was observed that when the DOX-MPEG-HAPE drug delivery system was injected, the survival rate of the mice was very high (Fig. 8). That is, it was confirmed that the pH-sensitive drug delivery system encapsulating doxorubicin could reduce the toxicity caused by doxorubicin as well as enhance the efficacy of cancer treatment.

Claims

1. A drug delivery system, comprising a hydrophobic drug encapsulated in a pH-sensitive block copolymer having both hydrophilic segments and hydrophobic segments.

2. The drug delivery system of claim 1 , wherein the hydrophilic segments include polyethylene glycol, poly(N-2-(hydroxypropyl)methacrylamide), poly(divinyl ether-co-maleic anhydride) or poly(styrene-co-maleic anhydride).

3. The drug delivery system of claim 2, wherein the hydrophilic segments are polyethylene glycol compounds having monofunctional acrylate or metacrylate.

4. The drug delivery system of claim 1 , wherein the hydrophobic segments are poly( β -amino ester)(PAE), poly(amido-amine) (PAA) or mixed copolymers thereof (PAEA).

5. The drug delivery system of claim 4, wherein the hydrophobic segments are poly( β -amino ester)(PAE).

6. The drug delivery system of claim 4, wherein amine compounds or diamine compounds are used in the hydrophobic segments.

7. The drug delivery system of claim 6, wherein the amine compounds include 3-methyl-4-(3-methylphenyl) piperazine, 3 methyl piperazine, 4-(bis-(chlorophenyl)methyl) piperazine, 4-(ethoxycarbonylmethyl) piperazine, 4-(phenyl methyl)piperazine, 4-(1-phenylethyl) piperazine, 4-( 1 ,1- dimethoxycarbonyl)piperazine, 4-(2-(bis-(2-propenyl)amino)ethyl) piperazine, methylamine, ethylamine, butylamine, hexylamine, 2-ethylhexylamine, 2-piperidine-1 -ethylamine, C-aziridine-1 -yl-methylamine,

1 -(2-aminoethyl)piperazine, 4-(aminomethyl)piperazine),

N-methylethylenediamine), N-ethylethylenediamine), N-hexylethylenediamine, pycoliamine or adenine.

8. The drug delivery system of claim 6, wherein the diamine compounds include piperazine, piperidine, pirrolidine, 3,3-dimethylpiperidine, 4,4'-trimethylene dipiperidine, N,N'-dimethylethylenediamine, N.N'-diethylethylenediamine, imidazolidine or diazepam.

9. The drug delivery system of claim 1 , wherein the hydrophobic drugs are an anti-cancer medicine selected from the group consisting of paclitaxel, doxorubicin, retinoic acid series, cis-platin, camptothecin, 5-FU, Docetaxel, Tamoxifen, anasterozole, carboplatin, topotecan, belotecan, irinotecan, gleevec and vincristine.

10. The drug delivery system of claim 1 , wherein the hydrophobic drugs are an anti-inflammatory agent selected from the group consisting of aspirin and salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenylbutazone, methotrexate, cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib, valdecoxib, nimesulide, cortisone and corticosteroid.

11. The drug delivery system of claim 1 , wherein particles of the drug delivery system are degraded in cancerous or inflammatory disease regions, which have a locally low pH of less than pH 7.2, thereby rapidly releasing the drug.

12. The drug delivery system of claim 2, wherein the cancer includes lung cancer, uterine carcinoma, uterine cervical cancer, prostatic carcinoma, head and neck cancer, pancreatic carcinoma, brain tumor, breast cancer, liver cancer, skin cancer, esophageal cancer, testicular cancer, kidney cancer, large intestine cancer or rectal cancer.

13. The drug delivery system of claim 2, wherein the inflammatory diseases include rheumatoid arthritis, osteoarthritis or arteriosclerosis.