JP2009132825A - Stimulus-responsive biodegradable polymer and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stimulus-responsive biodegradable polymer which is useful for biological applications including delivery of a bioactive agent and changes its physical/chemical characteristics in response to small external change in an environmental parameter. <P>SOLUTION: The stimulus-responsive polymer comprises a biodegradable polymer backbone and a stimulus-responsive pendant group attached to the biodegradable polymer backbone. The biodegradable polymer backbone is poly(amino ester) or poly(amide amine) which may optionally comprise a disulfide bond in the backbone. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates generally to stimulus-responsive biodegradable polymers useful for biological applications including delivery of bioactive agents.

  Stimulus-responsive macromolecules are defined as macromolecules that change physical or chemical properties in response to small external changes in environmental parameters such as pH, temperature or light. The stimulus-responsive polymer is also referred to as a stimulus-sensitive polymer, an intelligent polymer, a smart polymer, or an environment-sensitive polymer.

  Stimulus-responsive polymers are gaining attention because of their potential in a variety of biological applications, including their medical applications. Stimulus-responsive polymers are configured to form various types of polymer assemblies such as cross-linked hydrogels, reversible hydrogels, micelles, modified interfaces and conjugated solutions. The applications of these polymers have been reported as delivery in therapeutics, regenerative medicine, bioseparation techniques, or as sensors or actuators, indicating rapid progress in the field (Non-Patent Documents 1, 2, and Patent Documents). See 1, 2 and 3).

  Response to stimuli is a fundamental action in biological systems. Certain environmental conditions are found at specific locations in the body, such as low pH and high temperature (see Non-Patent Document 3). Considering that temperature and pH are relatively convenient and effective, as well as biologically relevant stimuli, research has focused on temperature and pH sensitive polymers.

  Thus, pH and / or temperature sensitive macromolecules can be used in preparing “good” drug delivery systems that utilize changes in biological temperature and pH to produce site-specific controlled drug release. .

  Large differences in pH are widespread in different organs, tissues, and intracellular compartments. For example, the pH varies along the gastrointestinal tract from acidic (pH 2) in the stomach to more basic (pH 5-8) in the intestine. Similarly, certain cancers, inflamed tissues, and injured tissues show a difference of 7.4 or more in blood circulation pH. In addition, the pH drops from a range of pH 6.0-6.5 in the early endosome to a pH of 5.0-6.0 in the late endosome, and then in the lysosome in cell endocytosis. It falls to the range of 5-5.0, which greatly changes the proton concentration in the various cell compartments. Thus, pH changes within the body can be used to direct the response of stimulus-sensitive macromolecules when directed to a particular tissue or cell compartment. Polycations in non-viral gene therapy, acid-induced drug release systems in targeted cancers, and polyanions and amphoteric polymers in endosomolytic delivery are some typical pH-dependent polymers studied in drug delivery (See Non-Patent Document 4).

Temperature is the most widely used stimulus in environmentally responsive polymer systems given that it is relatively easy to adjust and is applicable both in vitro and in vivo. Poly-N-substituted acrylamides (eg, poly (N-isopropylacrylamide) (PNIPAAm)
Amphiphilic balanced polymers such as poly (ethylene oxide) -poly (propylene oxide) -poly (ethylene oxide) (PEO-PPO-PEO), and biopolymers such as gelatin and agarose and artificial polypetides It is a certain representative group of temperature-responsive polymers (see Non-Patent Document 5).

  PNIPAAm is a stimulus-responsive polymer that is commonly studied. This polymer is hydrophilic and soluble in an aqueous solution having a low critical solution temperature (LCST) of about 32 ° C. or lower, and becomes hydrophobic and insoluble above the LCST. However, PNIPAAm is not biodegradable and can therefore accumulate in the body when used for in vivo applications.

Macromolecules used in biomedical applications usually require biocompatibility and biodegradability. For example, in drug delivery, biocompatible polymers are relatively low toxic, and biodegradable polymers can increase sustained drug release and reduce the need for surgical resection after drug disappearance. Accordingly, there is a need for further development of stimulus-responsive polymers that are biocompatible and biodegradable.
US Patent Application Publication No. 2006/0105001 US Patent Application Publication No. 2005/0169882 International Publication No. 2004/072258 Pamphlet Jeong et al., Trends. Biotechnol. , 2002, 20, 305 Roy et al., Chemistry & Biology, 2003, 10, 1161 Qiu et al., Adv. Drug. Deliv. Rev. , 2001, 53, 321 Schmaljohan, D.C. Adv. Drug. Deliv. Rev. 2006, 58, 1655 Gil et al., Prog. Polym. Sci. , 2004, 29, 1173

  In one aspect, a stimulus-responsive polymer comprising a biodegradable polymer skeleton and a stimulus-responsive pendant group pendant to the biodegradable polymer skeleton, wherein the biodegradable polymer skeleton is a poly (amino ester) ) Or poly (amidoamine), wherein the poly (amidoamine) optionally comprises a disulfide bond in the backbone.

  In some embodiments, the biodegradable polymer backbone of the stimulus-responsive polymer includes at least one secondary amine bond and at least one tertiary amine bond before the stimulus-responsive pendant group is pendant. The final stimulus responsive polymer can comprise at least one secondary amine linkage and at least one tertiary amine linkage.

In certain embodiments, the stimulus-responsive polymer is
Formula I:

A unit represented by
Formula II:

A unit represented by
Including one or more units each independently selected from
Optionally, Formula III:

Formula IV:

Formula V:

Formula VI:

And Formula VII:

Includes one or more units each independently selected from.

Where
z is O or NH;
R ₁ , R ₃ and R ₈ are each independently hydrogen, hydroxyl, halide, thiohydroxyl or hydrocarbyl;
R ₂ is a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S A substituted or unsubstituted C _2-30 alkenylene optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally substituted, unsubstituted or substituted C _2-30 alkynylene;
R ₅ is
(I) a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkenylene optionally containing 1 or 2 or more heteroatoms; or optionally 1 or 2 or more heteroatoms selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkynylene, comprising:
(Ii) -R < ₆ > -MR < ₇ >-
Wherein R ₆ is bonded to —N (R ₄ ) — and optionally includes one or more heteroatoms selected from the group consisting of N, O and S, substituted or non- Substituted C _1-6 alkylene, or substituted or unsubstituted C _2-6 alkenylene, optionally containing one or more heteroatoms selected from the group consisting of N, O and S;
M is CH or N;
R ₇ is a substituted or unsubstituted C _1-28 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S A substituted or unsubstituted _{C2-28alkenylene} optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted _C2-28 alkynylene. ) And
R ₄ is
(I) hydrocarbyl or
(Ii) When R ₅ is —R ₆ —M—R ₇ —, R ₄ is also bonded to M, and one or more heteroatoms selected from the group consisting of N, O and S are Optionally substituted, unsubstituted or substituted C _1-6 alkylene, or substituted or unsubstituted, optionally including one or more heteroatoms selected from the group consisting of N, O and S C _2-6 alkenylene, and R ₄ , M, R ₆ , and the nitrogen atom to which R ₄ and R ₆ are bonded form a saturated or unsaturated 4- to 12-membered heterocyclic ring. ,
R ₉ is
(I) a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkenylene optionally containing 1 or 2 or more heteroatoms; or optionally 1 or 2 or more heteroatoms selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkynylene, comprising:
(Ii) -R < ₁₁ > -M-R < ₁₂ >-
Wherein R ₁₁ is bonded to —N (R ₁₀ ) — and optionally includes one or more heteroatoms selected from the group consisting of N, O and S, substituted or non- Substituted C _1-6 alkylene, or substituted or unsubstituted C _2-6 alkenylene, optionally containing one or more heteroatoms selected from the group consisting of N, O and S;
M is CH or N;
R ₁₂ is a substituted or unsubstituted C _1-28 alkyl optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S Substituted or unsubstituted _C2-28 alkenyl optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted _C2-28 alkynyl. ) And
R ₁₀ is
(I) hydrocarbyl, or (ii) when R ₉ is —R ₁₁ —M—R ₁₂ —, R ₁₀ is also bonded to M and is selected from the group consisting of N, O and S 1 or Substituted or unsubstituted C _1-6 alkylene, optionally containing two or more heteroatoms, or optionally containing one or more heteroatoms selected from the group consisting of N, O and S And a nitrogen atom to which R ₁₀ , M, R ₁₁ , and R ₉ and R ₁₁ are bonded is a saturated or unsaturated 4- to 12-membered complex, which is a substituted or unsubstituted C _2-6 alkenylene. Forming a ring;
However, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₈ , R ₉ and R ₁₀ are C═C 2 conjugated to a primary amino group, a secondary amino group, or a carbonyl group. It cannot have a double bond.

The stimulus-responsive polymer can be responsive to pH, light, temperature, or ionic strength.
The stimulus-responsive pendant group has the formula X:

(Wherein R ₈ , R ₉ and R ₁₀ are as defined above.)
The structure may be

  In some embodiments, the stimulus responsive group is a reactive N-isopropylacrylamide, N, N′-diethylacrylamide, 2-carboxyisopropylamide, N- (L)-(1-hydroxymethyl) propylmethacrylamide, or N-acryloxyl- It may be N′-alkyl piperazine.

The stimulus-responsive polymer can further comprise a hydrophobic pendant group, wherein the hydrophobic pendant group is, in some embodiments,
Formula XII:

Formula XIII:

Or formula XIV:

(Where
x is O or NH;
R ₁₇ is substituted or unsubstituted C _3-30 alkyl, substituted or unsubstituted C _4-30 alkenyl, substituted or unsubstituted C _4-30 alkynyl, substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted C _6-18 aryl, any of which may optionally contain one or more heteroatoms selected from the group consisting of N, O and S. )
It has the following structure.

  Hydrophobic pendant groups include: reaction 4-tert-butylcyclohexyl acrylate, 2-butoxyethyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, octadecyl acrylate, lauryl acrylate, diacetone acrylamide, N- (butoxymethyl) acrylamide, N- (Isobutoxymethyl) acrylamide, cholesteryl chloroformate, nanonoyl chloride, undecanoyl chloride, lauroyl chloride, 4-heptylbenzoyl chloride, myristoyl chloride, 1-bromo-2-cyclohexylethane, 1-bromooctane, 1-adamantyl Bromomethyl ketone, 2-bromo-2 ′, 5′-dimethyloxyacetophenone, 1-bromo-3,7-dimethyloctane, 1-bromododecane, -Bromooctane, 1-bromodecane, 1-bromooctadecane, 2- (6-bromohexyloxy) tetrahydro-2H-pyran, 1-iodoadamantane, 1-iodohexane, 1-iodooctane, 1-iododecane, 1-iodo Dodecane or 1-iodooctadecane may be included.

In another form, a composition comprising a stimulus responsive polymer as described herein and a cross-linking group is provided.
The polymer has the formula XI:

(Where
x is O or NH;
R ₁₃ and R ₁₅ are each independently hydrogen, hydroxyl, halide, thiohydroxyl, or hydrocarbyl;
R ₁₄ is a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S A substituted or unsubstituted C _2-30 alkenylene optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted C _2-30 alkynylene. )
It can be crosslinked by a crosslinking group having the structure:

  In certain embodiments, the cross-linking group is a cross-linked 1,4-butanediol diacrylate, 1,4-butanediol dimethacrylate, 1,2-ethanediol diacrylate, 1,6-hexanediol diacrylate, 2,5 -Hexanediol diacrylate, poly (ethyl glycol) diacrylate, ethylene diacrylate, 1,3-propanediol diacrylate; 1,4-bis (acryloyl) piperazine, N, N'-bis (acryloyl) cystamine, N, N′-methylenebisacrylamide, N, N ′-(1,2-dihydroxyethylene) bisacrylamide; 1,3-dibromo-2-propanol, 1,4-dibromo-2-butanol, 1,5-dibromopentane, 1,6-dibromohexane, 1,5-diiodopentane 1,8-dibromo octane, 1,6-diiodo, or 1,8 may include diiodooctane.

