Inhibition of brain tumor growth by intravenous poly (β-L-malic acid) nanobioconjugate with pH-dependent drug release
Inhibition of brain tumor growth by intravenous poly (β-L-malic acid) nanobioconjugate with pH-dependent drug release
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DOI：
10.1073/pnas.1003919107
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发表时间：
2010-10-19
影响因子：
11.1
通讯作者：
Ljubimova, