생체적합/생분해성을 가지는 하이드로젤과 사슬/고리형 양친매성 마이크로분자 : 나노/마이크로 기능성 재료와 약물전달을 위한 매트릭스 Biocompatible degradable hydrogels and chain/cyclic amphiphilic micromolecules: matrices for nano/micro functional materials and drug delivery원문보기
생체 적합성 및 분해성 교차 결합된 하이드로젤 및 양친매성 마이크로 분자들의 합성과 정의 및 응용에 대한 연구는 활발히 진행되어왔다. 분해성 인산 및 인산아미드와 가교결합되어 멀티아민기로 치환된 PEG 하이드로젤(CMPHs)의 결합 구조는 propane-1,3-diamine의 one-stop process 를 이용한 chain-terminating amination에 의해 여러가지 ...
생체 적합성 및 분해성 교차 결합된 하이드로젤 및 양친매성 마이크로 분자들의 합성과 정의 및 응용에 대한 연구는 활발히 진행되어왔다. 분해성 인산 및 인산아미드와 가교결합되어 멀티아민기로 치환된 PEG 하이드로젤(CMPHs)의 결합 구조는 propane-1,3-diamine의 one-stop process 를 이용한 chain-terminating amination에 의해 여러가지 작용기의 PEG-O-P(O)Cl2와 3-arm-PEG-NH2폴리머 사이에서 가교반응으로 성공적으로 생성된다. PEG 하이드로젤 제조를 위해 새롭게 고안된 프로토콜은 반응시간 단축, 대량 생산, 분리의 용이성, 그리고 높은 수율을 포함하여 이전의 방법들에 비해 장점들을 나타낸다. 우리는 약물 전달 시스템에서 항암약물 doxorubicin이 pH 4.0 이하에서 특히 방출의 향상성이 유지되는 긍정적인 결과들을 또한 증명하였다. 합성된 하이드로젤은 또한 다른 환원제가 없을 때 순수 금속 나노입자들(MNPs) (Au, Ag, Pd, Pt and Ru NPs)의 연속적인 합성을 위한 템플릿과 환원제로서 사용된다. 제조된 MNPs은 반응 손실 작용을 일으키는 응집을 피하여 하이드로젤 안에서 효과적으로 잘 분산된다. 금속 나노입자-촉매제로 사용되는 포화된 하이드로젤은수분을 함유한 환경에서 수소화붕소나트륨에 의한 높은 촉매작용으로 다양한 질소방향족물질을 줄이는 용도로 재사용이 가능하다. 새롭게 개발된 무독성 하이드로젤 템플릿에서 in-situ growth와 석화작용에 의해 칼슘 탄산염과 수산화인회석과 같은 생체모방형 혼합 재료의 제조를 위한 프로토콜이 개발되었다. 이온 전달률, pH, 하이드로젤의 종류 그리고 석화작용 온도와 같은 성장 조절과, 석화작용 조건들은 나노로드, 나노와이어, 그리고 선명한 혼합 구조물을 포함한 다양한 칼슘 탄산염과 수산화인회석 구조물을 야기한다. 우리는 또한 π–π stacking interaction과 수소 결합을 통해 구형, 나노/마이크로 튜브형 그리고 속 비어있는 구조의 범위 걸쳐 구조를 제어할 수 286 있는 나노/마이크로 물질 제작을 위한 자가 조립 방법을 제시하고자 한다. 나노 벨트의 고위 응집에 의해 형성된 마이크로 구형 물질은 높은 내열성을 나타낸다. 특별한 과정과 원인들이 상세히 설명되어졌다. 에탄올(ethanol)/물(water) (1/0.1 v/v) 용액(5 mg mL−1)에서 올레익아미드 파생물의 자가조립이 점차적인 온도를 감소와 용액의 휘발을 통하여 평균 직경이 10 um인 마이크로 구를 만든다. 제조된 마이크로 구조물들은 doxorubicin의 생체 외 방출을 위한 scaffold로 활용된다. 이 결과는 pH에 민감한 방출 과정이고, 특히 낮은 pH 5.2 환경에서 방출율이 높아짐을 증명한다. ~1um 직경과 ~10um 길이의 다중 채널의 마이크로 튜브들은 di(chlorocarbonyl)pyridine과 디아민 파생물의 간단한 응축 반응으로 통합된 일련의 여러 화합물을 바탕으로 한 피리딘의 자가조립을 통해 제작된다. Multiple pyridylcarboxamide그룹을 함유한 MMTs 결과는 물속에서 중금속 이온을 묶기 위한 효율적인 방법을 제공한다. MMTs를 제조하기 위한 상세한 자가 조립 과정은 수용액에서Cu2+, Ni2+ and Zn2+와 같은 중금속 이온들에 대한 상호간의 흡착력에 의해증명된다.