  In another aspect, the present invention also provides a method for producing the stimulus-responsive polymer described herein. The method includes reacting a biodegradable polymer comprising a poly (amino ester) or poly (amidoamine) to form a polymer having stimuli-responsive pendant groups pendant to the polymer backbone, wherein The poly (amidoamine) optionally has a disulfide bond in the polymer skeleton.

  In some embodiments, the biodegradable polymer has at least one secondary amine bond and at least one tertiary amine bond in the backbone.

  The ratio of the biodegradable polymer unit to the stimulus-responsive molecular unit may be about 10: 1 to about 1: 4.

  The method of the present invention may further comprise cross-linking a biodegradable polymer having a stimulus-responsive pendant group pendant to the polymer backbone using a cross-linking molecule. The cross-linking molecule can include diacrylate, diacrylamide, or dibromo, or diiodo reagent.

  The ratio of biodegradable polymer unit to cross-linked molecular unit can be about 20: 1 to about 1: 2.

  The method of the present invention may further comprise reacting a biodegradable polymer having a stimulus responsive pendant group pendant to the polymer backbone with a hydrophobic molecule to pendant the hydrophobic pendant group onto the polymer backbone. .

  The ratio of biodegradable polymer unit to hydrophobic molecule unit can be from about 20: 1 to about 1: 4.

  In yet another aspect, there is provided a composition comprising a stimulus-responsive biodegradable polymer as described herein, or a composition as described herein, and a bioactive agent. This composition may form micelles or hydrogels.

  The bioactive agent can include small molecules, organometallic compounds, nucleic acids, proteins, peptides, polynucleotide metals, isotopically labeled compounds, drugs, vaccines, or immunizing agents.

  Other aspects and features of the present invention will become apparent to those skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the drawings.

DETAILED DESCRIPTION The present invention relates to a stimulus-responsive polymer. These polymers include polymers containing stimulus-responsive pendant groups pendant to a biodegradable polymer skeleton.

  Biodegradable polymer backbones include poly (amino esters) or poly (amidoamines) such as, for example, poly (amidoamines) having disulfide bonds.

  Poly (aminoesters) are excellent biomaterial candidates in biomedical applications, including their use as drug vectors and DAN delivery, due to their pH sensitivity, biodegradability and biocompatibility. Poly (amidoamines) with disulfide bonds allow for the formation, handling, and delivery of stable stimulus-responsive polymers, but are biodegradable in the presence of thiol-containing compounds (eg, glutathione). Furthermore, poly (amino esters), poly (amidoamines), and stimulus-responsive polymers derived from such polymers can be easily produced using simple and efficient synthetic methods.

  Thus, the present polymer is biocompatible and biodegradable and undergoes chemical or physical changes in response to specific stimuli through stimulus-responsive pendant groups. The stimulus-responsive polymer can then be formed into various structures, such as hydrogels and micelles, by washing specific cross-linking groups or additional hydrophobic pendant groups.

  The term “biodegradable” means that a given substance can be destroyed or degraded under natural conditions, such as by chemical or enzymatic degradation mechanisms, as found in cells or organic tissues.

  In one form, a stimulus responsive polymer comprising a biodegradable polymer backbone and a stimulus responsive pendant group is provided.

  The biodegradable polymer backbone before the stimulus-responsive pendant group is pendant contains at least a secondary amine linkage that can be used to pendant the pendant group via reaction at the secondary amine nitrogen. Thus, the polymer backbone prior to being derivatized to a stimulus responsive type can have at least one secondary amine bond in the skeleton, wherein the secondary amine bond is a suitable one such as a stimulus responsive pendant group. It can be used for reaction with pendant groups or crosslinking groups.

The stimulus-responsive polymer can include at least one amine bond in the polymer backbone even after the stimulus-responsive pendant group and other pendant groups or cross-linking groups are attached.
The polymer skeleton of the stimulus-responsive polymer can be linear or branched and includes hyperbranching.

  The scaffold of the present invention may comprise a poly (amido) amine having at least one secondary amine bond and at least one tertiary amine bond in the scaffold before the stimulus-responsive pendant group is pendant, The poly (amido) amine can contain disulfide bonds.

  The scaffold of the present invention may also comprise a poly (amino ester) having at least one secondary amine bond and at least one tertiary amine bond in the scaffold before the stimulus-responsive pendant group is pendant. .

  Suitable poly (amino esters) and methods for their preparation are described in US Patent Application Publication No. 2004/0260115, which is incorporated herein by reference. Thus, in some embodiments, the backbone has a polymeric backbone having at least one secondary amine bond and at least one tertiary amine bond in the polymeric backbone prior to derivatization with a pendant group. Poly (amino ester) compounds are included.

  In other embodiments, the poly (amino ester) backbone has at least one secondary amine linkage and at least one tertiary amine linkage in its macromolecular backbone, and is terminated before derivatization with a pendant group. Poly (amino ester) compounds having a polymer backbone that does not have primary amino groups are included.

In certain embodiments, the stimulus-responsive polymer can be a polymer comprising linear units, each independently of formula I:

And a linear unit of formula II:

Selected from the following linear units:

Also, the stimulus-responsive polymer can optionally be of formula III:

One or more units selected from:

Furthermore, not all stimulus units in the polymer have a stimulus-responsive group attached, and the formula IV:

Formula V:

Formula VI:

And Formula VII:

One or two or more units each independently selected from can be optionally included.

In the above formula,
z is O or NH.
R ₁ , R ₃ and R ₈ are each independently hydrogen, hydroxyl, halide, thiohydroxyl or hydrocarbyl.

R ₂ is a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S A substituted or unsubstituted C _2-30 alkenylene optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted C _2-30 alkynylene.

R ₅ is
(I) a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkenylene optionally containing 1 or 2 or more heteroatoms; or optionally 1 or 2 or more heteroatoms selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkynylene, comprising:
(Ii) -R < ₆ > -MR < ₇ >-
Wherein R ₆ is bonded to —N (R ₄ ) — and optionally includes one or more heteroatoms selected from the group consisting of N, O and S, substituted or non- Substituted C _1-6 alkylene, or substituted or unsubstituted C _2-6 alkenylene, optionally containing one or more heteroatoms selected from the group consisting of N, O and S;
M is CH or N;
R ₇ is a substituted or unsubstituted C _1-28 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S A substituted or unsubstituted _{C2-28alkenylene} optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted _C2-28 alkynylene. ).

R ₄ is
(I) hydrocarbyl or
(Ii) When R ₅ is —R ₆ —M—R ₇ —, R ₄ is also bonded to M, and one or more heteroatoms selected from the group consisting of N, O and S are Optionally substituted, unsubstituted or substituted C _1-6 alkylene, or substituted or unsubstituted, optionally including one or more heteroatoms selected from the group consisting of N, O and S C _2-6 alkenylene, and R ₄ , M, R ₆ , and the nitrogen atom to which R ₄ and R ₆ are bonded form a saturated or unsaturated 4- to 12-membered heterocycle. .

R ₉ is
(I) a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkenylene optionally containing 1 or 2 or more heteroatoms; or optionally 1 or 2 or more heteroatoms selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkynylene, comprising:
(Ii) -R < ₁₁ > -M-R < ₁₂ >-
Wherein R ₁₁ is bonded to —N (R ₁₀ ) — and optionally includes one or more heteroatoms selected from the group consisting of N, O and S, substituted or non- Substituted C _1-6 alkylene, or substituted or unsubstituted C _2-6 alkenylene, optionally containing one or more heteroatoms selected from the group consisting of N, O and S;
M is CH or N;
R ₁₂ is a substituted or unsubstituted C _1-28 alkyl optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S Substituted or unsubstituted _C2-28 alkenyl optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted _C2-28 alkynyl. ).

R ₁₀ is
(I) hydrocarbyl, or (ii) when R ₉ is —R ₁₁ —M—R ₁₂ —, R ₁₀ is also bonded to M and is selected from the group consisting of N, O and S 1 or Substituted or unsubstituted C _1-6 alkylene, optionally containing two or more heteroatoms, or optionally containing one or more heteroatoms selected from the group consisting of N, O and S And a nitrogen atom to which R ₁₀ , M, R ₁₁ , and R ₉ and R ₁₁ are bonded is a saturated or unsaturated 4- to 12-membered complex, which is a substituted or unsubstituted C _2-6 alkenylene. A ring is formed.

However, in the above formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₈ , R ₉ and R ₁₀ are conjugated to a primary amino group, a secondary amino group, or a carbonyl group. It cannot have a C = C double bond.

Thus, in the above structural formula, when at least one or two or more of R ₂ , R ₄ or R ₅ contain a disulfide group, especially when the skeleton contains poly (amidoamine), the polymer skeleton has a disulfide bond. Can be included.

  In a particular form of the invention, the polymer backbone can comprise 1 to 2000 linear units independently selected from the linear units of formula I and II described above, optionally Contains one or more units of formula III-VII.

In one form, the polymer backbone used to form the stimulus-responsive polymer is
When the polymer skeleton is poly (amino ester), the content of the linear unit in the polymer skeleton is 20% to 45%, and R ₂ is ethylene, —N (R ₄ ) —R ₅ -NH- is not 1- (2-aminoethyl) piperazinylene, N-ethylethylenedi-aminylene, N-methyl-1,3-propanediaminylene, piperazinylene, or 4- (aminomethyl) piperidinylene; , The content of linear units in the polymer skeleton is 20% to 45%, R ₂ is — (CH ₂ CH ₂ O) _n CH ₂ CH ₂ , and n is 5, 7 or 13. _when, -N _{(R 4)} -R 5 -NH- is 1- (2-aminoethyl) piperazinylene, N- ethyl ethylene Zia mini Le - ene, N- methyl-1,3-propane Zia mini Ren, or 4 -(Aminomethyl) -Not piperidinylene.

  In this disclosure, the term “hydrocarbyl” refers to a hydrocarbon group that may contain one or more heteroatoms, including but not limited to branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched. Branched alkynyl, aryl, alkoxyl, carbamoyl, carboxyl ester, carbonyldioxyl, amide, alkylthioether, dialkylamino, trialkylamino, cyano, ureido, substituted alkanoyl groups, cyclic, cyclic aromatic, heterocyclic, and aromatic Each group includes branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, dialkylamino, trialkylamino, aryl, ureido, heterocycle, aromatic heterocycle, cyclic , Aromatic cyclic, halogen, hydroxyl, alkoxy, Bruno, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyl benzodioxyl, alkyl thioether, and may be substituted with one or more substituents selected from the group consisting of a thiol group. Thus, in the present disclosure, the term “hydrocarbyl” includes a hydrocarbon group (eg, an alkoxy radical) attached to a compound via a heteroatom.

Thus, when R ₁ , R ₃ , R ₄ , R ₈ and R ₁₀ are hydrocarbyl, suitable values for these groups include substituted or unsubstituted C _1-30 alkyl, substituted or non-substituted Included are substituted C _2-30 alkenyl, substituted or unsubstituted C _2-30 alkynyl, substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted C _6-18 aryl. , Any of which may optionally contain one or more heteroatoms selected from the group consisting of N, O and S.

  In the present disclosure, the term “unit” in a stimulus-responsive polymer refers to a structural unit of a polymer that is covalently bonded to the polymer skeleton via one, two, or three covalent bonds. A unit extending a polymer skeleton and having a specific structure represents a unit repeated along the polymer, although the unit having a specific structure can be randomly scattered among other units having a specific structure. The term is used as a generic term covering all possible units in a polymer, including units having the structure of any one of formulas I-VII. A given unit can be covalently linked in crosslink with other units in the same polymer chain or in different polymer chains, and such a crosslink can be linked between units that extend the polymer backbone. It will be understood that it is not intended to be included in the above description of the backbone covalent bond.

  In the present disclosure, the term “linear unit” refers to a structural unit of a polymer that is covalently bonded to the polymer backbone via two covalent bonds, thereby extending the substantially linear polymer backbone. Say. The linear unit of the present invention may have a structure defined by Formulas I-VI.

