Multimeric peptide-based PEG nanocarriers with programmable elimination properties.
Multimeric peptide-based PEG nanocarriers with programmable elimination properties.
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DOI：
10.1016/j.biomaterials.2009.05.068
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发表时间：
2009-10
期刊：
影响因子：
14
通讯作者：
Sinko, Patrick J.
中科院分区：
文献类型：
--
作者：
Gunaseelan, Simi;Pooyan, Shahriar;Chen, Peiming;Samizadeh, Mahta;Palombo, Matthew S.;Stein, Stanley;Zhang, Xiaoping;Sinko, Patrick J.
本文介绍了可生物降解肽类聚乙二醇纳米载体的设计、合成可行性和生化特性。选择影响纳米载体生物降解的机体消除途径的组分。采用非聚乙二醇化和聚乙二醇化的肽核[CH3CO-(Lys-β ala -β ala)X- cys - conh2 (X= 2,4)]制备了两种原型纳米载体。通过二硫键连接两个聚乙二醇化的肽核（X=2），合成了具有4拷贝荧光素- peg5kda的二聚体纳米载体。同时合成了2个荧光素- peg5kda拷贝和4个德克萨斯红拷贝的双标记异二聚体纳米载体。确定了显像剂、PEG或肽核与肽核连接的最佳条件。使用2拷贝β-丙氨酸作为间隔物，随着DMSO浓度的增加，导致空间位阻降低，聚乙二醇化肽核的收率显著提高（69%对30%）。化学计量添加的成分也被证明，并发现是重要的，以减少多分散性。在模拟的细胞内和细胞外/血液环境中，分别使用3mM和10μM谷胱甘肽缓冲液评估纳米载体的生物降解。纳米载体在细胞外环境中的稳定性提高了9倍。结果表明，纳米载体选择性地在细胞内降解成具有已知身体消除途径的成分。
In the current study, the design, synthetic feasibility and biochemical characterization of biodegradable peptidic PEG-based nanocarriers is described. The components were selected to influence the body elimination pathway upon nanocarrier biodegradation. Two prototypical nanocarriers were prepared using non-PEGylated and PEGylated peptidic cores [CH3CO-(Lys-βAla-βAla)X-Cys-CONH2 (X= 2, 4)]. A homodimeric nanocarrier with 4 copies of fluorescein-PEG5kDa was synthesized by linking two PEGylated peptidic cores (X=2) using a disulfide bond. A dual-labeled heterodimeric nanocarrier with 2 copies of fluorescein-PEG5kDa and 4 copies of Texas Red was also synthesized. Optimum conditions for linking imaging agents, PEG, or a peptidic core to a peptidic core were determined. Significantly higher yields (69% versus 30%) of the PEGylated peptidic core were obtained by using 2 copies of β-alanine as a spacer along with increasing DMSO concentrations, which resulted in reduced steric hindrance. Stoichiometric addition of the components was also demonstrated and found to be important for reducing polydispersity. Nanocarrier biodegradation was evaluated in simulated intracellular and extracellular/blood environments using 3mM and 10μM glutathione in buffer, respectively. The nanocarrier was 9-fold more stable in the extracellular environment. The results suggest selective intracellular degradation of the nanocarrier into components with known body elimination pathways.
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