생체 적합성 및 분해성 교차 결합된 하이드로젤 및 양친매성 마이크로 분자들의 합성과 정의 및 응용에 대한 연구는 활발히 진행되어왔다. 분해성 인산 및 인산아미드와 가교결합되어 멀티아민기로 치환된 PEG 하이드로젤(CMPHs)의 결합 구조는 propane-1,3-diamine의 one-stop process 를 이용한 chain-terminating amination에 의해 여러가지 작용기의 PEG-O-P(O)Cl2와 3-arm-PEG-NH2폴리머 사이에서 가교반응으로 성공적으로 생성된다. PEG 하이드로젤 제조를 위해 새롭게 고안된 프로토콜은 반응시간 단축, 대량 생산, 분리의 용이성, 그리고 높은 수율을 포함하여 이전의 방법들에 비해 장점들을 나타낸다. 우리는 약물 전달 시스템에서 항암약물 doxorubicin이 pH 4.0 이하에서 특히 방출의 향상성이 유지되는 긍정적인 결과들을 또한 증명하였다. 합성된 하이드로젤은 또한 다른 환원제가 없을 때 순수 금속 나노입자들(MNPs) (Au, Ag, Pd, Pt and Ru NPs)의 연속적인 합성을 위한 템플릿과 환원제로서 사용된다. 제조된 MNPs은 반응 손실 작용을 일으키는 응집을 피하여 하이드로젤 안에서 효과적으로 잘 분산된다. 금속 나노입자-촉매제로 사용되는 포화된 하이드로젤은수분을 함유한 환경에서 수소화붕소나트륨에 의한 높은 촉매작용으로 다양한 질소방향족물질을 줄이는 용도로 재사용이 가능하다. 새롭게 개발된 무독성 하이드로젤 템플릿에서 in-situ growth와 석화작용에 의해 칼슘 탄산염과 수산화인회석과 같은 생체모방형 혼합 재료의 제조를 위한 프로토콜이 개발되었다. 이온 전달률, pH, 하이드로젤의 종류 그리고 석화작용 온도와 같은 성장 조절과, 석화작용 조건들은 나노로드, 나노와이어, 그리고 선명한 혼합 구조물을 포함한 다양한 칼슘 탄산염과 수산화인회석 구조물을 야기한다. 우리는 또한 π–π stacking interaction과 수소 결합을 통해 구형, 나노/마이크로 튜브형 그리고 속 비어있는 구조의 범위 걸쳐 구조를 제어할 수 286 있는 나노/마이크로 물질 제작을 위한 자가 조립 방법을 제시하고자 한다. 나노 벨트의 고위 응집에 의해 형성된 마이크로 구형 물질은 높은 내열성을 나타낸다. 특별한 과정과 원인들이 상세히 설명되어졌다. 에탄올(ethanol)/물(water) (1/0.1 v/v) 용액(5 mg mL−1)에서 올레익아미드 파생물의 자가조립이 점차적인 온도를 감소와 용액의 휘발을 통하여 평균 직경이 10 um인 마이크로 구를 만든다. 제조된 마이크로 구조물들은 doxorubicin의 생체 외 방출을 위한 scaffold로 활용된다. 이 결과는 pH에 민감한 방출 과정이고, 특히 낮은 pH 5.2 환경에서 방출율이 높아짐을 증명한다. ~1um 직경과 ~10um 길이의 다중 채널의 마이크로 튜브들은 di(chlorocarbonyl)pyridine과 디아민 파생물의 간단한 응축 반응으로 통합된 일련의 여러 화합물을 바탕으로 한 피리딘의 자가조립을 통해 제작된다. Multiple pyridylcarboxamide그룹을 함유한 MMTs 결과는 물속에서 중금속 이온을 묶기 위한 효율적인 방법을 제공한다. MMTs를 제조하기 위한 상세한 자가 조립 과정은 수용액에서Cu2+, Ni2+ and Zn2+와 같은 중금속 이온들에 대한 상호간의 흡착력에 의해증명된다.
