pH-RESPONSIVE CYCLODEXTRIN DERIVATIVE, PREPARATION METHOD THEREOF, AND pH-RESPONSIVE CONJUGATE OF pH-RESPONSIVE CYCLODEXTRIN DERIVATIVE AND DRUG
The present invention refers to pH responsiveness cyclodextrin derivatives, manufacturing method thereof and said pH of and the medication cyclodextrin derivatives is relates to response. Specific target for effective drugs to a safe delivery for, smart drug passing techniques (smart drug delivery technique) - response to development of various signal and receives the response to the question with (Fleige E et al. , Adv Drug Delivery Rev. , 2012, 64, 866 - 884). Temperature and light and such as pH as well as physical signal, glutathione and enzyme response to electrochemical signal such as smart material physical chemical properties in leaps of the encapsulation of drug certain conditions can be of the high-speed and. PH value is within the body for the plurality of target site a constant physiological conditions may indicate the pH number since the number (controlling trigger) the stimulation frequently as been selected. PH change through gastrointestinal tract produce and which presents a stronger acidic on or weak alkaline the small intestine on site - specific drug delivery is used for this came. A cancer tissue in a pH 6 to 5 year increased on winter and stepped down, similar pH lowered because of the inflammatory tissue and abscess. observed even (abscess). A slightly acidic pH value anticancer release of the drug, or antiinflammatory number for constitution: known as induction signal. In addition, initial to petty pH value 5 to 6, in which high intracellular difficult transmitting cell membrane (endocytic pathway) flowing to the left should be delivered into cells via a pDNA, of drugs automatically operating waste transfer or protein siRNA to petty sleepers and is frequently used as signals for which. However, pH number exception in some change in body under the outside since the not greater extremely and, small pH response to a change in the rapid degradation thereof, yet still smart material drug delivery system for more substantial in water has been demanded KIPO & the laboratory. Cyclodextrin to conventional based on pH response to a drug delivery system for the introduction of a polymeric and disolving silica thin film on substrate pH self-assembling in an insertion or taken forms, even though the placard is connected directly is large one of molecules caused toxicity permeation intracellular or improving photoresist on wafers KIPO & includes followings. In the background such, the present invention with cyclodextrin or its derivatives are maleic anhydride derivatives are formed by a covalent linkage of a short time, as cyclodextrin derivatives, for cyclodextrin of primary hydroxyl groups or cyclodextrin derivativesNH2, N3or amino acids, such as maleic anhydride derivatives residues terminal functional groups a CRT is provided is a conventional cyclodextrin derivatives pH the physiologically compatible drugs having a amine group in conditions and binds, acidic pH condition and within the range pH 6. 5 hereinafter, specifically pH 5 to 6. 5 amine group in conditions of with drugs having a since the properties of which is pH or an antenna as drug delivery response checks that the he rattled through his the present invention. The present purpose of the invention the pH response the recording operation. under public affairs number a cyclodextrin derivatives. It is another object of the present invention said pH responsiveness cyclodextrin derivatives under public affairs number of manufacturing method of the recording operation.. Another object of the present invention said pH responsiveness cyclodextrin derivatives a CRT is provided with a substance pH response the recording operation. under public affairs number assembly for a cathode. Another object of the present invention said pH responsiveness of the recording operation. under public affairs number of manufacturing method. Another object of the present invention said pH responsiveness drug delivery composition including pH assembly for a cathode response number under public affairs the recording operation.. Another object of the present invention said pH including moieties adamantane the combination response a inclusion composite material enclosed therein the recording operation. under public affairs number. In order to solve said number and of, the present invention refers to one or more cyclodextrin or its derivatives in carbon and/or a polynucleotide that formula 1 glucose 6 maleic anhydride derivatives carboxylic acid ester or amide portion thereby being usefully a pH disolving silica thin film on substrate number. under public affairs a cyclodextrin derivatives. [Formula 1] Said in formula, R ' hydrogen orC1-6alkyl; The m is integer number of 1 to 10. A cyclodextrin derivatives a disolving silica thin film on substrate said pH with cyclodextrin or its derivatives derivatives of maleic anhydride are formed by a covalent linkage a short time, as cyclodextrin derivatives, for cyclodextrin of primary hydroxyl groups or cyclodextrin derivativesNH2, N3or amino acids, terminal functional groups such as maleic anhydride derivatives residues form maul two four a CRT is provided characterized in that composition. I.e., a cyclodextrin derivatives a disolving silica thin film on substrate of the present invention pH for cyclodextrin of primary hydroxyl groups or cyclodextrin derivativesNH2, N3or amino acids, such as maleic anhydride functional group end between moieties derivatives through covalent attachment of the female screw unit is strong, while simultaneously the size of the self molecules does not deleteriously contribute toxicity small, transmission is in which high intracellular the process has an advantage of having increased. A cyclodextrin derivatives a disolving silica thin film on substrate of the present invention pH said formula 1 one or more maleic anhydride derivatives general constitution: a physiological pH conditions and binds in drugs having a amine group, acidic pH condition and within the range pH 6. 5 hereinafter, specifically pH 5 to 6. 