  In the present disclosure, the term “chain unit” refers to a structural unit of a polymer that is covalently bonded to the polymer skeleton via three covalent bonds, thereby branching the polymer skeleton. The branched chain unit of the present invention may have a structure defined by Formula VII.

In the present disclosure, the term “terminal unit” refers to a poly (amino ester) structural unit that appears at the end or end of a polymer chain. The poly (amino ester) described above may contain two or more terminal units. The terminal unit in the poly (amino ester) may have a structure according to Formula VIII or Formula IX below.

  In the formula, R4 and R5 have the same definitions as in formulas I to VII.

  FIG. 1 appears in a linear poly (amino ester) produced by reacting a bis (acrylate) ester with a diamine having secondary and primary amino groups to form a poly (amino ester) skeleton. 2 shows two modes of the obtained stimulus-responsive polymer and binding species. The structural units are linked in the polymer backbone via one tertiary amine and one secondary amine bond. It should be noted that in the indicated embodiment, the terminal unit has either the original secondary amino group or the original primary amino group as an unreacted amino group.

  The polymer backbone may further comprise an end capping unit at the end of the polymer. Suitable end capping agents include morpholine, N-methylpiperazine, N-ethylpiperazine, dimethylamine, diethylamine, and 1-methyl-4-methylaminopiperidine, and benzyl-1-piperazinecarboxylate.

  As referred to herein, the term “stimulus responsive” or “stimulus response” refers to physical in response to an external stimulus such as a specific pH, temperature, light (including light of a specific wavelength) or ionic strength. A representation or mention of a characteristic of a pendant group, compound or polymer that undergoes a change in its mechanical or chemical properties. For example, the hydrophobicity or hydrophilicity of a compound can change in response to the use of an external stimulus, resulting in a change in the solubility of the compound. Certain pendant groups, compounds or macromolecules can be responsive to a single stimulus or two or more stimuli and can exhibit different responses, changes in physical or chemical properties to different stimuli.

  Therefore, the “stimulus responsive pendant group” refers to a pendant group possessing the above-mentioned stimulus responsiveness when grafted onto a polymer skeleton, and imparts stimulus responsiveness to the grafted polymer.

  As described above, stimuli can be pH, temperature, light, ionic strength, and stimulus-responsive pendant groups, compounds, or macromolecules can undergo physical or chemical changes when exposed to specific stimuli. .

  The stimulus-responsive pendant group may be any stimulus-responsive pendant group. The pendant group can be a stimulus responsive or oligomer of a stimulus responsive monomer.

  In some forms, the stimulus responsive pendant group is a temperature responsive pendant group. In some forms, the stimulus-responsive pendant group comprises caprolactam, ethylene glycol, or propylene oxide.

In other forms, the stimulus-responsive pendant group comprises an N-substituted acrylamide group.
When the stimulus-responsive pendant group is an N-substituted acrylamide group, the substituent of the N-substituted acrylamide group must be less nucleophilic than the secondary amino group of the polymer backbone, so that the substituent is The secondary amine group in the skeleton is not provided for reaction with the vinyl group in the N-substituted acrylamide.

In some forms, the stimulus-responsive pendant group can have the formula X.

R ₈ , R ₉ and R ₁₀ are as defined in formulas I to VII.

  As described above, the stimulus-responsive pendant group can be grafted to the biodegradable polymer backbone via reaction with secondary amino groups in the polymer backbone. However, depending on the polymer backbone and the specific functional groups present in the pendant group prior to grafting, the stimulus-responsive pendant group can be pendant through groups other than secondary amino groups in the polymer.

  The saturation of available sites in the polymer backbone to which the stimulus-responsive pendant groups are grafted can be changed by changing the conditions of the grafting reaction, as shown below. Thus, the stimulus-responsive polymer is at least 1%, at least 2%, at least 3%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25% at the site available for grafting. At least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least It may comprise stimulus responsive pendant groups grafted at 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 100%. The stimulus responsive polymer can comprise from about 1% to about 99% grafted stimulus responsive pendant groups, or can comprise from about 1% to about 100% grafted stimulus responsive pendant groups.

  It will be appreciated that depending on the particular pendant group used, there will be extremely few pendant groups grafted onto the polymer, resulting in a loss of stimulus responsiveness. The relationship between stimulus responsiveness and the degree of grafting can be easily determined by routine laboratory methods.

FIG. 2 shows the result of ¹ HNMR spectroscopy of a product obtained by grafting N-isopropylacrylamide (NIPAAm) to poly (amino ester) poly (PEG258DA-AEPZ) in a specific form of the stimulus-responsive polymer. The resulting poly (PEG258DA-AEPZ) -g-NIPAAm has either a NIPAAm with a grafting degree of 46% or a NIPAAm with a grafting degree of 100%.

  The hydrophobicity or hydrophilicity of the polymer can be adjusted to adjust the stimulus responsiveness of the polymer so that the stimulus responsiveness is suitable for a given use. Stimulus responsiveness can be changed by shifting the ratio of hydrophilicity and hydrophilic groups in the polymer. For example, the hydrophilic / hydrophobic properties of the biodegradable polymer backbone, and the nature and degree of grafting of additional pendant groups such as N-substituted acrylamide pendant groups can be tailored to adjust stimulus responsiveness.

  In addition, the introduction of additional pendant groups that are not temperature responsive but are hydrophilic or hydrophobic may affect the stimulus responsiveness of the stimulus responsive polymer.

  In embodiments where the stimulus responsive pendant group is a temperature responsive group, the polymer is defined as the critical temperature at which the polymer solution undergoes a phase transition from soluble to insoluble (eg, exceeds the critical temperature and becomes insoluble in aqueous solution). The critical solution temperature (LCST) can be lower. LCST can be determined using routine laboratory procedures. For example, LCST can be measured as a transition point in a plot of transmittance characteristics as a function of temperature of a stimulus-responsive polymer aqueous solution and is monitored with an ultraviolet spectrometer. Here, the transition point is a point at which the transmittance starts to change due to an increase or decrease from a constant transmittance value (for example, at a temperature equal to or lower than the LCST), or conversely, a transmittance at which the transmittance increases or decreases. It is intended to refer to the point at which a value begins to change from a constant transmittance value. For example, reference can be made to FIG.

  The LCST of the temperature-responsive polymer can be prepared to be suitable for a given application. For example, the LCST can be selected such that the polymer is within the range of body temperature and room temperature for applications used in the body. Thus, the polymer can be designed to have one structure external to the body and a different structure within the body.

  For example, poly (PEG258DA-AEPZ) -g-NIPAAm, in which the percentage of grafted NIPAAm pendant groups varies, exhibits a different LCST. As shown in FIG. 6, a polymer having a NIPAAm grafting degree of 100% and a polymer having 46% of the polymer poly (PEG258DA-AEPZ) -g-NIPAAm has LCSTs of 33 ° C. and 36 ° C., respectively. However, when the graft degree of NIPAAm is 15%, loss of LCST is observed in the same polymer skeleton. In contrast, in poly (BDA-AEPZ) -g-NIPAAm, where the hydrophobicity of the main polymer chain is higher and the grafting degree of NIPAAm is 15%, the LSCT was still maintained at 34.5 ° C. . On the other hand, poly (PEG575DA-AEPZ) -g-NIPAAm in which the hydrophilicity of the main polymer chain is higher and the grafting degree of NIPAAm is 100% did not show LSCT.

  Protonation of the amino group in the polymer backbone also increases the hydrophilicity of the main chain, so the polymer can be adjusted to adjust the hydrophilic / hydrophobic balance of the polymer, thus affecting the stimulus response. Effect. In addition, the positive charge generated from protonation of amino groups can cause polymer aggregation, where exposure to sensory stimuli leads to structural changes in the polymer, such as reduction of pendant groups. Can be suppressed or reduced.

In a further example, poly (BDA-AEPZ) -g-NIPAAm _0.6 is at 30.5 ° C, 31.0 ° C, 34.5 ° C at pH 7, 5 and 3, respectively, as shown in FIG. Has LCST. The LCST of the polymer increases with decreasing pH due to increased hydrophilicity as a result of partial protonation of backbone amino groups at pH 5 and full protonation of amino groups at pH 3. Furthermore, the decrease in polymer agglomeration, as shown in FIG. 7, is only 1% transmittance at 36 ° C. at pH 7, whereas 89% transmittance at 40 ° C. at pH 5 and 3. Is proved by the fact that

  Polymers can conventionally be formed into a variety of compositions and structures, including hydrogels that are useful forms in stimuli-responsive polymers used in successful drug delivery systems, for example.

  Hydrogels are three-dimensional (3D) networks that can swell in water and retain large amounts of water in certain areas of the network, while chemically or physically connected in other areas of the network. Therefore, the hydrogel can maintain its structure even when swollen with water. 3D networks can be formed by cross-linked hydrophilic polymers via covalent bonds, hydrogen bonds, van der Waals interactions, or physical entanglement (Kamath et al., Adv. Drug. Deliv. Rev., 1993 , 11, 59).

  Stimulus responsive hydrogels manufactured using stimulus responsive polymers are intended to protect drugs or bioactive agents from adverse environments (eg, the presence of enzymes and low pH in the stomach) when administered to the body. Can be used. In addition, hydrogels can be used to expose to appropriate environmental stimuli as a result of their response through site-specific drug release.

  Stimulus-responsive hydrogels are used to form artificial muscles (Kajiwara et al., Nature, 1992, 355, 208; Osada et al., Nature, 1992, 355, 242), chemical valves (Osada et al., Chem. Lett., 1985, 9, 1285). ), Enzyme and cell immobilization (Chen et al., Biotechnol. Prog., 1998, 14, 473), and concentration of dilute solutions in bioseparation (Park et al., Biotechnol. Prog., 1992, 8, 521), etc. Developed in various applications.

  The above-mentioned stimulus-responsive polymer can be constructed into a hydrogel structure by cross-linking of the polymer skeleton, and can form a cross-linked polymer network. Thus, the stimulus-responsive polymer can be in the form of a stimulus-responsive hydrogel and includes a bridging group that connects two sites in the polymer. Here, the two sites include sites in different polymer chains.

  The crosslinkable group is any crosslinkable group that connects two sites on one or more polymer chains to a reactive group on the second polymer skeleton via a reactive group on one polymer skeleton. It may be a group. Each specific reactive group on the polymer skeleton linked by the crosslinking agent may be the same or different. That is, the cross-linking group before reacting with the polymer skeleton is composed of two functional groups (typically one end of the cross-linking molecule) that can be used for reaction with a complementary functional group on the polymer. Part). The bonding of the cross-linking group to the stimulus-responsive pendant group can affect the stimulus-responsiveness of the resulting hydrogel, but the cross-linking group is linked via the reactive group of the pendant group (including the stimulus-responsive pendant group). Can do.

  Conventionally, the polymer backbone contains secondary amino functional groups, so that the bridging group can be bonded via secondary amino groups on one or more polymer chains. When the degree of grafting of the pendant group on the stimulus-responsive polymer is 100% and the pendant group is bonded at the secondary amino group, any cross-linking group can be linked via a different functional group on the polymer skeleton. It will be understood that they can be combined.

  In one form, the bridging group is attached to the two polymer chains via secondary amino groups present in each polymer chain backbone prior to reaction with the crosslinking molecule. In some forms, the bridging group is a reactive diacrylate, diacrylamide, or dibromo or diiodo reagent. FIG. 9 shows a typical hydrogel.

In certain forms, the bridging group can have the structure of Formula XI.

In the above formula XI, x is O or NH.
R ₁₃ and R ₁₅ are independently hydrogen, hydroxyl, halide, thiohydroxyl or hydrocarbyl.

R ₁₄ is a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S A substituted or unsubstituted C _2-30 alkenylene optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted C _2-30 alkynylene.

  The stimulus-responsive hydrogel has at least 1%, at least 2%, at least 3%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, At least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98 %, At least 99%, or at least 100% crosslinking content, which is determined by the amount of crosslinking molecules added and the number of sites available for crosslinking. The stimulus-responsive polymer can include about 1% to about 99%, or about 1% to about 100% cross-linking groups.