The thesis describes synthesis, characterization and applications of cross-linked biocompatible and degradable hydrogels, and chain/cyclic amphiphilic micromolecules. The cross-linked and multiamine-functionalized PEG hydrogels (CMPHs) with degradable phosphoester and phosphoamide linkages in the ba...
The thesis describes synthesis, characterization and applications of cross-linked biocompatible and degradable hydrogels, and chain/cyclic amphiphilic micromolecules. The cross-linked and multiamine-functionalized PEG hydrogels (CMPHs) with degradable phosphoester and phosphoamide linkages in the backbone were successfully produced by the condensation crosslinking reactions between PEG-O-P(O)Cl2 with different functionalities and 3-arm-PEG-NH2 pre-polymers, followed by the chain-terminating amination using propane-1,3-diamine in a one-pot process. The newly invented protocol for the fabrication of PEG hydrogels exhibits promising advantages over prior methods including a short reaction time, mass-production, easy separation, and high yield. The structures of the pre-polymers and CMPHs were well characterized with FT–IR, 1H NMR, and solid state 31P NMR analyses. The mechanical properties of the CMPHs measured by rheometer indicate both storage modulus (G′) and loss modulus (G″) increase as the functionality of PEG-O-P(O)Cl2 increases. All the CMPHs have high water swellabitity with the equilibrium swelling ratio of 16 to 20. The non-hemolytic property and reasonable biocompatibility of the CMPHs were proven by in vivo histological assays and in vitro cell viability tests using 293T and HCT-116 cells. The CMPHs are hydrolytically degradable via P–O and P–N bond cleavage under basic and acidic conditions. We also demonstrated promising positive results for the use of such polymers as sustained drug delivery system, by mounting an anticancer drug–doxorubicin in vitro, with specifically enhanced release at low pH 4.0. Synthesized hydrogels have been also used as a template and reducer for the synthesis of a series of noble metal nanoparticles (MNPs) (Au, Ag, Pd, Pt and Ru NPs) in the absence of any other reducers. Created MNPs were well dispersed inside hydrogel, efficiently avoiding aggregation-causing catalysis activity loss. The metal nanoparticle–impregnated hydrogels used as catalysts are reusable in reducing various nitroaromatics by sodium borohydride in aqueous media with high catalytic activity. The reaction rate constants at 10, 30 and 50 °C and the activation energies with other activation parameters were calculated. The activation energy for the reduction of 2,6–dinitrophenol, 2,4–dinitrophenol, 4–nitrophenol and 2,4,6-trinitrophenol catalyzed by PEOPPA hydrogel supported AuNPs (HS–AuNP) is 35.13, 29.08, 22.03 and 32.01 kJmol–1, respectively. It was found that the catalytic activity in enhancing conversion rate increases in accordance with a series: HS-RuNP < HS-AgNP < HS-AuNP < HS-PtNP < HS-PdNP. A simple protocol has been developed for the creation of the biomimetic hybrid materials, calcium carbonate and hydroxyapatite, by in situ growth and mineralization in newly developed nontoxic hydrogel templates. Careful control of growth and mineralization conditions such as ions transport rate, pH, type of hydrogel, and mineralization temperature resulted in variety of calcium carbonate and hydroxylapatite architectures including nanorods, nanowires and well–defined hybrid structures. The resulting materials were analyzed by infrared spectroscopy, electron microscopes, energy-dispersive X–ray spectroscopy and X–ray powder diffraction. In this thesis, we have also presented a self-assembly route to fabricate nano/micro materials with tunable morphologies ranging from solid spheres, nano/microtubes, and hollow structures through π–π stacking interaction and hydrogen bonds. Firstly, a series of amphiphilic monochain derivatives of stearic acid, CH3(CH2)16CONH(CH2)nNH2 (n = 2, 3, 4, 6), CH3(CH2)16CONH(CH2)2S2(CH2)2NH2, [CH3(CH2)16CONH]2(CH2)2, are synthesized and their self-assembly behaviors have been investigated in 1,2-dichloroethane (DCE). In addition to the concentration of the compound in DCE and the number of methylene units in hydrophilic segments play a crucial role in determining the final morphology of self-assembling structures from nanotubules with 20 nm inner diameter to