A novel approach for long term protein delivery
一种长期蛋白质输送的新方法
基本信息
- 批准号:7269465
- 负责人:
- 金额:$ 22.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-08-01 至 2010-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmino AcidsAnimal ModelBiodegradationBiologicalBuffersChargeChemicalsChronicComplexConditionDevicesDiabetes MellitusDrug FormulationsElectrostaticsEnvironmentEnzymesExcipientsGlycolic-Lactic Acid PolyesterGoalsHalf-LifeIn VitroIndividualInjectableInjection of therapeutic agentInsulinKineticsMicroclimateMicrospheresModelingModificationMolecularMolecular ConformationMolecular WeightNatureNumbersPatient NoncompliancePatientsPerformancePhysiologicalPolymersPoriferaPropertyProteinsProtocols documentationRangeReactionResearchResearch PersonnelRole playing therapySolutionsStressStructureSubcutaneous InjectionsSystemTechnologyTestingTreatment ProtocolsWateraqueousbiodegradable polymerbiomaterial compatibilityconceptcontrolled releasecopolymerdesigndesiredi-block copolymerdiabeticimprovedin vivointerfacialnovelnovel strategiesperformance testspoly(L-histidine)polycationpolylactic acid-polyglycolic acid copolymerpreventprogramsprotein aggregationprotein structuresizetherapeutic protein
项目摘要
DESCRIPTION (provided by applicant): Poly(lactide-co-glycolide) (PLGA) has been widely applied in microspheres (MS) as a protein delivery carrier. However, proteins undergo physical and chemical denaturation during the fabrication of PLGA MS and release in the body. In addition, such formulations often cause undesirable and unpredictable release profiles, characterized by a burst effect and incomplete release. This makes PLGA MS appraoch unsuccessful for most labile proteins. The results from our preliminary study are a clear pointer to the validity of the role played by PEG-polycation (poly(L-histidine)) as a pH-dependent 'reversible molecular shield' in 1) preserving protein structure and preventing aggregation at water/organic interface, 2) exerting a pH buffering (protein sponge effect) in PLGA MS, 3) enhancing protein's physical stability in solution and in MS, and 4) an overall better control over release of the proteins from the PLGA MS ('all-in-one' concept). Although our preliminary results demonstrate the feasibility, there are still a number of variables which can be altered to optimize or tailor this polymer design for specific proteins, such as insulin. This includes changing the size of polyHis and copolymerizing with other amino acids to alter charge spacing or polyHis conformation. The proposal goes well beyond therapeutic proteins in suggesting potential applications for enzymes and other applications. The long-term goal of this project is to preserve >90 % bioactivity of a model protein, insulin, when released from PLGA MS and to achieve pseudozero-order release kinetics for more than one month period in in vitro and in vivo tests. The research specific aims include 1) experimental verification of optimized PEG-polyHis (or PEG-modified polyHis)/insulin complex for maximum insulin stability in aqueous solutions, in PLGA MS and during release, 2) a better control over release profile and 3) in vivo performance tests combined with biocompatibility and the fate of the diblock copolymer.
描述(由申请人提供):聚(丙交酯-共-乙交酯)(PLGA)已广泛应用于微球(MS)中作为蛋白质递送载体。然而,蛋白质在PLGA MS的制造过程中会经历物理和化学变性并在体内释放。此外,这样的制剂通常引起不期望的和不可预测的释放曲线,其特征在于突释效应和不完全释放。这使得PLGA MS方法对于大多数不稳定蛋白质是不成功的。从我们的初步研究的结果是一个明确的指针的有效性所发挥的作用PEG-聚阳离子(聚(L-组氨酸))作为pH依赖性“可逆分子屏蔽”,1)保持蛋白质结构并防止在水/有机界面聚集,2)施加pH缓冲,(蛋白质海绵效应),3)增强蛋白质在溶液和MS中的物理稳定性,和4)对蛋白质从PLGA MS的释放的总体更好的控制(“一体化”概念)。虽然我们的初步结果证明了可行性,但仍然有许多变量可以改变,以优化或定制特定蛋白质(如胰岛素)的聚合物设计。这包括改变聚组氨酸的大小和与其他氨基酸共聚以改变电荷间距或聚组氨酸构象。该提案远远超出了治疗性蛋白质,提出了酶和其他应用的潜在应用。该项目的长期目标是当从PLGA MS释放时,保持模型蛋白胰岛素> 90%的生物活性,并在体外和体内测试中实现假零级释放动力学超过一个月。该研究的具体目标包括:1)优化的PEG-聚His(或PEG修饰的聚His)/胰岛素复合物的实验验证,以实现在水溶液中、PLGA MS中和释放过程中的最大胰岛素稳定性; 2)更好地控制释放曲线; 3)结合生物相容性和二嵌段共聚物命运的体内性能测试。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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You Han Bae其他文献
“On–Off“ Thermocontrol of Solute Transport. II. Solute Release from Thermosensitive Hydrogels
- DOI:
10.1023/a:1015860824953 - 发表时间:
1991-01-01 - 期刊:
- 影响因子:4.300
- 作者:
You Han Bae;Teruo Okano;Sung Wan Kirn - 通讯作者:
Sung Wan Kirn
Cancer targeting paradigm: does it need to be shifted?
