Cathepsin B-sensitive polymers for compartment-specific degradation and nucleic acid release.
Cathepsin B-sensitive polymers for compartment-specific degradation and nucleic acid release.
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DOI：
10.1016/j.jconrel.2011.10.016
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发表时间：
2012-02-10
期刊：
影响因子：
--
通讯作者：
Pun SH
中科院分区：
文献类型：
--
作者：
Chu DS;Johnson RN;Pun SH
可降解阳离子聚合物是体内核酸传递的理想选择，因为它们比不可降解的对应物提供了显著降低的毒性。肽连接物为特定的内多肽酶提供了化学稳定性和高特异性，但尚未广泛研究核酸传递应用。在这项工作中，酶降解的肽-HPMA共聚物是由HPMA与甲基丙烯酸化的肽大单体通过RAFT聚合合成的，这种聚合物具有低的多分散性和近定量的肽结合。对三种肽- hpma共聚物进行了评估：(i) pHCathK10，包含由连接物pH -lys- pH -leu （FKFL）组成的肽，FKFL是内体/溶酶体内肽酶cathepsin B的底物，与寡聚赖氨酸连接以进行核酸结合；（ii） pHCath(d)K10，包含寡聚赖氨酸的FKFL连接物；（iii） pH(d)Cath(d)K10，包含所有(d)氨基酸。组织蛋白酶B在1小时内降解共聚物pHCathK10和pHCath(d)K10，而pH(d)Cath(d)K10没有降解。pHCathK10共聚物形成的多聚物经组织蛋白酶B处理4小时后显示DNA释放；相比之下，pHCath(d)K10和pH(d)Cath(d)K10形成的多聚体在8小时内没有DNA释放。两种共聚物在HeLa和NIH/3T3细胞中的转染效率相当，但pHCathK10毒性较小。这项工作证明了肽连接物在可降解阳离子聚合物和DNA释放中的成功应用。
Degradable cationic polymers are desirable for in vivo nucleic acid delivery because they offer significantly decreased toxicity over non-degradable counterparts. Peptide linkers provide chemical stability and high specificity for particular endopeptidases but have not been extensively studied for nucleic acid delivery applications. In this work, enzymatically degradable peptide-HPMA copolymers were synthesized by RAFT polymerization of HPMA with methacrylated peptide macromonomers, resulting in polymers with low polydispersity and near quantitative incorporation of peptides. Three peptide-HPMA copolymers were evaluated: (i) pHCathK10, containing peptides composed of the linker phe-lys-phe-leu (FKFL), a substrate of the endosomal/lysosomal endopeptidase cathepsin B, connected to oligo-(l)-lysine for nucleic acid binding, (ii) pHCath(d)K10, containing the FKFL linker with oligo-(d)-lysine, and (iii) pH(d)Cath(d)K10, containing all (d) amino acids. Cathepsin B degraded copolymers pHCathK10 and pHCath(d)K10 within one hour while no degradation of pH(d)Cath(d)K10 was observed. Polyplexes formed with pHCathK10 copolymers show DNA release by 4 hrs of treatment with cathepsin B; comparatively, polyplexes formed with pHCath(d)K10 and pH(d)Cath(d)K10 show no DNA release within 8 hrs. Transfection efficiency in HeLa and NIH/3T3 cells were comparable between the copolymers but pHCathK10 was less toxic. This work demonstrates the successful application of peptide linkers for degradable cationic polymers and DNA release.
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影响因子：
4.7
作者：
Dubowchik, GM;Firestone, RA;Trail, PA
通讯作者：
Trail, PA
影响因子：
4.3
作者：
Hunter, A. Christy;Moghimi, S. Moein
通讯作者：
Moghimi, S. Moein
DOI：
10.1016/j.jconrel.2011.07.009
发表时间：
2011-10-30
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Johnson RN;Chu DS;Shi J;Schellinger JG;Carlson PM;Pun SH
通讯作者：
Pun SH
影响因子：
4.8
作者：
Droga-Mazovec, Gabriela;Bojic, Lea;Turk, Boris
通讯作者：
Turk, Boris
影响因子：
4.7
作者：
Burke, Rob S.;Pun, Suzie H.
通讯作者：
Pun, Suzie H.