Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid
Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid
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DOI：
10.1038/sj.gt.3302843
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发表时间：
2007-01-01
期刊：
影响因子：
5.1
通讯作者：
Harashima, H.
中科院分区：
文献类型：
--
作者：
Hatakeyama, H.;Akita, H.;Harashima, H.
通过静脉注射（i. v.）进行成功的癌症基因治疗在施用中，必须优化载体在体循环中的稳定性和载体在肿瘤组织中积累后的细胞缔合。然而，关于聚（乙二醇）（PEG）的使用存在困境，其可用于赋予体循环中的稳定性，但对于细胞摄取和随后的过程是不期望的。我们报告了PEG-肽-脂质三元缀合物（PEG-肽-DOPE缀合物（PPD））的开发。在该策略中，PEG通过基质金属蛋白酶（MMP）的切割从载体中去除，所述基质金属蛋白酶（MMP）在肿瘤组织中特异性表达。体外研究表明，PPD修饰的基因载体（多功能包膜型纳米器件：MEND）表现出依赖于宿主细胞中MMP表达水平的pDNA表达活性。体内研究进一步揭示，PPD在稳定体循环中的MEND和促进肿瘤蓄积方面是有效的。此外，与常规PEG修饰的MEND相比，PPD或PEG/PPD双重修饰的MEND的静脉内施用导致肿瘤组织中pDNA表达的刺激。因此，用PPD修饰的MEND是一种有前途的装置，其具有使体内癌症基因治疗可实现的潜力。
For successful cancer gene therapy via intravenous (i.v.) administration, it is essential to optimize the stability of carriers in the systemic circulation and the cellular association after the accumulation of the carrier in tumor tissue. However, a dilemma exists regarding the use of poly(ethylene glycol) (PEG), which is useful for conferring stability in the systemic circulation, but is undesirable for the cellular uptake and the following processes. We report the development of a PEG-peptide-lipid ternary conjugate (PEG-Peptide-DOPE conjugate (PPD)). In this strategy, the PEG is removed from the carriers via cleavage by a matrix metalloproteinase (MMP), which is specifically expressed in tumor tissues. An in vitro study revealed that the PPD-modified gene carrier (Multifunctional Envelope-type Nano Device: MEND) exhibited pDNA expression activity that was dependent on the MMP expression level in the host cells. In vivo studies further revealed that the PPD was potent in stabilizing MEND in the systemic circulation and facilitating tumor accumulation. Moreover, the i.v. administration of PPD or PEG/PPD dually-modified MEND resulted in the stimulation of pDNA expression in tumor tissue, as compared with a conventional PEG-modified MEND. Thus, MEND modified with PPD is a promising device, which has the potential to make in vivo cancer gene therapy achievable.