  The stimulus-responsive polymer can be designed as an amphiphilic molecule suitable for formation into a polymeric micelle composition in aqueous solution, as well as suitable for formation into a hydrogel structure.

  Polymeric micelles can be formed by aggregation of amphiphilic polymers by aggregation of the hydrophobic portion of the polymer in an aqueous medium, forming an inner hydrophobic core and an outer hydrophilic surface that excludes water. Polymeric micelles are useful for bioactive agent delivery because they can encapsulate and encapsulate guest molecules in a hydrophobic core.

  The amphipathic stimulus-responsive polymer can be obtained by introducing a hydrophobic group into the stimulus-responsive polymer of the present invention in the same manner as described above for the introduction of a crosslinking group. That is, the hydrophobic group can be bonded to the polymer skeleton via a functional group in the polymer skeleton, and the functional group includes an available secondary amino group.

  The hydrophobic group may be any hydrophobic group that is actually hydrophobic and binds to the polymer backbone via a functional group of the hydrophobic group that reacts with a complementary functional group on the polymer backbone. That is, the hydrophobic group before reacting with the polymer skeleton is a monofunctional molecule having a functional group that can be used for the reaction between the hydrophobic portion and the complementary functional group of the polymer.

  Since the polymer backbone conventionally includes secondary and tertiary amino functional groups, hydrophobic groups can be attached via secondary and / or tertiary amino groups on the polymer chain. Alternatively, they can be attached at different functional groups on the polymer chain. When the degree of grafting of the stimulus-responsive pendant group in the stimulus-responsive polymer is 100% and the pendant group is bonded at the secondary amino group, any hydrophobic pendant group has a different functional group on the polymer skeleton. It will be understood that they may be coupled via.

  In some forms, the hydrophobic group is attached to the macromolecular backbone through secondary or tertiary amino groups present in the backbone prior to reaction with the hydrophobic pendant group molecule. In some forms, the hydrophobic group is a reactive hydrophobic acrylate, hydrophobic acrylamide, acyl chloride, or monobromo or monoiodo reagent. FIG. 10 shows a typical amphipathic stimulus-responsive poly (network ester).

The hydrophobic group may have a structure shown in the following formulas XII to XIV. In Formula XII, x = O is acrylate and x = NH is acrylamide.

In formulas XII-XIV, x is O or NH.
R ₁₇ is a hydrophobic hydrocarbyl group. R ₁₇ may be a synthetic hydrophobic group or a naturally occurring hydrophobic group. It will be appreciated that R ₁₇ should be selected to be low toxic and biocompatible.

Accordingly, suitable values for R ₁₇ include substituted or unsubstituted C _3-30 alkyl, substituted or unsubstituted C _4-30 alkenyl, substituted or unsubstituted C _4-30 alkynyl, One or more heteroatoms which are substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted C _6-18 aryl, each selected from the group consisting of N, O and S May optionally be included.

  The amphipathic stimulus-responsive polymer of the present invention comprises at least 1%, at least 2%, at least 3%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% , At least 97%, at least 98%, or at least 99% hydrophobic content. The stimulus-responsive polymer can comprise from about 1% to about 99% grafted hydrophobic pendant groups, or from about 1% to about 100% grafted hydrophobic pendant groups, or at least 1% At least 2%, at least 3%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% grafting It may contain a hydrophobic pendant group. These are determined by the sites available for hydrophobic group attachment.

  The stimulus-responsive polymer can be easily produced by standard chemical techniques such as Michael addition reaction. The poly (amino ester) skeleton of the stimulus-responsive polymer is a Michael addition of a bis (acrylate ester) monomer to a diamine monomer in the case of poly (amino ester), and bisacrylamide in the case of poly (amidoamine). It can be prepared via Michael addition of a monomer to a diamine monomer, the diamine monomer having one primary amino group and one secondary amino group. A suitable method for producing a poly (amino ester) backbone prior to the addition of a stimulus-responsive pendant group is described in US Patent Application Publication No. 2004/0260115, which is incorporated herein by reference.

  Where a linear skeleton is described, bis (acrylate ester) or bisacrylamide and diamine react in approximately equimolar amounts.

  In certain forms, the biodegradable polymer backbone can be formed using a bis (acrylate ester) or bisacrylamide monomer of formula XV.

Formula XV:

In formula XV, z is O or NH. R ₁ and R ₃ are each independently hydrogen, hydroxyl, halide, thiohydroxyl or hydrocarbyl, and R ₂ optionally represents one or more heteroatoms selected from the group consisting of N, O and S including, substituted or unsubstituted C _1-30 alkylene; N, is selected from the group consisting of O and S containing one or more heteroatoms optionally substituted or unsubstituted C _2-30 Alkenylene; or substituted or unsubstituted C _2-30 alkynylene, optionally containing one or more heteroatoms selected from the group consisting of N, O and S.

  Bis (acrylate ester) or bisacrylamide monomers can react with the diamine monomer of formula XVI.

Formula XVI:

In Formula XVI, R ₅ is
(I) a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkenylene optionally containing 1 or 2 or more heteroatoms; or optionally 1 or 2 or more heteroatoms selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkynylene, comprising:
(Ii) -R < ₆ > -MR < ₇ >-
Wherein R ₆ is bonded to —N (R ₄ ) — and optionally includes one or more heteroatoms selected from the group consisting of N, O and S, substituted or non- Substituted C _1-6 alkylene, or substituted or unsubstituted C _2-6 alkenylene, optionally containing one or more heteroatoms selected from the group consisting of N, O and S;
M is CH or N;
R ₇ is a substituted or unsubstituted C _1-28 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S A substituted or unsubstituted _{C2-28alkenylene} optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted _C2-28 alkynylene. ).

In Formula XVI, R ₄ is
(I) hydrocarbyl or
(Ii) When R ₅ is —R ₆ —M—R ₇ —, R ₄ is also bonded to M, and one or more heteroatoms selected from the group consisting of N, O and S are Optionally substituted, unsubstituted or substituted C _1-6 alkylene, or substituted or unsubstituted, optionally including one or more heteroatoms selected from the group consisting of N, O and S C _2-6 alkenylene, and R ₄ , M, R ₆ , and the nitrogen atom to which R ₄ and R ₆ are bonded form a saturated or unsaturated 4- to 12-membered heterocycle. .

However, in Formula XV and Formula XVI, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are C═C double bonds conjugated to a primary amino group, a secondary amino group, or a carbonyl group. Can not have. The R group in the diamine monomer and bis (acrylate ester) or bisacrylamide monomer must be less nucleophilic than the secondary and tertiary amino groups of the diamine, so that the R group is bis (acrylate ester). Or the amino group which reacts with the vinyl group in bisacrylamide is not provided.

  In the present disclosure, the term “diamine monomer” means a compound having one secondary amino group and one primary amino group, but further includes a compound containing one or more tertiary amino groups. It is not excluded. Thus, the term “diamine monomer” as used in this disclosure includes compounds having one secondary amino group, one primary amino group, and optionally one or more tertiary amino groups. It is.

  Bis (acrylate ester) monomers that can be used to produce the poly (amino ester) of the present invention include 1,4-butanediol diacrylate, 1,4-butanediol dimethacrylate, 1,2-ethanediol Diacrylate, 1,6-hexanediol diacrylate, 2,5-hexanediol diacrylate, poly (ethyl glycol) diacrylate, ethylene diacrylate, and 1,3-propanediol diacrylate are included.

  Bisacrylamide monomers that can be used to produce the poly (aminoamide) of the present invention include N, N′-bis (acryloyl) cystamine, N, N′-methylenebisacrylamide, N, N ′-(1, 2-dihydroxyethylene) bisacrylamide, 1,4-bis (acryloyl) piperazine, and N, N′-ethylenebis (acrylamide).

  Diamine monomers that can be used to produce the biodegradable polymer of the present invention include 1- (2-aminoethyl) piperazine, 3-aminopyrrolidine, N-ethylethylenediam, N-methyl-1, 3-propanediamine, N-isopropylethylenediamine, N-hexylethylenediamine, N-butylethylenediamine, N- (2-hydroxypropyl) ethylenediamine, and N, N-diethyldi-ethylenetriamine are included.

  The reaction can be carried out under a wide range of temperatures and pressures, although the reaction time increases at low temperatures. For example, the reaction may be performed at a temperature of about -20 ° C to about 100 ° C, about -10 ° C to about 90 ° C, about 0 ° C to about 80 ° C, about 10 ° C to about 70 ° C, or about 20 ° C to about 50 ° C. Can be implemented. The reaction can be incubated for a period of time, for example, 10 hours to 10 days, 18 hours to 7 days, 24 hours to 96 hours, or 24 hours to 72 hours.

  The reaction is preferably carried out in the presence of one solvent or a mixture of solvents. Solvents that can be used in the method of the present invention include, but are not limited to, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, chloroform, dichloromethane, methyl chloride, tetrahydrofuran, methanol, ethanol, isopropanol, water, hexane, toluene. , Benzene, carbon tetrachloride, glyme and diethyl ether.

  In one form, the biodegradable polymer can react with an end capping agent. Suitable end capping agents include, but are not limited to, morpholine, N-methylpiperazine, N-ethylpiperazine, dimethylamine, diethylamine, and 1-methyl-4-methylaminopiperidine, and benzyl-1-piperazinecarboxyl. The rate is included.

  The biodegradable polymer may be used as it is or may be purified before further use. Purification can be performed using known techniques such as precipitation, crystallization, chromatography, drying under vacuum, and the like. For example, the biodegradable polymer of the present invention can also be purified by precipitation with ether, then washing with fresh ether and drying under vacuum.

  The biodegradable polymer scaffold is then grafted onto the scaffold as described above by reaction with a suitable stimulus-responsive molecule as described above. Therefore, the stimulus-responsive pendant group is bonded to the biodegradable polymer skeleton via a functional group.

In some forms, the stimulus responsive molecule can be an N-substituted acrylamide.
The stimulus responsive molecule can have the structure of Formula XVII.

Formula XVII:

In the above, R ₈ is hydrogen, hydroxyl, halide, thiohydroxyl or hydrocarbyl.
R ₉ is
(I) a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkenylene, optionally containing one or more heteroatoms, or any one or more heteroatoms selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkynylene, comprising:
(Ii) -R < ₁₁ > -M-R < ₁₂ >-
Wherein R ₁₁ is bonded to —N (R ₁₀ ) — and optionally includes one or more heteroatoms selected from the group consisting of N, O and S, substituted or non- Substituted C _1-6 alkylene, or substituted or unsubstituted C _2-6 alkenylene, optionally containing one or more heteroatoms selected from the group consisting of N, O and S;
M is CH or N;
R ₁₂ is a substituted or unsubstituted C _1-28 alkyl optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S Substituted or unsubstituted _C2-28 alkenyl optionally containing one or more heteroatoms selected; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted _C2-28 alkynyl. ).

R ₁₀ is
(I) hydrocarbyl, or (ii) when R ₉ is —R ₁₁ —M—R ₁₂ —, R ₁₀ is also bonded to M and is selected from the group consisting of N, O and S 1 or Substituted or unsubstituted C _1-6 alkylene, optionally containing two or more heteroatoms, or optionally containing one or more heteroatoms selected from the group consisting of N, O and S And a nitrogen atom to which R ₁₀ , M, R ₁₁ , and R ₉ and R ₁₁ are bonded is a saturated or unsaturated 4- to 12-membered complex, which is a substituted or unsubstituted C _2-6 alkenylene. A ring is formed.

However, in the above formula XVII, R ₈ , R ₉ and R ₁₀ have a C═C double bond conjugated to a primary amino group, a secondary amino group, a tertiary amino group, or a carbonyl group. I can't.