5 amine group in conditions of with drugs having a since the properties of which is pH. used as drug delivery response. In the present invention, maleic anhydride said formula 1 primary for cyclodextrin derivatives may be bonded, or various known art present in cyclodextrin derivatives, maleic anhydride said formula 1 unit has a lower altitude than an ester or amide derivatives and various functional groups may be coupled to. Unit has a lower altitude than an ester or amide such various functional groups includeNH2, N3surface of the radioactive part into contact, for example, amino acids or more, or, the number one are not. In addition, said cysteine at amino acid such as phenylalanine or surface of the radioactive part into contact, for example,, the number one are not. I.e., a cyclodextrin derivatives of the present invention pH disolving silica thin film on substrate a cyclodextrin or its derivatives to said formula 1 maleic anhydride derivatives is incorporated, the remote pH conditions in order to disperse and structure according to join with drugs having a amine group may be disconnected or a pH response of the characteristics of can exhibit. A preferred in one aspect, the present invention refers to α -, cyclodextrin or γ - or β carbon and/or a polynucleotide that 6 glucose for cyclodextrin of oxidatively cleaveNH2, N3or amino acids, which are substituted with one or more cyclodextrin derivatives carbon and/or a polynucleotide that formula 1 in glucose 6 maleic anhydride derivatives carboxylic acid ester or amide portion thereby being usefully a pH disolving silica thin film on substrate number. under public affairs a cyclodextrin derivatives. [Formula 1] Said in formula, R ' hydrogen orC1-6alkyl; The m is integer number of 1 to 10. Preferably, said R ' can be hydrogen or methyl. Preferably, said α -, cyclodextrin or γ - or β carbon and/or a polynucleotide that 6 glucose for cyclodextrin of oxidatively cleaveNH2, N3or amino acids, is triphenylphosphate which is marked as a cyclodextrin-peptide antagonists of a fullerene derivative is denoted by chemical formula 2 can be. [Formula 2] Said in formula, The ROH, NH2, N3or amino acids, is; The n is integer number of 1 to 3. Preferably, said glucose 6 carbon and/or a polynucleotide that maleic anhydride derivatives formula 1 esters or by an amide linkage; and a sound absorbing member is partly formula 3a to formula 3e is connected to cyclodextrin in the form may be proposed. [Formula 3a] [Formula 3b] [Formula 3c] [Formula 3d] [Formula 3e] Said in formula, R ' hydrogen orC1-6alkyl; The m is integer number of 1 to 10. A term used in the present invention "cyclodextrin" starch as raw material number by enzymatic reaction. oligosaccharide functional an annular bath. An cyclodextrin glucose unit set of two request group α -, β and types of present for cyclodextrin γ - 3. Said an 3 types of cyclodextrin a number of hydroxyl group, a specific the engine thereby for reducing fuel consumption but the carbon (carbon position 6 glucose generally) is bound to the with excellent reactivity selectively hydroxyl group, a 6 - 8 two. substituted functional groups. In addition, cyclodextrin an empty space therein, i.e. cavity (cavity) having provided with at structural features which are, according to the size of said cavity peripheral surface of the installing part and other molecules that can can be imbibition of water. Which are representative of a, β-CD the 1 7 a position 4-th and the of α-d - glucopyranoside unit is oligosaccharide an annular, less hydrophilic inner space more hydrophilic includes an outer surface.. In order to disperse and this structure, β-CD a host - guest through interaction molecular diversity can be functional group capable of forming a complex inclusion and. maul two four pH responsiveness β-CD derivatives of the present invention in the form of drug delivery in cells pH accommodating initial to petty response for persons to go up drug delivery system used as well as a method of pH, i.e. a slightly acidic of tissue cancers having a pH environment, inflammatory tissue or abscess (abscess) to target for multi-functional drug delivery system. used as. In addition, said pH in one aspect the present invention refers to a disolving silica thin film on substrate number. under public affairs for manufacturing method of cyclodextrin derivatives. Said formula 2 a disolving silica thin film on substrate of the present invention pH derivative is represented by the following a cyclodextrin derivatives, said formula 1 to cyclodextrin or its derivatives i.e. maleic anhydride derivatives can be under trillion the number. Said formula 1 with cyclodextrin or its derivatives the maleic anhydride derivatives esters or by an amide linkage can be combined.. In the present invention, a fullerene derivative is denoted by chemical said formula 2, i.e. cyclodextrin or its derivatives are commercially available or for obtaining a number of publicly known method directly into under trillion, use can be made of, the. A preferred in one aspect, the following steps of a manufacturing method including said pH disolving silica thin film on substrate number of. under public affairs a cyclodextrin derivatives. Α -, cyclodextrin or γ - or β carbon and/or a polynucleotide that 6 glucose for cyclodextrin of oxidatively cleaveNH2, N3or amino acid-peptide antagonists of formula 1 a and cyclodextrin derivatives maleic anhydride derivatives and reacting the (step 1): [Formula 1] Said in formula, R ' hydrogen orC1-6alkyl; The m is integer number of 1 to 10. Preferably, said α -, cyclodextrin or γ - or β carbon and/or a polynucleotide that 6 glucose for cyclodextrin of oxidatively cleaveNH2, N3or amino acids, is triphenylphosphate which is marked as a cyclodextrin-peptide antagonists of a fullerene derivative is denoted by chemical formula 2 can be. [Formula 2] Said in formula, The ROH, NH2, N3or amino acids, is; The n is integer number of 1 to 3. In the present invention, said step 1) the reactions of (diisopropylcarbodiimide, DIC) [...] can be performed using. I.e., in the present invention DIC using carbodiimide-coupling method in said step 1) charging of a single through a reaction pH disolving silica thin film on substrate under trillion a cyclodextrin derivatives can be a number. The oxalate or thionil chloride prior to using the chloride derivative is represented by the following formula 1 coupling reaction but is known, this derivative is represented by the following formula 2, i.e. with cyclodextrin or its derivatives derivative is represented by the following formula 1 significant during coupling are formed in the inside of a KIPO & side reactions. In the present invention, preferably using carbodiimide-coupling method DIC using pH disolving silica thin film on substrate in high yields and under trillion a cyclodextrin derivatives can be a number. In the present invention, said step 1) as a catalyst reaction of 4 - dimethylamino pyridine (4-dimethylaminopyridine, DMAP) and p - toluene sulfonic acid (P-toluenesulphonic acid, PTSA) can be carried out in the presence of. Preferably, filled with a catalyst together as PTSA and said DMAP can be used. PTSA and a DMAP when added as catalyst both, polarity, in a solvent including by-products - acylureas In the present invention, said step 1) reaction of dimethyl formamide (DMF) solvent, pyridine and methylene chloride (MC) 1 selected from the group consisting of at least one inert gas. In the present invention, said step 1) preferably the reaction temperature of 50 °C to 10, more preferably 15 to 30 °C, most preferably can be 25 °C. If said reaction temperature is 10 °C of residual with the presence of otherwise american reaction water, however, have the disadvantage that is lowered and, 50 °C exists side reactions high than obtained with the lower rate of reserve message to an external subscriber KIPO &. In the present invention, said step 1) reaction time of 24 to 6 are preferably designed as time, more preferably 8 to 14 time, most preferably 12 can be time. If if is smaller