Henry Scott M, El-Sayed Mohamed E H, Pirie Christopher M, Hoffman Allan S, Stayton Patrick S
University of Washington, Department of Bioengineering, Seattle, Washington 98195, USA.
Biomacromolecules. 2006 Aug;7(8):2407-14. doi: 10.1021/bm060143z.
Many macromolecular therapeutics such as peptides, proteins, antisense oligodeoxynucleotides (ASODN), and short interfering RNA (siRNA) are active only in the cytoplasm or nucleus of targeted cells. Endocytosis is the primary route for cellular uptake of these molecules, which results in their accumulation in the endosomal-lysosomal trafficking pathway and loss of therapeutic activity. In this article, we describe the synthesis and pH-dependent membrane-destabilizing activity of a new "smart" polymer family that can be utilized to enhance the intracellular delivery of therapeutic macromolecules through the endosomal membrane barrier into the cytoplasm of targeted cells. These polymers are propylamine, butylamine, and pentylamine derivatives of poly(styrene-alt-maleic anhydride) (PSMA) copolymers. The PSMA-alkylamide derivatives are hydrophilic and membrane-inactive at physiological pH; however, they become hydrophobic and membrane-disruptive in response to endosomal pH values as measured by their hemolytic activity. Results show that the pH-dependent membrane-destabilizing activity of PSMA derivatives can be controlled by varying the length of the alkylamine group, the degree of modification of the copolymer, and the molecular weight of the PSMA copolymer backbone. Butylamine and pentylamine derivatives of PSMA copolymers exhibited more than 80% hemolysis at endosomal pH values, which suggests their potential as a platform of "smart" polymeric carriers for enhanced cytoplasmic delivery of a variety of therapeutic macromolecules.
许多大分子治疗药物，如肽、蛋白质、反义寡脱氧核苷酸（ASODN）和小干扰RNA（siRNA），仅在靶细胞的细胞质或细胞核中具有活性。内吞作用是这些分子进入细胞的主要途径，这导致它们在内体-溶酶体运输途径中积累并丧失治疗活性。在本文中，我们描述了一种新型“智能”聚合物家族的合成及其pH依赖性膜破坏活性，该聚合物家族可用于增强治疗性大分子通过内体膜屏障进入靶细胞细胞质的细胞内递送。这些聚合物是聚（苯乙烯-alt-马来酸酐）（PSMA）共聚物的丙胺、丁胺和戊胺衍生物。PSMA-烷基酰胺衍生物在生理pH下是亲水的且无膜活性；然而，通过其溶血活性测量，它们在内体pH值下会变得疏水并破坏膜。结果表明，PSMA衍生物的pH依赖性膜破坏活性可以通过改变烷基胺基团的长度、共聚物的修饰程度以及PSMA共聚物主链的分子量来控制。PSMA共聚物的丁胺和戊胺衍生物在内体pH值下表现出超过80%的溶血率，这表明它们作为“智能”聚合物载体平台用于增强多种治疗性大分子的细胞质递送具有潜力。