  Conventionally, several N-substituted acrylamide monomers are commercially available. N-substituted acrylamide monomers that can be used in the production of the stimulus-responsive polymer of the present invention include N-isopropylacrylamide, N, N′-diethylacrylamide, 2-carboxyisopropylamide, N- (L)-( 1-hydroxymethyl) propylmethacrylamide, and N-acryloxyl-N′-alkylpiperazines are included.

  The ratio of biodegradable polymer to stimulus responsive molecule can be from about 10: 1 to about 1: 4, or from about 5: 1 to about 1: 2.

  The grafting reaction is performed under suitable reaction conditions between complementary functional groups that can react between the stimulus-responsive pendant molecule and the biodegradable polymer.

  The grafting reaction can be carried out under a wide range of temperatures and pressures, although the reaction time becomes longer at low temperatures. For example, the reaction can be carried out at a temperature of about −20 ° C. to about 150 ° C.

  Preferably, the biodegradable polymer grafting reaction is performed in the presence of a suitable solvent, and the solvent is selected based on the particular biodegradable polymer and the stimulus-responsive pendant group molecule.

  Solvents that can be used in the grafting reaction with poly (aminoesters) include dimethyl sulfoxide, dimethylformamide, dimethylacetamide, chloroform, dichloromethane, methyl chloride, tetrahydrofuran, toluene, benzene, and carbon tetrachloride.

  The grafting reaction of poly (amidoamine) is carried out using a solvent such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, methanol, ethanol, isopropanol, 1-propanol, 1-butanol and water.

  The degree of grafting of the stimulus-responsive pendant group that is grafted onto the biodegradable polymer can be changed by changing the type of stimulus-responsive molecule used and the amount of the molecule present during the reaction. For example, if the stimulus-responsive monomer is present in excess, the degree of grafting of the stimulus-responsive pendant group in the biodegradable polymer tends to increase. Furthermore, low steric hindrance of secondary amino groups in the biodegradable polymer, higher reaction temperature, longer reaction time, and selection of a suitable solvent promote the grafting reaction, The degree of grafting of the stimuli-responsive pendant group can be increased.

  As described above, the stimulus-responsive biodegradable polymer can be formed into a hydrogel by cross-linking the stimulus-responsive polymer using a cross-linking agent, which includes diacrylate, diacrylamide, Cross-linking molecules such as dibromo or diiodo compounds are included.

  As described above, to form a hydrogel, a cross-linked molecule is linked via a poly (amino ester) skeleton and a functional group on the skeleton by reacting a stimulus-responsive biodegradable polymer with a suitable cross-linking molecule. Can be reacted. In this way, the bridging group binds via a reaction between the bridging molecule and the complementary functional group on the biodegradable polymer backbone.

  The cross-linking reaction can be performed using standard chemical techniques, and the method can depend on cross-linking molecules and specific functional groups in the biodegradable polymer backbone. For example, diacrylate or diacrylamide can react with secondary amino groups in the polymer backbone by Michael addition. Alternatively, secondary amino groups in the backbone can be alkylated using dibromo or diiodo reagents.

Thus, the bridging molecule can have the structure of formula XVIII or XIX.
Formula XVIII or XIX:

x is O or NH.
y is Br or I.
R ₁₃ and R ₁₅ are independently hydrogen, hydroxyl, halide, thiohydroxyl or hydrocarbyl.

  Conventionally, diacrylate that can be used as a cross-linking molecule that reacts with a stimulus-responsive polymer has been commercially available. 1,4-butanediol diacrylate, 1,4-butanediol dimethacrylate, 1,2-ethane Examples include diol diacrylate, 1,6-hexanediol diacrylate, 2,5-hexanediol diacrylate, poly (ethyl glycol) diacrylate, ethylene diacrylate, and 1,3-propanediol diacrylate.

  Similarly, diacrylamide that can be used as a cross-linking molecule that reacts with a stimulus-responsive polymer is commercially available, 1,4-bis (acryloyl) piperazine, N, N′-bis (acryloyl) cystamine, N, N'-methylenebisacrylamide and N, N '-(1,2-dihydroxyethylene) bisacrylamide are mentioned.

  Dibromo and diiodo reagents that can be used as crosslinking molecules that react with stimuli-responsive polymers are also commercially available, 1,3-dibromo-2-propanol, 1,4-dibromo-2-butanol, 1,5- Examples include dibromopentane, 1,6-dibromohexane, 1,5-diiodopentane, 1,8-dibromooctane, 1,6-diiodohexane, and 1,8-diiodooctane.

  The ratio of stimuli-responsive polymer to cross-linking molecule can be about 20: 1 to about 1: 2, or about 10: 1 to 1: 1.

  The cross-linking reaction is performed under suitable reaction conditions between complementary functional groups that can react between the cross-linking molecule and the biodegradable polymer.

  Stimulus responsive biodegradable polymers can also be amphiphilically modified to form polymeric micelles. The amphipathic stimulus-responsive polymer of the present invention can be produced by introducing a hydrophobic group into a biodegradable polymer skeleton.

  Hydrophobic group introduction method includes Michael addition of hydrophobic acrylate or acrylamide to secondary amine in biodegradable polymer skeleton, nucleophilic substitution reaction of secondary amine in polymer skeleton with acrylic chloride, And alkylation or quaternization of secondary and tertiary amines in the biodegradable polymer backbone using monobromo or monoiodo reagents.

Hydrophobic acrylates or acrylamides may have the structure shown in Formula XX below, where x = O is an acrylate and x = NH is acrylamide. The acyl chloride can have the structure shown in Formula XXI and the monobromo or monoiodo reagent can have the structure shown in Formula XXII.

In formulas XX, XXI and XII, x is O or NH.
R ₁₇ is a hydrophobic hydrocarbyl group. R ₁₇ may be a synthetic hydrophobic group or a naturally occurring hydrophobic group. It will be appreciated that R ₁₇ should be selected to be low toxic and biocompatible.

Accordingly, suitable values for R ₁₇ include substituted or unsubstituted C _3-30 alkyl, substituted or unsubstituted C _4-30 alkenyl, substituted or unsubstituted C _4-30 alkynyl, One or more heteroatoms which are substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted C _6-18 aryl, each selected from the group consisting of N, O and S May optionally be included.

  Conventionally, acrylates that can be used as hydrophobic pendant groups in the amphipathic stimulus-responsive poly (amino ester) are commercially available, such as 4-tert-butylcyclohexyl acrylate, 2-butoxyethyl acrylate, hexyl acrylate, Examples include 2-ethylhexyl acrylate, octadecyl acrylate, and lauryl acrylate.

  Acrylamides that can be used are commercially available and include diacetone acrylamide, N- (butoxymethyl) acrylamide, and N- (isobutoxymethyl) acrylamide.

  Acyl chlorides that can be used are commercially available and include cholesteryl chloroformate, nanonoyl chloride, undecanoyl chloride, lauroyl chloride, 4-heptylbenzoyl chloride, and myristoyl chloride.

  Monobromo and monoiodo reagents that can be used are commercially available and include 1-bromo-2-cyclohexylethane, 1-bromooctane, 1-adamantyl bromomethyl ketone, 2-bromo-2 ′, 5′-dimethyloxyacetophenone, 1-bromo-3,7-dimethyloctane, 1-bromododecane, 1-bromooctane, 1-bromodecane, 1-bromooctadecane, 2- (6-bromohexyloxy) tetrahydro-2H-pyran, 1-iodoadamantane, Examples include 1-iodohexane, 1-iodooctane, 1-iododecane, 1-iodododecane, or 1-iodooctadecane.

  The ratio of the stimulus-responsive polymer to the hydrophobic molecule can be about 20: 1 to about 1: 4, or about 10: 1 to about 1: 1.

  The grafting reaction is performed under suitable reaction conditions between complementary functional groups that can react between the hydrophobic molecule and the biodegradable polymer.

  The stimulus-responsive polymer of the present invention can be highly soluble in an aqueous solution, for example. Furthermore, the stimulus-responsive polymer of the present invention can be easily decomposed in an aqueous solution by hydrolysis of an ester bond, and is highly biodegradable. The stimulus-responsive polymer described above can be designed to be biocompatible. That is, the poly (amino ester) or poly (amidoamine) backbone is low cytotoxic and can be stimulated responsive poly (amino) by appropriate selection of stimuli responsive pendant groups and possible bridging or hydrophobic pendant groups. Esters) or poly (amidoamines) can be broken down into non-toxic by-products.

  Because of biodegradability and biocompatibility, biodegradable polymers are useful as excellent vectors for delivering bioactive agents such as drugs, proteins and DNA to cells and as excellent scaffolds in regenerative medicine. . For example, hydrogels formed using stimuli-responsive polymers can be used as scaffolds or supports for tissue growth in regenerative medicine applications.

  In order to deliver the bioactive agent, the stimulus-responsive biodegradable polymer contacts the specific reagent to be delivered to form a complex.

  If the bioactive agent is hydrophilic or has a hydrophilic region, it can be linked to the charged or hydrophilic region of the stimulus-responsive polymer via electrostatic or hydrogen bonding interactions. Bioactive agents, such as nucleic acids and proteins, can be covalently attached to stimuli-responsive macromolecules for delivery to cells or organic tissues.

  When the bioactive agent is hydrophobic or has a hydrophobic region, it is encapsulated and encapsulated within the inner core of a polymeric micelle formed using a stimulus responsive reagent. Micelles can be formed by dispersing an amphiphilic stimulus-responsive biodegradable polymer in an aqueous solution with a bioactive agent encapsulated by encapsulation. The amphiphilic polymer may include a hydrophobic bioactive agent in the inner core if it self-assembles to form micelles and includes the hydrophobic bioactive agent in the dispersion.

  Since micelles can be formed from stimuli-responsive macromolecules, they can be delivered to a subject in a non-swelling state with a bioactive agent, and once delivered to the subject can be exposed to stimuli that cause the macromolecule to swell, In this way, the release of the bioactive agent at an appropriate site within the subject body is facilitated.

  Alternatively, the bioactive agent can be included in a hydrogel formed from a cross-linking stimulus responsive biodegradable polymer. The bioactive agent is contained within the hydrogel and delivered to the body of interest. After being delivered, the hydrogel can be exposed to stimuli that cause release of the bioactive agent from the hydrogel, for example, by swelling the hydrogel.

  The bioactive agent that can be delivered using the stimulus-responsive biodegradable polymer can be a therapeutic, diagnostic or prophylactic agent. Reagents can be, for example, small molecules, organometallic compounds, nucleic acids, proteins, peptides, polynucleotide metals, isotope-labeled chemical compounds, drugs, vaccines, immunological agents, and the like. Reagents can be described as a single entity or a compound, or a combination of independent and compound.

  In one form, the bioactive agent is a compound having pharmacological activity, such as a clinically useful drug. Suitable drugs include, but are not limited to, antibiotic preparations, antiviral drugs, anesthetics, steroid drugs, anti-inflammatory drugs, antitumor drugs, antigenic drugs, vaccines, antibodies, decongestants, antihypertensives, Contains sedatives, contraceptives, luteinizing hormones, anticholinergics, analgesics, antidepressants, antipsychotics, diuretics, cardiovascular agents, vasoactive agents, non-steroidal anti-inflammatory agents, or nutritional agents .

  The bioactive agent delivered may be a reagent used in diagnosis or screening. Diagnostic agents that can be delivered in vivo by stimuli-responsive poly (amino esters) include gas, metal, positron emission tomography (PET), computed tomography (CAT), x-ray, fluoroscopy, magnetic resonance imaging ( Commercially available imaging agents used in MRI) as well as contrast agents are included. Examples of suitable materials for use as contrast agents in MRI include gadolinium chelates and iron, magnesium, manganese, copper, and chromium, or chelates thereof. Examples of substances useful for CAT and X-ray images include iodine-based substances.

  Prophylactic agents that can be delivered by the biodegradable polymers of the present invention include, but are not limited to, antibiotics, nutrients and vaccines. A vaccine may contain isolated proteins or peptides, inactive organisms and viruses, inactivated organisms and viruses, genetically modified organisms or viruses, and cell extracts.