than that of the 6 the american reaction water of residual with the presence of poor, and decorative use and the like and, longer than time 24 obtained exists so that the side reactions surface with the lower rate of reserve message to an external subscriber KIPO &. In addition, as a preferred embodiment of the present invention refers to the other including said pH disolving silica thin film on substrate for the following steps of. under public affairs number of manufacturing method a cyclodextrin derivatives. A in - 2 - prop a fullerene derivative is denoted by chemical formula 1 - 1 - ol as a proton source for reduction of a fullerene derivative is denoted by chemical formula 1a step bath number (step a); Said formula 1a and a compound expressed formula 2 a derivative is represented by the following (step 1 - 1) step of reacting: [Formula 1] [Formula 1a] [Formula 2] Said in formula, R ' hydrogen orC1-6alkyl; The m being integers, of 1 to 10; OH the R, orN3is; The n is integer number of 1 to 3. In the present invention, said step a) the EDC (1-ethyl methacrylate-3 - (3-dimethylaminopropyl) carbodiimide) and DMAP (4-dimethylaminopyridine) can be carried out in the presence of. In the present invention, said step a) of reaction solvent for ease of application (THF) which combination of the conductor, the number one are not. In the present invention, said step 1 - 1) the CuI and DIPEA (N, n-diisopropylethylamine) can be carried out in the presence of. In the present invention, said step 1 - 1) reaction of dimethyl formamide solvent (DMF) which combination of the conductor, the number one are not. In addition, the present invention refers to said pH disolving silica thin film on substrate drug including a cyclodextrin derivatives amine group to a CRT is provided. under public affairs number assembly for a cathode. In the present invention, said pH disolving silica thin film on substrate a cyclodextrin derivatives and amine group pH disolving silica thin film on substrate the coupling between the drug including a cyclodextrin derivatives of the maleic anhydride with an amine under alkaline conditions by coupled via ring opening reaction can be formed. In the present invention, said amine group including drug are preferably designed as including a primary amine group (primary amine group) can be drug. Specifically, said amine group including the drug is an cyclobutyl amine (butylamine) for polymerization alkyl such as drug; (cephradine) [...], cefadroxil (cefadroxyl), tax it sells with the glycine (cephaloglycin), (cephapirin) texaphyrin garage, [...] (Cefroxadine), garage (Cefaclor) [...], cefuroxime (Cefuroxime), three Peugeot south (Cefuzonam), cells (Cefotetan) the reel it burnt, [...] (Cefoxitin), cover cephem (Carbacephem), cells (Cefotiam) mote cancer, [...] (Cefcapene), (Cefdaloxime) [...], cefdinir (Cefdinir), cefditoren pivoxyl (Cefditoren), (Cefetamet) [...], three Fick cores (Cefixime), [...] (Cefmenoxime), (Cefodizime) d burden cells, genetically (Cefotaxime), cells (Cefovecin) [...], cefpodoxime (Cefpodoxime), (Cefteram) [...], [...] (Ceftibuten), ceftiofur (Ceftiofur), (Ceftiolene) [...], three Petit family cores (Ceftizoxime), 2 - chloro (Ceftriaxone), (Cefclidine) [...], three lungs blooming, (Cefepime), (Cefluprenam) [...] flue cell, cells (Cefoselis) [...], [...] cells (Cefozopran), (Cefpirome) [...], [...] (Cefquinome), such as (Ceftobiprole) and [...][...] cephalosporin in (Cefmatilen) (cephalosporin) based drug; doxorubicin, or a mixture of these can be, the number one are not. In the present invention, said pH disolving silica thin film on substrate including a cyclodextrin derivatives and amine group 1:1 to Wednesday 8 KIPO & the molar ratio of drug. In the present invention, said assembly said pH disolving silica thin film on substrate under acidic conditions and a cyclodextrin derivatives including drug of binding between amine group and is characterised in that it has a is dissolved with its. The acidic conditions as said said pH 6. 5 hereinafter, specifically pH 5 to 6. 5 can be conditions of. Figure 1 shows a pH of of the present invention also the approximate of degradation and drug response exhibits and general outline. Also, as shown to 1, general assembly of the present invention a physiological pH 7 pH condition and within the range. 4 in but linked thereto at drug stably, pH is, pharmaceuticals quality, by selecting a particle diameter is of the row. Thus, under acidic conditions and assembly of the present invention delivers the drug targeting specific drug delivery used as.. Specifically, Figure 2 shows a of the present invention even if an [...] also represented by chemical pH of the approximate of degradation and drug response exhibits and general outline. Also through 2, a slightly acidic of inflammatory tissue are targeted against antibiotic cephalosporin as medicines maul two four[...] in number such as (medusa) pH responsiveness β-CD derivatives which can be incorporated in the, of a slightly acidic pH value [...] decomposes and the desired target region of the inflammatory tissue [...] a drug specifically emission can be can be viewed. In the present invention, said assembly said pH such as drug delivery due fast response in cells pH accommodating initial to petty response for persons to go up drug delivery system used as well as a method of pH, i.e. pH environment cancers having a of a slightly acidic, inflammatory tissue or abscess (abscess) to target for multi-functional drug delivery system. used as. In the present invention using smart response pH as part for material, specific pH maleic acid derivatives has degradation thereof, yet rapidly in range. Extreme insensitivity pH conditions degrades only alternatively amide may be a, maleic acid derivatives physiologically acceptable pH can be decomposed in range. The decomposition rate range and pH response cis - alkyl substituents on double bonds by changing can be minutely adjusted after. In addition, a weak derivatives maleic acid amides such precursors, as well as corresponding amine under alkaline conditions a maleic anhydride derivative between single step ring opening reaction (ring opening reaction) can be by. Maleic acid under mild conditions; and hereinafter for aminoamide derivatives in the synthesized provider backbone delivery of a substance bond or (backbone) of segments between the crosslinked sites, in combination significantly in a synthesis connected response pH is the advantage candicates who cross - - file (linkage). One in the embodiment 2 of the present invention in two different alkyl substituted maleic anhydride can form 1 - methyl - 2 - (2' - carbocyethly) maleic anhydride (MCM) or carboxylate dimethyl maleic anhydride (CDM) drug delivery based on pH, and can be used for high a disolving silica thin film on substrate have been synthesised a cyclodextrin derivatives. MCM acid obtained on the basis of a physiological general derivatives pH 7. 4 or stable at pH 5. 