microspheres with an average diameter of 20 μm. The external texture of microsphere is also influenced by the number of methylene units in hydrophilic segment. The microspheres formed by highly ordered aggregation of nanobelts show high thermal stability. The particular processes and causations have been expatiated. Secondly, a series of oleamide derivatives, (C18H34NO)2(CH2)n [n = 2 (1a), 3 (1b), 4 (1c), or 6 (1d); C18H34NO = oleic amide fragment] and (C18H34NO)(CH2)6NH2 (2), have been synthesized and their self–assembly is investigated in ethanol/water media. Quantum chemical calculations and polymorph prediction show that compound 1a is best fitted with P21 space group, and all other compounds, 1b–1d and 2, are best fitted with P1. Self-assembly of 1a and 1b in ethanol/water (1/0.1 v/v) solution (5 mg mL−1) yields microspheres (MSs) with the average diameter ∼10 μm via a gradual temperature reduction and solvent volatilization process. Under the same self-assembly conditions, microrods (average diameter ∼6 μm and several tens of micrometers in length), micronecklaces and shape-irregular microparticles are formed from 1c, 1d and 2, respectively. The kinetics of evolution for their self-assemblies by dynamic light scattering technique and in situ observation by optical microscopy reveals that the microstructures formation is from a well-behaved aggregation of nanoscale micelles induced by solvent volatilization. Among the fabricated microstructures, the MSs from 1a possess of the best dispersity, which thus have been used as a scaffold for the in vitro release of doxorubicin (DOX). The results demonstrate a pH-sensitive release process, enhanced release specifically at low pH 5.2. Thirdly, multichannel microtubules (MMTs) of ~1 μm in the aperture diameter and ~ 10 μm in length have been fabricated via the self-assembly of a series of pyridine-based macrocyclic compounds synthesized by a simple condensation reaction of di(chlorocarbonyl)pyridine and diamine derivatives. The resulting MMTs bearing multiple pyridyl carboxamide groups provide an efficient host to bind heavy metal ions in water. The detailed self-assembly process to fabricate the MMT is demonstrated together with their adsorption capability for heavy metal ions such as Cu2+, Ni2+ and Zn2+ in aqueous solution.
The thesis describes synthesis, characterization and applications of cross-linked biocompatible and degradable hydrogels, and chain/cyclic amphiphilic micromolecules. The cross-linked and multiamine-functionalized PEG hydrogels (CMPHs) with degradable phosphoester and phosphoamide linkages in the backbone were successfully produced by the condensation crosslinking reactions between PEG-O-P(O)Cl2 with different functionalities and 3-arm-PEG-NH2 pre-polymers, followed by the chain-terminating amination using propane-1,3-diamine in a one-pot process. The newly invented protocol for the fabrication of PEG hydrogels exhibits promising advantages over prior methods including a short reaction time, mass-production, easy separation, and high yield. The structures of the pre-polymers and CMPHs were well characterized with FT–IR, 1H NMR, and solid state 31P NMR analyses. The mechanical properties of the CMPHs measured by rheometer indicate both storage modulus (G′) and loss modulus (G″) increase as the functionality of PEG-O-P(O)Cl2 increases. All the CMPHs have high water swellabitity with the equilibrium swelling ratio of 16 to 20. The non-hemolytic property and reasonable biocompatibility of the CMPHs were proven by in vivo histological assays and in vitro cell viability tests using 293T and HCT-116 cells. The CMPHs are hydrolytically degradable via P–O and P–N bond cleavage under basic and acidic conditions. We also demonstrated promising positive results for the use of such polymers as sustained drug delivery system, by mounting an anticancer drug–doxorubicin in vitro, with specifically enhanced release at low pH 4.0. Synthesized hydrogels have been also used as a template and reducer for the synthesis of a series of noble metal nanoparticles (MNPs) (Au, Ag, Pd, Pt and Ru NPs) in the absence of any other reducers. Created MNPs were well dispersed inside hydrogel, efficiently avoiding aggregation-causing catalysis activity loss. The metal nanoparticle–impregnated hydrogels used as catalysts are reusable in reducing various