  In one form, the bioactive agent delivered by the stimulus-responsive biodegradable polymer is a polynucleotide. The polynucleotide may be any nucleic acid, including but not limited to RNA and DNA. The polynucleotide can be of any size and sequence and can be single-stranded or double-stranded. The polynucleotide may be, for example, 1000 or more base pairs long, and may be more than 10,000 base pairs long. In many cases, the polynucleotide can be purified prior to use and is substantially free of impurities. That is, the polynucleotide preferably has a purity of greater than about 50%, more preferably a purity of greater than about 75%, and particularly preferably a purity of greater than about 95%. The polynucleotide can be obtained by any means known in the art. In particular, polynucleotides can be designed using recombinant techniques. Alternatively or additionally, polynucleotides can be obtained from natural sources and purified from contaminating components that are commonly found in nature. Alternatively, the polynucleotide can be chemically synthesized in the laboratory. For example, polynucleotides are synthesized using standard solid phase chemistry. A polynucleotide can be modified by chemical or biological techniques, for example, to increase the stability of the polynucleotide. Examples of polynucleotide denaturation methods include methylation, phosphorylation, and end capping. Derivatives of polynucleotides can also be used in the present invention. These derivatives include base, sugar, and / or phosphate linkages of the polynucleotide.

  In one form, the biodegradable polymer drug complex is formed through contact of the polynucleotide or salt thereof with the biodegradable polymer of the present invention. For this purpose, the biodegradable polymer is preferably at least partially protonated in order to interact electrostatically with a negatively charged polynucleotide. The biodegradable polymer, for example, solubilizes poly (amino ester) or poly (amidoamine) in an aqueous solution at a pH suitable for protonating at least secondary amines present in the biodegradable polymer. Can be solubilized. The biodegradable polymer-polynucleotide complex can form nanoparticles that can be used later to deliver the polynucleotide to the cell. The biodegradable polymer-polynucleotide complex can be used to protect the polynucleotide to at least partially inhibit degradation during the delivery and uptake process. By neutralizing the charge of the polynucleotide backbone, neutral or slightly positively charged biodegradable polymer-polynucleotide complexes can more easily pass through hydrophobic cell membranes.

  In various forms, the biodegradable polymer-drug conjugates of the present invention can be used therapeutically in pharmaceutical compositions or drugs to prevent or treat various diseases. The present invention provides a method corresponding to drug therapy, in which the dosage of a stimulus-responsive biodegradable polymer-bioactive agent complex requires, for example, a pharmaceutically acceptable formulation. Administered to a patient or subject. Accordingly, the present invention also provides a pharmaceutical composition comprising a bioactive compound complexed with a stimulus-responsive biodegradable polymer and a pharmaceutically acceptable excipient or carrier. The pharmaceutical composition can be soluble in an aqueous solution at a physiologically acceptable pH.

  Depending on the intended method of administration, the form of the pharmaceutical composition can be a solid, semi-solid, or liquid dosage form such as a tablet, suppository, tablet, capsule, powder, liquid, suspension, lotion, cream, A gel or the like, preferably in a unit dose suitable for single administration of the correct dose. As pointed out above, the composition may contain an effective amount of the drug selected in combination with a pharmaceutically acceptable single substance, and further contains other drugs, pharmaceuticals, single substances, adjuvants, diluents and the like. May be included.

  Administration in vivo can be performed by parenteral administration, for example, by intravenous injection including local perfusion through blood vessels supplying cells or organs with the target cells. Other means of administration include aerosol inhalation, subcutaneous injection, intraperitoneal administration, intramuscular injection, such as direct transfection into bone marrow cells prepared for transplantation into an organ that is later transplanted into a subject. Can be mentioned. Furthermore, administration methods include oral administration, particularly when the complex is encapsulated, or rectal administration, particularly when the complex is in the form of a suppository.

  “Therapeutically effective amount” refers to an amount effective to achieve the desired therapeutic effect at the required dosage and duration. Any therapeutically effective amount of a particular drug can vary depending on factors such as the condition, age, sex, individual weight, and the ability of the compound to elicit the desired response in the individual. Dosage regimes may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount also has a therapeutically beneficial effect that exceeds the toxic or harmful effects of the compound. A “prophylactically effective amount” refers to an amount effective to achieve a desired prophylactic effect that suppresses or prevents the onset or progression rate of a disease at the required dose and duration. A prophylactically effective amount can be determined as described above for the therapeutically effective amount. For a particular subject, specific dosage regimens can be adjusted over time according to the needs of the individual and professional judgment by those skilled in the art of administering or managing the composition.

  Pharmaceutically acceptable carriers or excipients used in the present invention include all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. Is included. In one form, the carrier is suitable for parenteral administration. Alternatively, the carrier may be suitable for intravenous, intraperitoneal, intramuscular, sublingual or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such pharmaceutically acceptable carriers or excipients for pharmaceutically active substances is well known in the art. Except where conventional pharmaceutically acceptable carriers and excipients are incompatible with the active compound, its use in the pharmaceutical compositions of the present invention is contemplated. Supplementary active compounds can also be included in the compositions.

  A pharmaceutical composition typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, lyophilized powder, spray-dried powder, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the desired particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents in the composition, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. In addition, the poly (amino ester) -drug complex can be administered in a sustained release formulation, eg, a composition containing a sustained release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release preparation, including implants and microencapsulated delivery systems. For this purpose, biodegradable, biocompatible polymers can be used including, but not limited to, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic acid. Lactic acid, polyglycolic acid copolymer (PLG) are included. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art.

  Sterile injectable solutions can be prepared by including a poly (amino ester)-, or poly (amidoamine) -drug complex, in one or a combination of the above-listed components, in the desired amount in a suitable solvent. . Generally, dispersions are prepared by including the active ingredient in a sterile vehicle that contains a basic dispersion medium and the desired other ingredients selected from those listed above. In sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is to obtain the active ingredient and further additional desired ingredient powders from their pre-sterilized solutions by vacuum drying, freeze drying and spray drying. It is. According to another aspect of the present invention, the biodegradable polymer-drug complex can be prepared with one or more additional compounds that increase the solubility of the biodegradable polymer-drug complex.

  According to another aspect of the present invention, a pharmaceutical composition containing a stimulus-responsive biodegradable polymer-bioactive agent complex is biodegraded for therapeutic use such as prevention and / or treatment of various diseases. Can be provided in a container or commercial package further comprising precautions for use of the functional polymer-drug complex.

  Accordingly, the present invention further comprises a commercial package comprising a stimulus-responsive biodegradable polymer-bioactive agent complex, or a composition as described above, and instructions for the prevention and / or treatment of a related disease, and / or Or provide packaging or containers.

The terms “including” or “including” as used in this disclosure represent a non-limiting meaning. Therefore, it indicates that a specific element or feature is included without excluding other specific elements or features.
The invention is further illustrated by the following non-limiting examples.

Materials and reagents:
1- (2-aminoethyl) piperazine (AEPZ), poly (ethylene glycol) diacrylate (Mn = 258), N-isopropylacryl-amide (NIPAAm), 1,6-diiodohexane (DIH), and cholesteryl chloro Formate (CEC) was purchased from Aldrich (Milwaukee, Wis., USA) and used without further purification.
All other materials including the solvent were used as received, ie without further purification.

General properties:
¹ H-NMR studies were performed on a Bruker DRX-400 spectrometer using CDCl ₃ and D ₂ O as solvents. Two consecutive columns (Waters ULTRAHYDROGEL® 250, 200) using 0.5 M acetic acid / 0.5 M sodium acetate as eluent at a flow rate of 0.5 ml / min against a poly (ethylene oxide) standard; Gel permeation chromatography (GPC) was used in a Waters 2690 instrument with a Waters 410 refractive index detector. Ultraviolet and visible light spectra were obtained on a Shimazu 2501 PC spectrometer at room temperature. Reference samples were pure deionized water or 1x PBS buffer. Fluorescence measurements were performed on a Perkin-Elmer LS 50B photoluminescence spectrometer with a xenon lamp as the light source.

Example 1: Synthesis and properties of linear poly (amino ester) poly (PEG258DA-AEPZ) AEPZ (11.6 mmol) was dissolved in 25 mL of dimethyl sulfoxide (DMSO) at room temperature. PEG258DA (11.6 mmol) was added dropwise to the solution with stirring, followed by 5 mL DMSO. The mixture was stirred at room temperature for about 48 hours. 0.2 g of N-methylpiperazine (NMP) was added and stirring was continued for 2 hours to seal the end vinyl groups. The product was precipitated from the reaction using 200 mL of diethyl ether with vigorous stirring. The polymer was collected and purified by reprecipitation from chloroform solution into diethyl ether and dried under vacuum at 50 ° C. for 24 hours.

  A water-soluble poly (amino ester) having an average molecular weight of 9900 g / mol having a broad molecular weight distribution index of 4.71 was obtained.

Example 2 Synthesis and Properties of Stimulus Responsive Polymer Poly (PEG258DA-AEPZ) -g-NIPAAm In a solution of poly (PEG258DA-AEPZ) (11.6 mmol) in 30 mL DMSO in a 100 mL round bottom flask. , NIPAAm (23.2 or 17.4 mmol) was added. The reaction was placed under argon protection at 80 ° C. for 1 week. The solution is then precipitated into 500 mL diethyl ether, the polymer is collected and purified by reprecipitation at 50 ° C. from a chloroform solution (10 mL) into a mixed solution containing 80 mL hexane and 20 mL toluene, It dried for 24 hours at 50 degreeC under vacuum.

The reactants produced different degrees of grafting of NIPPm. As shown in FIG. 2, ¹ H-NMR spectroscopy was performed to determine the degree of grafting from the characteristic relative peak ratio. As can be seen in FIG. 2, there are two types of hydrogen belonging to the isopropyl group of NIPAAm, 4.0 ppm (1H, CH (CH ₃ ) ₂ ) and 1.1 ppm (6H, CH (CH ₃ ) _{2, respectively.} ) Has a peak. In addition, a characteristic peak of one ester of poly (amino ester) is observed at 4.2 ppm (4H, COOCH ₂ CH _2- ).

Thus, the degree of grafting of NIPAAm can be determined by Equation 1.
GD _NIPAA = 2I _1.1 / 3I _4.2 * 100% or 4I _4.0 / I _4.2 * 100% Equation 1
As shown in FIGS. 2A and 2B, the degree of grafting of NIPAAm after reacting NIPAAm and poly (PEG258DA-AEPZ) at a molar ratio of 2: 1 and 1.5: 1 for one week at 80 ° C. , About 100% and 46%, respectively.

The resulting poly (PEG258DA-AEPZ) -g-NIPAAm was tested for degradability. FIG. 3 shows the ¹ H-NMR spectrum of poly (PEG258DA-AEPZ) -g-NIPAAm _0.46 in aqueous solution. Upon hydrolysis of the ester group, the peak was attributed to protons attached to the α carbon adjacent to the ester group, from about 4.2 ppm to about 3.6 ppm. Thus, the degree of hydrolysis can be monitored by the change in the intensity ratio of the two peaks, I _3.6 / (I _3.6 + I _4.2 ). In comparison, linear poly (PEG258DA-AEPZ) and poly (PEG258DA-AEPZ) -g-NIPAAm _1.0 were also tested for degradability. The total hydrolysis profile of the three polymers is shown in FIG. All polymers show similar hydrolysis profiles independent of the degree of grafting of NIPAAm, which may be due to the similar hydrophilicity of NIPAAm and poly (PEG258DA-AEPZ).

Example 3: Synthesis and Properties of Stimulus-Responsive Stimulus Degradable Polymer Poly (BAC / MBA-AEPZ) -g-NIPAAm First, linear poly (BAC / MBA-AEPZ) containing a secondary amine in the skeleton Manufactured. N, N-bis (acryloyl) cystamine (BAC, 1.915 mmol) and N, N-methylenebisacrylamide (MBA, 1.915 mmol) were dissolved in a mixed solvent of 8 mL of methanol and 2 mL of pure water at room temperature. . AEPZ (3.83 mmol) was added dropwise to the solution with stirring, followed by 2 mL of methanol. The mixture was stirred at 50 ° C. for about 48 hours. 0.1 g of N-methylpiperazine (NMP) was added and stirring was continued for 2 hours to seal the end vinyl groups. The product was precipitated from the reaction using 100 mL of cold acetone with vigorous stirring. The polymer was collected and purified by reprecipitation from methanol solution into chilled acetone and then dried under vacuum at 50 ° C. for 24 hours.