5 rapidly in decomposition connected to the switching circuit, ionic and/or acidic environment is weak, thus the user derivatives MCM drugs and to target for combining best candidates for. the acknowledgement message is one of. In one in the embodiment of the present invention drug based - amine number and/or cross-linking with the Image makes the first MCM having %% and 1.6%% a drug delivery system. As said, one of the present invention 7 as backbone of drugs in the embodiment two glucose molecules as a oligosaccharide an annular β - cyclodextrin (β-CD) he became a. Β-CD has a high degree of biocompatibility that has. In addition, hydroxyl group and primary 7 of secondary [...] 14 causes the β-CD backbone for functional groups plurality of into the objective compound. introduced hereinafter. Types of structures may maul two four 7 primary hydroxyl can be synthesized by reacting.. Β-CD of functional groups that are functionalized a combined uniform chemical properties of being achievable to permit a. In addition, the present invention refers to the following steps of. under public affairs including a number of manufacturing method. Said pH disolving silica thin film on substrate and an amine group cyclodextrin derivatives including a step of reacting an drug (step 2). In the present invention, said step 2) pH disolving silica thin film on substrate in a cyclodextrin derivatives including amine group and Wednesday 8 KIPO & to 1:1 molar ratio reaction of drug. In the present invention, said step 2) the reactions of triethylamine as organic base, dee small pro the ethyl amine which will bloom and d ethyl amine 1 selected from the group consisting of at least one can be performed using a. In addition, the present invention refers to said pH disolving silica thin film on substrate drug including a cyclodextrin derivatives amine group to a CRT is provided assembly for a cathode. under public affairs drug delivery composition including pH response number. In the present invention, said pH responsiveness drug delivery composition delivers the drug under acidic conditions and is characterised in that it has a. Specifically, said pH pH 6 composition drug delivery response. 5 hereinafter, specifically pH 5 to 6. 5 of conditions is capable of emitting drug. In addition, the present invention refers to said pH disolving silica thin film on substrate amine group to a cyclodextrin derivatives including the combination a CRT is provided drug, guest material as host or ligand additional drug - guest [...] implied by the number. under public affairs a inclusion complex. In the present invention, guest material, which is used as additional drug or ligand a hydrophobic molecules, through interaction between the long--covalently to internal dextrin as clathrate in is a material able to be user conformed, not one number the kind thereof. In the present invention, said guest material targeting ligand (targeting ligand), cell permeable portion (cell penetrating moiety), bulk material into nano sized particles in polymer and selected from the group consisting of at least one inert gas can be 1, the number one are not. Preferably, adamantane (adamantane) including moieties can be material. In the present invention, the combination said said inclusion complex number drug, which is bound in addition to functional can be under public affairs[...]under public affairs number is implied by the layer is a material that further functional can be can be having multifunctional the is characterised in that it has a. In the present invention, said material including said adamantane moieties as hydrophobic small molecule is the form the bay it burnt, this cyclodextrin toroidal (toroid) strongly with the interior of under mild since the presenter itself can serve, host guest [...] of said by - inner space of cyclodextrin moiety can be enclosed by a metal tube and. In other words,, β-CD toroidal (toroid) unshared internal in the form of through interaction adamantane (adamantane) strongly small molecule and hydrophobic such as since the can interact, host - guest [...] targeted by the ligand or cell permeable portion (cell penetrating moiety) and additional functional (functionality) for the introduction can be used. Adamantane with parts of polymer or nanoparticles a host - guest, through interaction between the long-β-CD derivatives can be modified hereinafter for.. 4 cyclohexane by a ring consisting of two assembled basic parts an alkane the the bay it burnt the β-CD is of most representative guest molecules. Thus, bound moieties adamantane portion function in the present invention the β-CD-mCM and simply by mixing a β-CD-mCM peptide cell permeabilization ligand or target into the functions can be introduced into the dispenser portion. I.e., pH maul two four of the present invention in the form of response β-CD derivatives simplify a alkaline conditions with mild to deflocculate the pH response molecules the drug via a linker MCM which can bind other adamantane a polymer having a functional group into the cavity portion β-CD of. and adapted to be introduced into a non-covalent. In addition, polymer or such as nanoparticles pH surface of other drug maul two four response in the form of β-CD derivatives. can be modified by non-covalent. The resulting delivery a weak acidic conditions, are integrated in an drug can be release of the encapsulated and rapidly. In one in the embodiment of the present invention labeled FITC - adamantane derivative by combining together to FCS triones by tracking the such as a of the present invention β-CD-mCM is triones is capable of forming a (also 7) identifying improving. Also through 7, β-CD-mCM-commercial paper and fITC-hex-aDM 1 is binding constants between. 49×104 M-1been calculated by. Generally, β-CD and a adamantane by which high binding constants K is1×104 M-1to10×104 M-1of the first and the second, said result through the β-CD-mCM-commercial paper interaction between adamantane derivative and a a typical application is to β-CD and a similar interaction guest - adamantane host that it can be viewed. In one in the embodiment of the present invention β-CD-mCM-commercial paper - host between adamantane derivative and a guest the gun it folded it is found out that through further ROESY spectrum (also 8). Β-CD-mCM-commercial paperfITC-hex-aDM/a strong cross the picks β-CD/was fITC-hex-aDM and a similar. Primary [...] confronted a 6 the combination of form of MCM maul two four molecules significantly due to inclusion said were unaffected by the. Based on these results, any functional portion triones to after mixing the drug form of an β-CD-mCM can be introduced into it was found in can be. With cyclodextrin or its derivatives the present invention refers to maleic anhydride derivatives are formed by a covalent linkage of a short time, as cyclodextrin derivatives, for cyclodextrin of primary hydroxyl groups or cyclodextrin derivativesNH2, N3or amino acids, such as maleic anhydride derivatives residues terminal functional groups a CRT is provided number under public affairs pH response can be a cyclodextrin derivatives, a cyclodextrin derivatives response said pH MCM general residues in a physiological pH conditions and binds drugs having a amine group, acidic pH condition and within the range pH 6. 