- DOI:
10.1016/j.nano.2007.10.041 - 发表时间:
2007-12-01 - 期刊:
- 影响因子:
- 作者:
You Han Bae - 通讯作者:
You Han Bae
Low‐temperature processable biodegradable block copolymers embedded with proteins
嵌入蛋白质的可低温加工的可生物降解的嵌段共聚物
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
Yu Matsumoto;Joseph W. Nichols;Kazuko Toh;Takahiro Nomoto;Horacio Cabral;Yutaka Miura;R. James Christie;Naoki Yamada;Tadayoshi Ogura;Mitsunobu R. Kano;Yasuhiro Matsumura;Nobuhiro Nishiyama;Tatsuya Yamasoba;You Han Bae;Kazunori Kataoka;Yasuhiko Iwasaki - 通讯作者:
Yasuhiko Iwasaki
“On–Off” Thermocontrol of Solute Transport. I. Temperature Dependence of Swelling of N-Isopropylacrylamide Networks Modified with Hydrophobic Components in Water
- DOI:
10.1023/a:1015871732706 - 发表时间:
1991-01-01 - 期刊:
- 影响因子:4.300
- 作者:
You Han Bae;Teruo Okano;Sung Wan Kim - 通讯作者:
Sung Wan Kim
Hydrogels: Swelling, Drug Loading, and Release
- DOI:
10.1023/a:1015887213431 - 发表时间:
1992-01-01 - 期刊:
- 影响因子:4.300
- 作者:
Sung Wan Kim;You Han Bae;Teruo Okano - 通讯作者:
Teruo Okano
You Han Bae的其他文献
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{{ truncateString('You Han Bae', 18)}}的其他基金
WELL-DEFINED MULTIFUNCTIONAL POLYMERIC NANOCARRIERS FOR EFFECTIVE GENE DELIVERY
明确的多功能聚合物纳米载体可实现有效的基因传递
- 批准号:
8257580 - 财政年份:2009
- 资助金额:
$ 22.07万 - 项目类别:
WELL-DEFINED MULTIFUNCTIONAL POLYMERIC NANOCARRIERS FOR EFFECTIVE GENE DELIVERY
明确的多功能聚合物纳米载体可实现有效的基因传递
- 批准号:
7817124 - 财政年份:2009
- 资助金额:
$ 22.07万 - 项目类别:
Intelligent Polymeric Nanogel Technology Overcoming Drug Resistance in Ovarian Ca
智能聚合物纳米凝胶技术克服卵巢钙耐药性
- 批准号:
7696849 - 财政年份:2009
- 资助金额:
$ 22.07万 - 项目类别:
WELL-DEFINED MULTIFUNCTIONAL POLYMERIC NANOCARRIERS FOR EFFECTIVE GENE DELIVERY
明确的多功能聚合物纳米载体可实现有效的基因传递
- 批准号:
8085835 - 财政年份:2009
- 资助金额:
$ 22.07万 - 项目类别:
Micelle surface engineering for active targeting by acidic tumor extracellular pH
胶束表面工程通过酸性肿瘤细胞外 pH 值主动靶向
- 批准号:
7130778 - 财政年份:2006
- 资助金额:
$ 22.07万 - 项目类别:
A novel approach for long term protein delivery
一种长期蛋白质输送的新方法
- 批准号:
7141503 - 财政年份:2006
- 资助金额:
$ 22.07万 - 项目类别:
A novel approach for long term protein delivery
一种长期蛋白质输送的新方法
- 批准号:
7664879 - 财政年份:2006
- 资助金额:
$ 22.07万 - 项目类别:
Micelle surface engineering for active targeting by acidic tumor extracellular pH
胶束表面工程通过酸性肿瘤细胞外 pH 值主动靶向
- 批准号:
7279446 - 财政年份:2006
- 资助金额:
$ 22.07万 - 项目类别:
Micelle surface engineering for active targeting by acidic tumor extracellular pH
胶束表面工程通过酸性肿瘤细胞外 pH 值主动靶向
- 批准号:
7893033 - 财政年份:2006
- 资助金额:
$ 22.07万 - 项目类别:
A novel approach for long term protein delivery
一种长期蛋白质输送的新方法
- 批准号:
7472401 - 财政年份:2006
- 资助金额:
$ 22.07万 - 项目类别:
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