The optimization of polymalic acid peptide copolymers for endosomolytic drug delivery.
The optimization of polymalic acid peptide copolymers for endosomolytic drug delivery.
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DOI：
10.1016/j.biomaterials.2011.03.073
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发表时间：
2011-08
期刊：
影响因子：
14
通讯作者：
Holler, Eggehard
中科院分区：
文献类型：
--
作者：
Ding, Hui;Portilla-Arias, Jose;Patil, Rameshwar;Black, Keith L.;Ljubimova, Julia Y.;Holler, Eggehard
关键词：
溶膜大分子是一种很有前途的细胞质给药载体，但其效率和安全性仍然是主要问题。为了解决这些问题，广泛研究了各种聚（β-l-苹果酸）（PMLA）共聚物的膜溶解性能作为浓度和pH的函数。PMLA是一种天然存在的可生物降解聚合物，在用疏水氨基酸衍生物取代侧链羧酸酯后获得膜溶解活性。由疏水化和电荷中和，PMLA共聚物的膜分解增加作为聚合物分子量的函数，并表现出最大与50%的羧酸酯取代。电荷中和实现有条件的pH值依赖性质子化或永久掩蔽羧酸。含有亮氨酸、色氨酸和苯丙氨酸三肽的PMLA共聚物的膜分解是pH依赖性的，而亮氨酸乙酯和Leu-Leu-Leu-NH 2的共聚物具有永久电荷中和作用，与pH无关。PMLA和三肽似乎是pH依赖性膜溶解的独特组合。与无毒的pH依赖性PMLA共聚物相反，pH非依赖性共聚物在高浓度下被发现是有毒的，这归因于它们在生理pH下对质膜的非特异性破坏。pH依赖性共聚物仅在成熟内体典型的酸性pH下具有膜溶解活性，因此没有细胞毒性。PMLA三肽共聚物可用于通过内体的安全和有效的细胞质递送。
Membranolytic macromolecules are promising vehicles forcytoplasmic drug delivery, but their efficiency and safety remains primary concerns. To address those concerns, membranolytic properties of various poly(β-l-malic acid) (PMLA) copolymers were extensively investigated as a function of concentration and pH. PMLA, a naturally occurring biodegradable polymer, acquires membranolytic activities after substitution of pendant carboxylates with hydrophobic amino acid derivatives. Ruled by hydrophobization and charge neutralization, membranolysis of PMLA copolymers increased as a function of polymer molecular weight and demonstrated a maximum with 50% substitution of carboxylates. Charge neutralization was achieved either conditionally by pH-dependent protonation or permanently by masking carboxylates. Membranolysis of PMLA copolymers containing tripeptide ofleucine, tryptophan and phenylalanine were pH-dependent in contrast to pH-independent copolymers of Leucineethylester and Leu-Leu-Leu-NH2 with permanent charge neutralization. PMLA and tripeptides seemed a unique combination for pH-dependent membranolysis. In contrast to nontoxic pH-dependent PMLA copolymers, pH-independent copolymers were found toxic at high concentration, which is ascribed to their nonspecific disruption of plasma membrane at physiological pH.pH-dependent copolymers were membranolytically active only at acidic pH typical of maturating endosomes, and are thus devoid of cytotoxicity. The PMLA tripeptide copolymers are useful for safe and efficient cytoplasmic delivery routed through endosome.
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影响因子：
6.2
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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通讯作者：
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影响因子：
4.1
作者：
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通讯作者：
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