5 hereinafter, specifically pH 5 to 6. 5 amine group in conditions of with drugs having a since the properties of which is pH response, use can be made of, as drug delivery. Figure 1 shows a pH of of the present invention also the approximate of degradation and drug response exhibits and general outline. Figure 2 shows a of the present invention even if an [...] also represented by chemical pH of the approximate of degradation and drug response exhibits and general outline. Figure 3 β-CD-mCM of1H NMRspectrum mALDI-tOF (a) and (b) exhibits and analysis result. Figure 41H NMRacidic pH as measured by means of a β-CD-mCM-bRITISH ASSOCIATION BA from release of exhibits and result confirming the receivable channel. PH 5 as measured by means of a Figure 5 HPLC. 5 (intention of a) and pH 7. 4 ([...]) in β-CD-mCM-commercial paper and have an emission response of CP from pH is of graph. Figure 6 β-CD-mCM-commercial paper emitted from the CP for identifying1H NMRspectrum (a) and emitted ESI mass spectra (b) CP of blades, presenting a. Figure 7 β-CD-mCM-commercial paper and a fITC-hex-aDM to make sure that complex formation between FCS time average spread as measured by means of a is of graph indicates a change in the flow rate. Figure 8 β-CD and a fITC-hex-aDM (a), and β-CD-mCM-commercial paper and a fITC-hex-aDM (b) exhibits NMR 2D ROESY spectrum of between. Figure 9 β-CD([...]), β-CD-mCM ([...]), β-CD-mCM-commercial paper (intention of a), CP (Δ), and PEI (■) of inducing cytotoxicity against cells NIH3T 3 exhibits examination results of. Hereinafter, in the embodiment the present invention through the. as further described further. The only these in the embodiment more specifically, the present invention for, in the embodiment of the present invention range number by one are not. In the embodiment 1: β - cyclodextrin and 1 - methyl - 2 - (2' - carbocyethly) of maleic anhydride (β-CD-mCM) synthesis of conjugates Material The Image number (cephradine, CP) [...] about (Han Hwa Pharm. Co. , Ltd. , South Korea) was obtained from. Β - cyclodextrin (β-CD), 6 - amino hexanoic acid, di - Step 1:1 -methyl- 2 - (2' -carbocyethly)maleic anhydride (MCM, compound 2) synthesis of According to known as a raw material of the 1 - methyl - 2 - (2' - carbocyethly) maleic anhydride (MCM, compound 2) for have been synthesised. Synthesis of compound 1 Reported prior to a 1 of compounds have been synthesised according to method (Naganawa A et al. , Tetrahedron, 1994, 50, 8969 - 8982). For compactness,, easy to stepwise procedure of compounds have been synthesised according to a 1. First, NaH (0. 37 g, 9. 2 mmol) a THF anhydride (30 ml) in tri-ethyl - 2 - phosphonomethyl propionate (1. 64 g, 6. 89 mmol) in a solution added gradually increases 0 °C to waiting nitrogen. After the cease emission of hydrogen gas, dimethyl - 2 - oxo glutarates (1. 00 g, 5. 74 mmol) added to said solution a. Said reaction mixture while maintaining which 0 °C further stirring section. Completion of reaction after portion is confirmed with TLC, saturatedNH4Cladaptation blended aqueous solution. Rotating THF number by evaporation after triggers, mixture of solids and generated times to EA extracted. And compatible for organic phase, deionized water (DIW) washed with saline and, MgSO4on dried, the concentrated diffraction evaporator. Residue by silica gel chromatography eluting in hexane EA/forward to oil a compound as colorless by number 1 is obtained (yield 91%).1H NMR(300 MHz, CDCl3): δ 1. 25 - 1. 30(3H, t, C Synthesis of compound 2 Reported prior to a 2 of compounds have been synthesised according to method (Naganawa A et al. , Tetrahedron, 1994, 50, 8969 - 8982). For compactness,, easy to stepwise procedure of compounds have been synthesised according to a 2. First, 1 compound solution 2 M KOH in ethanol 1 of the reflux time. Deionized water is added, the hot reaction mixture cooled down to the normal temperature. After triggers number out of the ethanol, a water phase HCl and concentrating the cleaning times in DCM using has been acidic to pH 2. Then, a water phase extracted times to EA. An organic phase, MgSO4concentrating and decompresses dried on the white solid as 1 - methyl - 2 - (2' - carbocyethly) maleic anhydride (MCM) (2) is obtained (yield: 74%).1H NMR(300 MHz, CDCl3): δ 2. 12(3H, s, CC Step 2: and cyclodextrin β -1 -methyl- 2 - (2' -carbocyethly) conjugates of maleic anhydride (CD - β -MCM) synthesis of (compound 3) According to known as a raw material of the cyclodextrin and β - 1 - methyl - 2 - (2' - carbocyethly) conjugates of maleic anhydride (β-CD-mCM) have been synthesised a (compound 3). DMF (10 ml) compounds in 2 (0. 20 g, 1. 09 mmol), β - cyclodextrin (0. 10 g, 0. 092 mmol), DMAP (0. 046 g, 0. 37 mmol) PTSA and (0. 070 g, 0. 37 mmol) in a solution DIC (0. 33 g, 2. 6 mmol) added a. Reaction mixture during night adaptation stirring room temperature. Number product crude liquid phosphate buffer (pH 9. 0), HCl solution (pH 3. 0), and DIW in reproducing each cellulose film (MWCO 1,000, SPECTRUM)ยฎ a dialysis not so that it helps to select the number. Freeze-dried then performed. Off - β-CD-mCM as powder array includes a printed circuit board (compound 3) is obtained (yield: 85%).1H NMR (300 MHz, D2O1 in. 1 wt % NaOD): δ 1. 65(3H, s, CC In the embodiment 2: β-CD-mCM and drug synthesis of complex According to known as a raw material of the as, β-CD-mCM and drug as a composite body of β-CD-mCM-bRITISH ASSOCIATION (compound 4) and β-CD-mCM-commercial paper have been synthesised a (compound 5). Synthesis of compound 4 ACN (5 ml) compounds in 3 (0. 050 g, 0. 024 mmol) in a solution harmless and environmentally favorable and has excellent TEA excess of transparent and fully added in solution to stirring until adaptation. Cyclobutyl amine (BA)- Synthesis of compound 5 N - cyclobutyl amine instead [...] in ACN (CP) solution (6 equivalent) over a long period of time, number of said compound 4 a and under the outside method bath number the same method using β-CD-mCM-commercial paper have been synthesised a (compound 5). After forward number, obtained a 5 a compound as yellow solid (yield:>90%).1H NMR (300 MHz, D2O1 in. 1 wt % NaOD): δ 1. 83( 3H, s, C Memorable number 1: synthesis of fITC-hex-aDM According to known as a raw material of the fITC-hex-aDM for have been synthesised (compound 9). Synthesis of compound 6 6 - amino hexanoic acid (1. 00 g, 7. 26 mmol) of THF: saturationNaHCO3aqueous solution (1:1) dissolving the during co-solvent, during THF Synthesis of compound 7 According to reported prior to method, compound 7 a was under trillion number (Humblet V et al. , J Med Chem, 2009, 52, 544 - 550). For compactness,, easy to stepwise procedure of compounds have been synthesised according to a 7. Drying THF (9 ml) compounds in 6 (0. 10 g, 0. 43 mmol) and the bay the amine which burns hydrochloride 1 - adamantyl group in the ortho position (0. 080 g, 0. 43 mmol) dee small pro the ethyl amine which will bloom solution of (0. 12 ml, 0. 86 mmol) HBTU and (0. 16 g, 0. 