  NIPAAm (7.66 mmol) was added to a solution of poly (BAC / MBA-AEPZ) (3.83 mmol) in a mixed solvent of 10 mL methanol and 2 mL pure water in a 25 mL round bottom flask. The reaction was placed under argon protection at 50 ° C. for 6 days. The solution was then precipitated into 100 mL of cold acetone and the polymer was collected and purified by reprecipitation from methanol solution (10 mL) into cold acetone and dried at 50 ° C. under vacuum for 24 hours.

The reactants produced different degrees of grafting of NIPPm. As shown in FIG. 5, ¹ H-NMR spectroscopy was performed to determine the degree of grafting from the characteristic relative peak ratio. As seen in FIG. 5, there are two types of hydrogen attributed to the isopropyl group of NIPAAm, 3.8 ppm (1H, C H (CH ₃ ) ₂ ) and 1.1 ppm (6H, CH (C H ₃ ), respectively. ₂ ) There is a peak at position ₂ ) and as shown by the peaks at 4.4 ppm (2H, CONHC H ₂ NHCO) and 3.4 ppm (4H, CONHC H ₂ CH ₂ S-), MBA and BAC There are characteristic peaks of two amides in the repeating unit.

Therefore, the degree of grafting of NIPAAm when the molar ratio of BAC to MBA is n: m can be determined by Equation 2.
GD _NIPAAm = (n / (n + m)) * (2 * I _1.1 ) / (3 * I _3.4 ) Equation 2
As shown in FIG. 5, the degree of grafting of NIPAAm after reacting 2-fold molar NIPAAm with poly (BAC / MBA-AEPZ) at 50 ° C. for 6 days was about 70%.

Example 4: LCST analysis of stimulus-responsive polymers Poly (PEG258DA-AEPZ) -g-NIPAAm, Poly (BDA-AEPZ) -g-NIPAAm, and Poly (BAC / MBA-AEPZ) -g-NIPAAm (1 w / v%) solution was prepared in 1 × PBS buffer (pH = 7.4), 0.1 M NaAC / HAC buffer (pH 5) and citric acid / sodium hydroxide solution / sodium chloride buffer (pH 3). Visible light (λ = 500 nm) transmission was recorded as a function of solution temperature of 25-45 ° C. At the start of each experiment, the spectrophotometer was measured with pure PBS buffer solution. Once the transmission-temperature plot was obtained, the LCST was determined at the initial breakpoint of the curve.

As shown in FIG. 6, NIPAAm grafting degree of 100% and 46% is that poly (PEG258DA-AEPZ) -g-NIPAAm LCST is 33 ° C. and 36 ° C., respectively, while NIPAAm grafting degree is 15%. In LCST, LCST is deleted. As shown in FIG. 7, poly (BDA-AEPZ) -g-NIPAAm _0.6 has an LCST of 30.5, 31.0 and 34.5 ° C. at pH 7, 5, and 3, respectively. As shown in FIG. 8, poly _{(BAC 0.5 / MBA 0.5 -AEPZ)} -g-NIPAAm 0.7, poly _{(BAC 0.4 / MBA 0.6 -AEPZ)} -g-NIPAAm 0. ₇₆ and poly (BAC _0.33 / MBA _0.67 -AEPZ) -g-NIPAAm _0.8 have LCSTs of 34.5, 42.0 and 52.5 ° C., respectively, at pH 7.

Example 5: Preparation of stimulus-responsive hydrogel 0.17 g of 1,6-diiodohexane (DIH) is added to 0.5 g of poly (PEG258DA-AEPZ) -g-NIPAAm _1.0 solution in 10 mL of toluene. It was. The mixture was refluxed under argon protection. Two days later, a crosslinked hydrogel poly (PEG258DA-AEPZ) -g-NIPAAm-c-DIH was obtained. Washed 3 times with toluene to remove residual DIH and dried under vacuum at 50 ° C. for 24 hours.

Example 6: Poly _{(PEG258DA-AEPZ) -g-NIPAAm} 0.46 Synthesis 0.5g amphiphilic stimuli-responsive polymer was dissolved in anhydrous CHCl ₃ in 10 mL. 0.5 g cholesteryl chloroformate (CEC) and 0.18 mL triethyleneamine (TEA) were added to the solution and stirred at room temperature for 2 days under argon. After the reaction, the solution was precipitated into 100 mL diethyl ether with vigorous stirring. The polymer was collected and purified by reprecipitation from chloroform solution into diethyl ether and then dried at 50 ° C. under vacuum.

FIG. 11 is ¹ H-NMR spectroscopy of poly (PEG258DA-AEPZ) -g-NIPAAm-CEC at 0.6 ppm (signal g), 4.5 ppm (signal e), 5.4 ppm (signal f). A characteristic peak of CEC is shown. The degree of grafting of CEC in poly (PEG258DA-AEPZ) -g-NIPAAm-CEC was determined from the ratio of characteristic relative peaks as shown in Equation 3.

GD _CEC = 4I _5.4 / I _4.2 * 100% Equation 3
Therefore, the degree of grafting of CEC was calculated at 48% based on FIG.
Example 7: Determination of critical micelle concentration (CMC) of poly (PEG258DA-AEPZ) -g-NIPAAm _0.46 -CEC _0.48 An aliquot of pyrene solution (in 10 μg / mL acetone) is added to a 4 mL screw bottle. Acetone was evaporated. Then 4 mL of 0.1-200 mL of poly (PEG258DA-AEPZ) -g-NIPAAm _0.46- CEC _0.48 solution was added to the bottle containing the pyrene residue, so that all solutions were 0.1 μg Pyrene concentration greater than / mL. The solution was allowed to equilibrate overnight at room temperature before obtaining a fluorescence spectrum using an LS50B luminescence spectrometer (Perkin Elmer, USA).

Excitation spectra (300-360 nm) were recorded at an emission wavelength of 395 nm. The excitation and emission bandwidths were 3 nm. The ratio of peak intensities (I ₃₃₈ / I ₃₃₃ ) at ₃₃₈ nm and 333 nm in the excitation spectrum was analyzed as a function of polymer concentration. As shown in FIG. 12, the CMC value was 3.1 mg / L from the intersection of the tangent of the curve in the inflection and the horizontal tangent passing through the point at the low concentration.

Example 8: Poly _{(PEG258DA-AEPZ)} solution of LCST analysis poly _{(PEG258DA-AEPZ) -g-NIPAAm} 0.46 -CEC 0.48 of _{-g-NIPAAm 0.46 -CEC 0.48 (1w} / v% ) Was prepared at pH 7.4 in 1x PBS buffer. Visible light (λ = 500 nm) transmission was recorded as a function of solution temperature of 30-45 ° C. At the start of each experiment, the spectrophotometer was measured with pure PBS buffer solution. Once the transmission-temperature plot was obtained, the LCST was determined at the initial breakpoint of the curve.

As shown in FIG. 13, poly (PEG258DA-AEPZ) -g-NIPAAm _0.46 -CEC _0.48 is also at 36.5 ° C., similar to poly (PEG258DA-AEPZ) -g-NIPAAm _0.46. Shows the LCST. However, the transmissivity over LCST does not decrease sharply due to the amphiphilic poly (PEG258DA-AEPZ) -g-NIPAAm _0.46 -CEC _0.48 , which indicates rapid aggregation of polymer particles. Due to the formation of micelles in the aqueous solution to block.

  As will be appreciated by those skilled in the art, various modifications to the specific forms described in the present disclosure are possible. The invention is intended to cover all such modifications within the scope of the invention as defined in the claims.

  The form of the invention is illustrated in the drawings by way of example only.

FIG. 1 is a schematic representation of two possible structures of a stimuli-responsive polymer of the present invention that can be formed by reacting a diamine monomer with bis (acrylate ester) and grafting a thermoresponsive group. FIG. 2 shows the reaction of N-aminoethylpiperidine (AEPZ) and poly (ethylene glycol) diacrylate (Mn = 258) (PEG258DA) and then linear poly (PEG258DA-AEPZ) with N-isopropylacrylamide. It is the expanded ¹ H-NMR spectrum of poly (PEG258DA-AEPZ) -g-NIPAAm formed by this. A is NIPAAm with a grafting degree of 100%, and B is NIPAAm with a grafting degree of 46%. FIG. 3 shows the ¹ H-NMR spectrum of poly (PEG258DA-AEPZ) -g-NIPAAm _0.46 after holding in water for 2 hours for A and 70 hours for B. FIG. 4 is a hydrolysis profile of a polymer in water.

a) Poly (PEG258DA-APEZ),
b) Poly (PEG258DA-AEPZ) -g-NIPAAm _0.46 ,
c) Poly (PEG258DA-AEPZ) -g-NIPAAm _1.0 .
FIG. 5 shows a mixture of N-aminoethylpiperidine (AEPZ) and N, N-bis (acryloyl) cystamine (BAC) and N, N-methylenebisacrylamide (MBA), AEPZ: BAC: MBA 2: NIPAAm 70% graft degree poly (BAC _0.5 / n) formed by reacting in a 1: 1 molar ratio and then reacting linear poly (BAC / MBA-AEPZ) with N-isopropylacrylamide. It is the expanded ¹ H-NMR spectrum of MBA _0.5 -AEPZ) -g-NIPAAm. FIG. 6 shows the transmittance of a 1% (w / v) aqueous solution of poly (PEG258DA-AEPZ) -g-NIPAAm.

a) NIPPAm graft ratio: 15%
b) NIPPAm graft ratio: 46%
c) NIPPAm graft ratio: 100%.
FIG. 7 shows the reaction of N-aminoethylpiperidine (AEPZ) with 1,4-butanediol diacrylate (BDA) and then the reaction of linear poly (BDA-AEPZ) with N-isopropylacrylamide at different pH conditions. The transmittance of a 1% (w / v) aqueous solution of poly (BDA-AEPZ) -g-NIPAAm _0.6 formed.

a) pH 7,
b) pH 5,
c) pH3.
FIG. 8 shows a) poly (BAC _0.5 / MBA _0.5 -AEPZ) -g-NIPAAm _0.7 , b) poly (BAC _0.4 / MBA _0.6 -AEPZ) -g-NIPAAm _{0. 76} , c) transmittance of 1% (w / v) aqueous solution of poly (BAC _0.33 / MBA _0.67 -AEPZ) -g-NIPAAm _0.8 . FIG. 9 is a schematic representation of three possible structures of a stimulus-responsive biodegradable hydrogel that can be formed by crosslinking a thermo / pH-responsive polymer with diacrylate, diacrylamide, and dibromo or diiodo reagents. FIG. 10 shows the Michael addition of secondary amines in a poly (amino ester) backbone using acrylate and acrylamide, the acylation reaction of secondary amines and acyl chlorides in the poly (amino ester) backbone, and poly (amino Esters) Amphiphilic stimuli that can be formed by introducing hydrophobic groups into stimuli-responsive polymers via alkylation or quaternization reactions of secondary and tertiary amines in the backbone with monobromo or monoiodo reagents 3 is a schematic diagram of three possible structures of a responsive polymer. FIG. 11 is an expanded ¹ H-NMR spectrum of poly (PEG258-AEPZ) -g-NIPAAm _0.46- CEC _0.48 formed by the acylation reaction of a secondary amine using cholesteryl chloroformate. . FIG. 12 is a plot of I ₃₃₈ / I ₃₃₃ from the pyrene excitation spectrum as a function of poly (PEG258DA-AEPZ) -g-NIPAAm _0.46 -CEC _0.48 concentration. FIG. 13 shows a) the temperature dependence of the transmittance of an aqueous micelle solution formed in a 1% (w / v) aqueous solution of poly (PEG258DA-AEPZ) -g-NIPAAm _0.46 -g-CEC _0.48 , And b) shows temperature and pH effects on Rh of micelles formed in 0.05% (w / v) aqueous solution of poly (PEG258DA-AEPZ) -g-NIPAAm _0.46 -g-CEC _0.48. It is a graph.