nitroaromatics by sodium borohydride in aqueous media with high catalytic activity. The reaction rate constants at 10, 30 and 50 °C and the activation energies with other activation parameters were calculated. The activation energy for the reduction of 2,6–dinitrophenol, 2,4–dinitrophenol, 4–nitrophenol and 2,4,6-trinitrophenol catalyzed by PEOPPA hydrogel supported AuNPs (HS–AuNP) is 35.13, 29.08, 22.03 and 32.01 kJmol–1, respectively. It was found that the catalytic activity in enhancing conversion rate increases in accordance with a series: HS-RuNP < HS-AgNP < HS-AuNP < HS-PtNP < HS-PdNP. A simple protocol has been developed for the creation of the biomimetic hybrid materials, calcium carbonate and hydroxyapatite, by in situ growth and mineralization in newly developed nontoxic hydrogel templates. Careful control of growth and mineralization conditions such as ions transport rate, pH, type of hydrogel, and mineralization temperature resulted in variety of calcium carbonate and hydroxylapatite architectures including nanorods, nanowires and well–defined hybrid structures. The resulting materials were analyzed by infrared spectroscopy, electron microscopes, energy-dispersive X–ray spectroscopy and X–ray powder diffraction. In this thesis, we have also presented a self-assembly route to fabricate nano/micro materials with tunable morphologies ranging from solid spheres, nano/microtubes, and hollow structures through π–π stacking interaction and hydrogen bonds. Firstly, a series of amphiphilic monochain derivatives of stearic acid, CH3(CH2)16CONH(CH2)nNH2 (n = 2, 3, 4, 6), CH3(CH2)16CONH(CH2)2S2(CH2)2NH2, [CH3(CH2)16CONH]2(CH2)2, are synthesized and their self-assembly behaviors have been investigated in 1,2-dichloroethane (DCE). In addition to the concentration of the compound in DCE and the number of methylene units in hydrophilic segments play a crucial role in determining the final morphology of self-assembling structures from nanotubules with 20 nm inner diameter to microspheres with an average diameter of 20 μm. The external texture of microsphere is also influenced by the number of methylene units in hydrophilic segment. The microspheres formed by highly ordered aggregation of nanobelts show high thermal stability. The particular processes and causations have been expatiated. Secondly, a series of oleamide derivatives, (C18H34NO)2(CH2)n [n = 2 (1a), 3 (1b), 4 (1c), or 6 (1d); C18H34NO = oleic amide fragment] and (C18H34NO)(CH2)6NH2 (2), have been synthesized and their self–assembly is investigated in ethanol/water media. Quantum chemical calculations and polymorph prediction show that compound 1a is best fitted with P21 space group, and all other compounds, 1b–1d and 2, are best fitted with P1. Self-assembly of 1a and 1b in ethanol/water (1/0.1 v/v) solution (5 mg mL−1) yields microspheres (MSs) with the average diameter ∼10 μm via a gradual temperature reduction and solvent volatilization process. Under the same self-assembly conditions, microrods (average diameter ∼6 μm and several tens of micrometers in length), micronecklaces and shape-irregular microparticles are formed from 1c, 1d and 2, respectively. The kinetics of evolution for their self-assemblies by dynamic light scattering technique and in situ observation by optical microscopy reveals that the microstructures formation is from a well-behaved aggregation of nanoscale micelles induced by solvent volatilization. Among the fabricated microstructures, the MSs from 1a possess of the best dispersity, which thus have been used as a scaffold for the in vitro release of doxorubicin (DOX). The results demonstrate a pH-sensitive release process, enhanced release specifically at low pH 5.2. Thirdly, multichannel microtubules (MMTs) of ~1 μm in the aperture diameter and ~ 10 μm in length have been fabricated via the self-assembly of a series of pyridine-based macrocyclic compounds synthesized by a simple condensation reaction of di(chlorocarbonyl)pyridine and diamine derivatives. The resulting MMTs bearing multiple pyridyl carboxamide groups provide an efficient host to bind heavy metal ions in water. The detailed self-assembly process to fabricate the MMT is demonstrated together with their adsorption capability for heavy metal ions such as Cu2+, Ni2+ and Zn2+ in aqueous solution.
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