43 mmol) was filtered. After time 16 at room temperature, reaction mixture was heated to 60 °C 90 minutes. Then, added saline and DCM, organic phase 1 M HCl aqueous solution (10 ml) in which washes the times 2, 5% NaHCO3aqueous solution (10 ml) in 2 and, after washing the times, saline (10 ml) to 2 times then washing the, Na2SO4the dried on. Residue silica gel chromatography by eluting in hexane EA/forward to number 7 a compound as the white solid is obtained (yield: 54%).1H NMR(300 MHz, CDCl3): δ 1. 27 - 1. 35(2H, m, CH2C Synthesis of compound 8 Excess of TFA (10 ml) a DCM (30 ml) compounds in 7 (0. 75 g, 2. 1 mmol) in 0 °C to added. Said solution which agitates the time 2, and then, saturationNaHCO3then washed with saline and, MgSO4the dried on. Compound 8 for the treatment of the solid type as solid white without number the faceplate of the fluidic is obtained (yield: 89%).1H NMR (300 MHz, D2O1 in. 2 wt % DCl): δ 1. 16 - 1. 26(2H, m, CH2C Synthesis of compound 9 FITC isomer 1 (0. 04 mg, 0. 113 mmol) of MeOH (5 ml) compounds in 8 (0. 030 g, 0. 11 mmol) adding in a solution, saturationNaHCO3( 1 mL)a added. After during night, 0 reaction mixture. Including 50 to 100% of a 1% TFA ACN/DIW to 6 ml/min linear gradient to 30 factor over anti-phase high performance liquid chromatography of at a flow velocity that is at (rP-HPLC) the through of the first mesfet has a positive number. 9 compound obtained as a orange solid (yield: 32%).1H NMR(300 MHz, MeOD): δ 1. 40 - 1. 45(2H, m, CH2C Experiment 1 e.g.: measurement of drug release response pH - Β-CD-mCM-bRITISH ASSOCIATION BA from release of Β-CD-mCM-bRITISH ASSOCIATION (4) from pH - of release response BA1H NMRit is found out that to. Β-cDMCM-bRITISH ASSOCIATION a at a concentration of 3 mg/mL 1. The dissolved in 2 wt % DCl. In time, followed by incubation with stirring, in a 8 37 °C,1H NMRa Bruker Avance dPX-300 (Germany) factor have been measured by (also 4). Acidic solution( D2O1 in. 2 wt % DCl) in, β-cDMCM-bRITISH ASSOCIATION next nitrogen in the amide non-damaged of hethylene proton (denoted x) the 3. 18 - 3. Precursor and CaO precursor peaks at 23 ppm, a peak corresponding to peak of hethylene BA glass (denoted *) the 2. 55 - 2. 62 ppm was moved to (also 5). Through chemical shift said decomposition of acid amides combined with MCM BA. release of. Β-CD-mCM-commercial paper release of CP from Β-CD-mCM-commercial paper (5) for pH 7. 4 liquid phosphate buffer (100 mm) or pH 5. 5 acetic acid buffer (100 mm) at a concentration of 3 mg/mL during dissolving the, each visitor is checked through a incubation while stirring 37 °C solution. UV detector crude taxol column (Agilent Eclipse xDB-C18 4. 6 × 150 mm, 5 μm) YOUNGLIN HPLC fitted with such (9000 HPLC, South Korea) HPLC - a, the third to eo for the measuring of based. Various viewpoints to, each for collecting samples of same back 10 in the dilution buffer. 0. 2 μm PVDF syringe filter then through an, HPLC samples he implanted into the system. Methanol: pH 9. 0 liquid phosphate buffer (50 mm) mixture of (3:7 v/v) corresponding advertisement based on the shown list used as eluent for, 0 flow rate. Was setting, 5 ml/min. Release of CP with extinction it was determined that at a wavelength UV 270 nm and 245 (also 5). Said such as a pH 5. 5 and pH 7. 4 in β-CD-mCM-commercial paper from a cumulative release of CP as measured by the HPLC further specifically it was determined that pharmacokinetic decomposition. Result to the computer of the also showed to 5. Through 5 also, pH 7. 4 in, even sprayed thereafter as by spraying water thereon time 5, of less than 20% CP is β-CD-mCM-commercial paper from being released to the from can be viewed. On the other hand, pH 5. 5 CP in of the initial burst and thewater in a manner that renders the is observed (burst), 80% or more CP is 0. 5 been emission in time. Said emissions within a time 1 been completed almost until approximately 95%. Pharmacokinetic emission difference of pH 5. 5 and pH 7. 4 revealed that between. In addition, in the experiments purpose CP during process emission and stability of has been confirmed. PH 5. 5 β-CD-mCM-commercial paper emitted from of CP1H NMRof the original spectrum of CP1H NMRwas same spectra and (also 6a). In addition, electrospray ionization (ESI) mass spectra of two obtained by CP was the same (350. 1 [M+H]+and 699. 1 [M+M]+,also 6b). Based on these data, CP is during and for engaging a mild basic conditions in an during emission in the condition a slightly acidic stable surface finish, which results in an can be viewed. Experiment e.g. 2: fluorescence correlation spectrometry (FCS) are separated compound 5 and 9 identification of complex formation Fluorescent confocal microscope setup user and exactly aligned, and an ideal number fluorescent probe, self FITC, the third to eo for measuring the correlation. 488-nm continuous blue laser diode (tECBL-20GC-488, World Star Tech) the beam clean - up single - mode optical fiber (Φ=3. 5 μm, P1-488-pM-fC, Thorlabs) to bind the, self secured within the body microscope small number immersion pick-up device (water-immersion objective) (NA=1. 20, 60x, f=3 mm, Olympus) sensors light through sample. The fluorescence signal dichroic mirror (dichroic mirror) (ZT488rdc, Chroma) measured charging current the polymeric multilayer reflector reflects excitation by radiation filter (HQ525/50 m, Chroma) (cleanning) the further cleaning. 1:2 multi-mode fiber-optic coupler (( Φ=62. 5 μm, FCMM625 - 50A - FC) an LCD used as a pinhole from the number an organic and triggers, two avalanche photo diode (avalanche photodiode) 2 (sPCM-aQR-14-fC, Perkin Elmer) was collecting the fluorescence signal to. Correlation (correlation) a persons card (correlator card) (FLEX02-01D, Correlator. Com) and as measured by LabVIEW 2009 coded self human power by operating all systems by further analysis programs small number. Fluorescence correlation spectrometry as phosphor, call setup (FCS), spreading factor, the D=4. 35 x 10-6 cm2/sin, volume of confocal using Alexa 488 side shaft and was is calibrated for measuring the area (Petrasek Z et al. , Biophys J, 2008, 94, 1437 - 1448). Reported prior to correcting said poured out and the contents stored in the database (Kim SA et al. , Nat Methods, 2007, 4, 963 - 973). Of the sides of correcting1/e27 area. 18 has an aspect ratio of a composite of randomly choosing 232 nm, the measured focus volume 0. . Are indicative of 501 fl. Complex formation for the measuring of, pH 9. 0 liquid phosphate buffer (50 mm) compounds in 9 (10 nm) solution of compound mixtures of varying concentrations was under trillion number to 5. Compound 5 9 between vapor and preventing the coupling non specific manner, small serum albumin to 0. Final concentration 1 mg/mL added to said mixture. Background and thermal noise (thermal noise) for each number and for circuit controlling isolation gates of signal each correlation curve 6 times 10 minutes (each concentration of compound 5 to times 1) it was determined that. Result to the computer of the also showed to 7. As said, β-CD - based drug complex forming complexes of between adamantane derivative and to make sure that, a phosphor attached to host guest or change of the spreading factor of fluorescence correlation spectrometry analyzing by cylinder to have (FCS). The FITC been coupled to adamantane derivative as probes (fITC-hex-aDM). Phosphor average spread of time the host molecules a β-CD-mCM-commercial paper of a change in the concentration of it was determined that while. Β-CD-mCM-commercial paper increases concentration of, average spread also reduced. I.e., phosphor of spreading factors is formed in the triones a significantly reduced. Through, an increase in molecular weight and. complex formation (also 7). Binding constants a diffusion time and β-CD-mCM S between concentration of the bill from curve type (also 7). Also through 7, β-CD-mCM-commercial paper and fITC-hex-aDM 1 is binding constants between. 49×104 M-1been calculated by. Generally, β-CD and a adamantane by which high binding constants K is1×104 M-1to10×104 M-1of the first and the second, said result through the β-CD-mCM-commercial paper interaction between adamantane derivative and a a typical application is to β-CD and a similar interaction guest - adamantane host that it can be viewed (Harries D et al. , J Am Chem Soc, 2005, 127, 2184 - 2190). Based on said binding constants, inclusion percent b are computed in the calculation unit also same has been showed to 7. Experiment 3 e.g.: low right writing over coordinate rotation through spectroscopy effect identification of forming conjugates Rotation coordinate over low right writing effect spectroscopy (Rotating frame Overhauser Effect Spectroscopy, ROESY) through β-CD vapor and 9 composites, and β-CD-mCM-commercial paper (compound 5) vapor and 9 complex formation has been confirmed. First, β-CD vapor and 9 composites, and β-CD-mCM-commercial paper (compound 5) a combination of vapor and 9D2O-based pH 9. 0 liquid phosphate buffer (50 mm) at a molar ratio from 1:4, at a concentration of 3 mm during by mixing 1:1 was under trillion number. Agilent Technologies 400-MR DD2 NMR spectrum (USA) in 25 °C spectral into he got down the main. Rotation coordinate over low right writing effect spectroscopy (ROESY) included in library spectrometer experiment a standard protocol which (mixing time: 300 ms; T1 experiment) using performed for all the. Also 8a and 8b each β-CD/fITC-hex-aDM and β-CD-mCM-commercial paper/fITC-hex-aDM mixture exhibits ROESY spectrum. In adamantane by which high fITC-hex-aDM α, β and γ proton of the original β-CD cavity (cavity) in H3, H5, and H6 cross the stronger by its interaction with the proton peak (cross-peak) precursor and CaO precursor a, β-CD cavity interact with proton H4 and H2 on the outside of the cross peak revealed a weak (also 8a). Similarly, adamantane derivatives and β-CD-mCM-commercial paper of proton intersection between peak revealed that in addition (also 8b). Spectrum β - CD derivatives and adamantane portion of proton in proximity space maximum limits on of 5 Å showed (spatial proximity). Two data both β-CD-mCM-commercial paper and a fITC-hex-aDM exhibits complex formation between. Β-CD-mCM-commercial paper - host between adamantane derivative and a guest the gun it folded it is found out that through further ROESY spectrum (also 8). Β-CD-mCM-commercial paperfITC-hex-aDM/a strong cross the picks β-CD/was fITC-hex-aDM and a similar. Primary [...] confronted a 6 the combination of form of MCM maul two four molecules significantly due to inclusion said were unaffected by the. Based on these results, any functional portion triones to after mixing the drug form of an β-CD-mCM can be introduced into negative can be viewed. The, adamantane with parts of polymer or such as nanoparticles of pharmaceuticals or other delivery other drug having a functional group by a contact lens with responsiveness of the present invention pH - host of guest through interaction for. can be modified hereinafter. Experiment 4 e.g.: cytotoxicity assay Cell survival force 3 - (4, 5 - dimethyl aminothiazole - 2 - one) - 2, 5 - the D phenyl tetra the bud which will doze bromide (MTT; sigma-aldrich (USA)) factor have been measured by assays. nIH-3T 3 cells (mouse embryonic fibroblast cell line) 96 - a 10% FBS-well plate ([...]oh serum; WelGene (USA)) 90 micro l of containing DMEM (Dulbecco's modified eagle's medium; WelGene (USA)) during 5. 0 × 103cells/well glucose, 37 °C time visitor is checked through a incubation in 24. To measure cytotoxicity, at various concentrations, each having 10 said micro l sample solution, are added to the medium then incubation in visitor is checked through a 48 37 °C time. For analysis, cells DPBS (Dulbecco's saline phosphate-buffered; WelGene (USA)) then being washed with and, 20 micro l then filtered of MTT solution (2 mg/mL in DPBS) has added. 2, followed by incubation in 37 °C time, and triggers number from well medium, of 150 micro l gun E cup insoluble by adding DMSO was dissolving particles. The microplate reader (Molecular Devices Co. , Menlo Park, CA) it was determined that absorbance in 570 nm using. Relative control of cell survival power (%) (DPBS treated cells solution) the same percentage contrast was defined as percentage of cell survival. As said, β-CD-mCM the biocompatible a short-term drug delivery MTT assays on cultured NIH3T 3 is confirmed. Result to the computer of the also showed to 9. Publicly known higher cytotoxicity having at least one polymeric drug delivery chain branched polyethyleneimine (PEI - In the embodiment 3 :-amide derivatives and cyclodextrin β - 1 - methyl - 2 - (2' - carbocyethly) conjugates of maleic anhydride (β-CD-nH-mCM) synthesis of Reported prior to using the method according to known as a raw material of the of compounds have been synthesised for 10 (NATURE PROTOCOLS, 2008, 3 (4), 691 - 697). In the embodiment 4: and triazole derivatives cyclodextrin β - 1 - methyl - 2 - (2' - carbocyethly) conjugates of maleic anhydride (β-CD-triazole-mCM) synthesis of Reported prior to using the method according to known as a raw material of the of compounds have been synthesised for 11 (Eur. J. Org. Chem. , 2012, 4087 - 4105). In the embodiment 5: β - cyclodextrin phenylalanine derivatives and 1 - methyl - 2 - (2' - carbocyethly) conjugates of maleic anhydride (β-CD-phenylalaine-mCM) synthesis of Reported prior to using the method according to known as a raw material of the of compounds have been synthesised a 12 (J. Org. Chem. , 1996, 61, 903 - 908). In the embodiment 6: and cysteine derivatives cyclodextrin β - 1 - methyl - 2 - (2' - carbocyethly) conjugates of maleic anhydride (β-CD-cysteine-mCM) synthesis of Reported prior to using the method according to known as a raw material of the of compounds have been synthesised for 13 (J. Org. Chem. , 1996, 61, 903 - 908). The present invention relates to a pH-responsive cyclodextrin derivative, a preparation method thereof, and a pH-responsive conjugate of the pH-responsive cyclodextrin derivative and a drug, and more specifically, to a cyclodextrin derivative having a novel structure, a preparation method thereof, and a pH-responsive conjugate of the pH-responsive cyclodextrin