Claims (25)

  A stimulus-responsive polymer comprising a biodegradable polymer skeleton and a stimulus-responsive pendant group pendant to the biodegradable polymer skeleton, wherein the biodegradable polymer skeleton comprises poly (amino ester) or poly ( A stimuli-responsive polymer, wherein the poly (amidoamine) optionally comprises a disulfide bond in the backbone.   2. The stimulus responsive high of claim 1, wherein the biodegradable polymer backbone comprises at least one secondary amine bond and at least one tertiary amine bond before pendant of the stimulus responsive pendant group. molecule.   The stimulus-responsive polymer according to claim 1, wherein the biodegradable polymer skeleton includes at least one secondary amine bond and at least one tertiary amine bond. Formula I:

A unit represented by
Formula II:

A unit represented by
Including one or more units each independently selected from
Optionally, Formula III:

Formula IV:

Formula V:

Formula VI:

And Formula VII:

Including one or more units each independently selected from
z is O or NH;
R ₁ , R ₃ and R ₈ are each independently hydrogen, hydroxyl, halide, thiohydroxyl or hydrocarbyl;
R ₂ is a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S A substituted or unsubstituted C _2-30 alkenylene optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally substituted, unsubstituted or substituted C _2-30 alkynylene;
R ₅ is
(I) a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkenylene optionally containing 1 or 2 or more heteroatoms; or optionally 1 or 2 or more heteroatoms selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkynylene, comprising:
(Ii) -R < ₆ > -MR < ₇ >-
Wherein R ₆ is bonded to —N (R ₄ ) — and optionally includes one or more heteroatoms selected from the group consisting of N, O and S, substituted or non- Substituted C _1-6 alkylene, or substituted or unsubstituted C _2-6 alkenylene, optionally containing one or more heteroatoms selected from the group consisting of N, O and S;
M is CH or N;
R ₇ is a substituted or unsubstituted C _1-28 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S A substituted or unsubstituted _{C2-28alkenylene} optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted _C2-28 alkynylene. ) And
R ₄ is
(I) hydrocarbyl or
(Ii) When R ₅ is —R ₆ —M—R ₇ —, R ₄ is also bonded to M, and one or more heteroatoms selected from the group consisting of N, O and S are Optionally substituted, unsubstituted or substituted C _1-6 alkylene, or substituted or unsubstituted, optionally including one or more heteroatoms selected from the group consisting of N, O and S C _2-6 alkenylene, and R ₄ , M, R ₆ , and the nitrogen atom to which R ₄ and R ₆ are bonded form a saturated or unsaturated 4- to 12-membered heterocyclic ring. ,
R ₉ is
(I) a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkenylene optionally containing 1 or 2 or more heteroatoms; or optionally 1 or 2 or more heteroatoms selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkynylene, comprising:
(Ii) -R < ₁₁ > -M-R < ₁₂ >-
Wherein R ₁₁ is bonded to —N (R ₁₀ ) — and optionally includes one or more heteroatoms selected from the group consisting of N, O and S, substituted or non- Substituted C _1-6 alkylene, or substituted or unsubstituted C _2-6 alkenylene, optionally containing one or more heteroatoms selected from the group consisting of N, O and S;
M is CH or N;
R ₁₂ is a substituted or unsubstituted C _1-28 alkyl optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S Substituted or unsubstituted _C2-28 alkenyl optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted _C2-28 alkynyl. ) And
R ₁₀ is
(I) hydrocarbyl, or (ii) when R ₉ is —R ₁₁ —M—R ₁₂ —, R ₁₀ is also bonded to M and is selected from the group consisting of N, O and S 1 or Substituted or unsubstituted C _1-6 alkylene, optionally containing two or more heteroatoms, or optionally containing one or more heteroatoms selected from the group consisting of N, O and S And a nitrogen atom to which R ₁₀ , M, R ₁₁ , and R ₉ and R ₁₁ are bonded is a saturated or unsaturated 4- to 12-membered complex, which is a substituted or unsubstituted C _2-6 alkenylene. Forming a ring;
However, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₈ , R ₉ and R ₁₀ are C═C 2 conjugated to a primary amino group, a secondary amino group, or a carbonyl group. It cannot have a double bond. ),
The stimulus-responsive polymer according to claim 1.   The stimulus-responsive polymer according to claim 1, wherein the stimulus-responsive polymer is responsive to pH, light, temperature, or ionic strength. The stimulus-responsive pendant group is of formula X:

(Where
R ₈ is hydrogen, hydroxyl, halide, thiohydroxyl or hydrocarbyl;
R ₉ is
(I) a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkenylene, optionally containing one or more heteroatoms, or any one or more heteroatoms selected from the group consisting of N, O and S Substituted or unsubstituted C _2-30 alkynylene, comprising:
(Ii) -R < ₁₁ > -M-R < ₁₂ >-
(Wherein R ₁₁ is
A substituted or unsubstituted C _1-6 alkylene bonded to —N (R ₁₀ ) — and optionally containing one or more heteroatoms selected from the group consisting of N, O and S; Or substituted or unsubstituted C _2-6 alkenylene, optionally containing one or more heteroatoms selected from the group consisting of N, O and S;
M is CH or N;
R ₁₂ is a substituted or unsubstituted C _1-28 alkyl optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S Substituted or unsubstituted _C2-28 alkenyl optionally containing one or more heteroatoms selected; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted _C2-28 alkynyl. ) And
R ₁₀ is
(I) hydrocarbyl, or (ii) when R ₉ is —R ₁₁ —M—R ₁₂ —, R ₁₀ is also bonded to M and is selected from the group consisting of N, O and S 1 or Substituted or unsubstituted C _1-6 alkylene, optionally containing two or more heteroatoms, or optionally containing one or more heteroatoms selected from the group consisting of N, O and S And a nitrogen atom to which R ₁₀ , M, R ₁₁ , and R ₉ and R ₁₁ are bonded is a saturated or unsaturated 4- to 12-membered complex, which is a substituted or unsubstituted C _2-6 alkenylene. Forming a ring;
However, R ₈ , R ₉ and R ₁₀ cannot have a C═C double bond conjugated to a primary amino group, a secondary amino group, a tertiary amino group, or a carbonyl group. )
The stimulus-responsive polymer according to claim 1, having the structure:   The stimulus-responsive group is a reactive N-isopropylacrylamide, N, N′-diethylacrylamide, 2-carboxyisopropylamide, N- (L)-(1-hydroxymethyl) propylmethacrylamide, or N-acryloxyl-N′-alkyl. The stimulus-responsive polymer according to claim 5, which is piperazine.   The stimulus-responsive polymer according to claim 1, further comprising a hydrophobic pendant group. The hydrophobic pendant group is of formula XII:

Formula XIII:

Or Formula XIV:

(Where
x is O or NH;
R ₁₇ is substituted or unsubstituted C _3-30 alkyl, substituted or unsubstituted C _4-30 alkenyl, substituted or unsubstituted C _4-30 alkynyl, substituted or unsubstituted C _3-8 cycloalkyl, substituted or unsubstituted C _6-18 aryl, any of which may optionally contain one or more heteroatoms selected from the group consisting of N, O and S. )
The stimuli-responsive polymer according to claim 8, which has the following structure.   Hydrophobic pendant groups are reacted 4-tert-butylcyclohexyl acrylate, 2-butoxyethyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, octadecyl acrylate, lauryl acrylate, diacetone acrylamide, N- (butoxymethyl) acrylamide, N- (Isobutoxymethyl) acrylamide, cholesteryl chloroformate, nanonoyl chloride, undecanoyl chloride, lauroyl chloride, 4-heptylbenzoyl chloride, myristoyl chloride, 1-bromo-2-cyclohexylethane, 1-bromooctane, 1-adamantyl Bromomethyl ketone, 2-bromo-2 ′, 5′-dimethyloxyacetophenone, 1-bromo-3,7-dimethyloctane, 1-bromododecane, -Bromooctane, 1-bromodecane, 1-bromooctadecane, 2- (6-bromohexyloxy) tetrahydro-2H-pyran, 1-iodoadamantane, 1-iodohexane, 1-iodooctane, 1-iododecane, 1-iodo The stimulus-responsive polymer according to claim 8, comprising dodecane or 1-iodooctadecane.   A composition comprising the stimulus-responsive polymer according to claim 1 and a crosslinking group. The polymer is of formula XI:

(Where
x is O or NH;
R ₁₃ and R ₁₅ are each independently hydrogen, hydroxyl, halide, thiohydroxyl, or hydrocarbyl;
R ₁₄ is a substituted or unsubstituted C _1-30 alkylene optionally containing one or more heteroatoms selected from the group consisting of N, O and S; from the group consisting of N, O and S A substituted or unsubstituted C _2-30 alkenylene optionally containing one or more selected heteroatoms; or one or more heteroatoms selected from the group consisting of N, O and S Optionally, substituted or unsubstituted C _2-30 alkynylene. )
The composition according to claim 11, which is crosslinked by a crosslinking group having the structure:   The cross-linking group is cross-linked 1,4-butanediol diacrylate, 1,4-butanediol dimethacrylate, 1,2-ethanediol diacrylate, 1,6-hexanediol diacrylate, 2,5-hexanediol diacrylate , Poly (ethyl glycol) diacrylate, ethylene diacrylate, 1,3-propanediol diacrylate, 1,4-bis (acryloyl) piperazine, N, N′-bis (acryloyl) cystamine, N, N′-methylenebis Acrylamide, N, N ′-(1,2-dihydroxyethylene) bisacrylamide, 1,3-dibromo-2-propanol, 1,4-dibromo-2-butanol, 1,5-dibromopentane, 1,6-dibromo Hexane, 1,5-diiodopentane, 1,8-dibromoo Tan, 1,6-diiodo hexane, or 1,8-including diiodooctane composition of claim 11.   The stimulus of claim 1, comprising reacting a biodegradable polymer comprising poly (amino ester) or poly (amidoamine) to form a polymer having a stimulus-responsive pendant group pendant to the polymer backbone. A method for producing a responsive polymer, wherein the poly (amidoamine) optionally has a disulfide bond in the polymer skeleton.   15. The method of claim 14, wherein the biodegradable polymer has at least one secondary amine bond and at least one tertiary amine bond in the backbone.   15. The method of claim 14, wherein the ratio of the biodegradable polymer unit to the stimulus responsive molecular unit is from about 10: 1 to about 1: 4.   The method according to claim 14, further comprising crosslinking a biodegradable polymer having a stimulus-responsive pendant group pendant to a polymer skeleton with a crosslinking molecule.   18. The method of claim 17, wherein the cross-linking molecule comprises a diacrylate, diacrylamide, or dibromo or diiodo reagent.   18. The method of claim 17, wherein the ratio of biodegradable polymer unit to cross-linked molecular unit is from about 20: 1 to about 1: 2.   The method according to claim 14, further comprising reacting a biodegradable polymer having a stimulus-responsive pendant group pendant on the polymer skeleton with a hydrophobic molecule to cause the polymer skeleton to pendant with a hydrophobic pendant group. Method.   21. The method of claim 20, wherein the ratio of biodegradable polymer unit to hydrophobic molecular unit is from about 20: 1 to about 1: 4.   A composition comprising the stimulus-responsive biodegradable polymer according to claim 1, or the composition according to claim 11, and a bioactive agent.   23. The composition of claim 22, wherein the bioactive agent comprises a small molecule, organometallic compound, nucleic acid, protein, peptide, polynucleotide metal, isotopically labeled compound, drug, vaccine, or immunizing agent.   23. The composition of claim 22, wherein the composition forms micelles.   24. The composition of claim 22, wherein the composition forms a hydrogel.

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