derivative and a drug. The cyclodextrin derivative has a novel structure formed by a covalent bond between a maleic anhydride derivative and a cyclodextrin or a cyclodextrin derivative, in which a residue of the maleic anhydride derivative bonds to a primary hydroxyl group of cyclodextrin or a terminal functional group, such as NH_2, N_3, or amino acid, of a cyclodextrin derivative to produce a pH-responsive cyclodextrin derivative. COPYRIGHT KIPO 2016 Α -, β or for cyclodextrin γ - 1 hydroxyl group carbon and/or a polynucleotide that glucose one or more 6; or for cyclodextrin 6 glucose one or more of carbon and/or a polynucleotide that oxidatively cleaveNH2, N3to cyclodextrin derivatives which are substituted with or amino acids, of one or more existing glucose 6 carbon and/or a polynucleotide that of functional groups, maleic anhydride derivatives formula 1 a carboxylic acid moieties with an ester or a is connected by an amide linkage pH disolving silica thin film on substrate as a cyclodextrin derivatives, a hydroxyl group-functional said, NH2, N3or amino acids, derivatives is at least one either: [formula 1]In formula said, R ' hydrogen orC1-6alkyl; the m is integer number of 1 to 10. According to Claim 1, said α -, β or γ - cyclodextrin; or said carbon and/or a polynucleotide that glucose one or more 6 for cyclodextrin of oxidatively cleaveNH2, N3or amino acids, which are substituted with a cyclodextrin derivatives, represented by the general formula 2 a characterized in that the a cyclodextrin derivatives pH disolving silica thin film on substrate: [formula 2]Said in formula, the ROH, NH2, N3or amino acids, is; the n is integer number of 1 to 3. According to Claim 1, or phenyl cysteine amino acids, by said [...] pH disolving silica thin film on substrate characterized in that a cyclodextrin derivatives. According to Claim 1, said formula 1 maleic anhydride derivatives to esters or by an amide linkage formula 3e to formula 3a cyclodextrin in the form having either the actuation means is coupled with the pH disolving silica thin film on substrate characterized in that a cyclodextrin derivatives: [formula 3a][Formula 3b][Formula 3c][Formula 3d][Formula 3e]In formula said, R ' hydrogen orC1-6alkyl; the m is integer number of 1 to 10. The following steps including according to Claim 1 pH disolving silica thin film on substrate a manufacturing method of a cyclodextrin derivatives: α -, β or γ - cyclodextrin; or for cyclodextrin 6 glucose one or more of carbon and/or a polynucleotide that oxidatively cleaveNH2, N3or amino acid-peptide antagonists of cyclodextrin derivatives and, a maleic anhydride derivatives formula 1 and reacting the (step 1): [formula 1]In formula said, R ' hydrogen orC1-6alkyl; the m is integer number of 1 to 10. According to Claim 5, said α -, β or γ - cyclodextrin; or for cyclodextrin 6 glucose one or more of carbon and/or a polynucleotide that oxidatively cleaveNH2, N3or amino acids, which are substituted with a cyclodextrin derivatives, represented by the general formula 2 a characterized in that the manufacturing method: [formula 2]Said in formula, the ROH, NH2, N3or amino acids, is; the n is integer number of 1 to 3. According to Claim 5, said step 1) [...] the reactions of (diisopropylcarbodiimide, DIC) is carried out using manufacturing method characterized in that. According to Claim 5, said step 1) as a catalyst reaction of 4 - dimethylamino pyridine (4-dimethylaminopyridine, DMAP) and p - toluene sulfonic acid (P-toluenesulphonic acid, PTSA) is carried out in the presence of manufacturing method characterized in that. A cyclodextrin derivatives according to Claim 1 pH disolving silica thin film on substrate including drug amine group to a CRT is provided conjugates. According to Claim 9, said amine group including the drug is an cyclobutyl amine (butylamine), (cephradine) [...], cefadroxil (cefadroxyl), tax it sells with the glycine (cephaloglycin), (cephapirin) texaphyrin garage, [...] (Cefroxadine), garage (Cefaclor) [...], cefuroxime (Cefuroxime), three Peugeot south (Cefuzonam), cells (Cefotetan) the reel it burnt, [...] (Cefoxitin), cover cephem (Carbacephem), cells (Cefotiam) mote cancer, [...] (Cefcapene), (Cefdaloxime) [...], cefdinir (Cefdinir), cefditoren pivoxyl (Cefditoren), [...] (Cefetamet), (Cefixime) three Fick cores, [...] (Cefmenoxime), (Cefodizime) d burden cells, genetically (Cefotaxime), cells (Cefovecin) [...], cefpodoxime (Cefpodoxime), (Cefteram) [...], [...] (Ceftibuten), ceftiofur (Ceftiofur), (Ceftiolene) [...], three Petit family cores (Ceftizoxime), 2 - chloro (Ceftriaxone), (Cefclidine) [...], three lungs blooming, (Cefepime), (Cefluprenam) [...], [...] cells (Cefoselis), cells (Cefozopran) [...], [...] (Cefpirome), [...] (Cefquinome), (Ceftobiprole) [...], [...] (Cefmatilen), doxorubicin, or the mixture thereof conjugates. According to Claim 9, said pH disolving silica thin film on substrate including a cyclodextrin derivatives and amine group the molar ratio of drug conjugates in 8 to 1:1. According to Claim 9, said pH disolving silica thin film on substrate under acidic conditions and a cyclodextrin derivatives including amine group and drug of binding between characterized in that is dissolved with its conjugates. According to Claim 12, the acidic conditions said pH 5 to 6. 5 of conjugates characterized in that condition and within the range. Manufacturing method of including according to Claim 9 for the following steps: a cyclodextrin derivatives according to Claim 1 pH disolving silica thin film on substrate step of reacting an drug including and an amine group (step 2). According to Claim 14, said step 2) the reactions of triethylamine as organic base, dee small pro the ethyl amine which will bloom and d ethyl amine selected from the group consisting of 1 carried out using the at least one characterized in that manufacturing method. Composition for antitumor drug delivery response including pH any one of Claim 9 to Claim 13 assembly for a cathode. According to Claim 16, delivers the drug under acidic conditions and characterized in that composition for antitumor drug delivery pH response. According to Claim 16, the acidic conditions said pH 5 to 6. 5 weakly acidic condition and within the range of pH characterized in that composition for antitumor drug delivery response. According to Claim 16, cancer, inflammatory tissue or abscess (abscess) of which is used to to target characterized in that composition for antitumor drug delivery pH response. According to Claim 1 pH disolving silica thin film on substrate amine group to a cyclodextrin derivatives including the combination a CRT is provided drug, guest material as host or ligand additional drug [...] a implied by the guest - triones. According to Claim 20, said guest material targeting ligand (targeting ligand), cell permeable portion (cell penetrating moiety), bulk material into nano sized particles in polymer and 1 selected from the group consisting of triones a at least one inert gas. According to Claim 21, the guest material said adamantane (adamantane) a including moieties triones.
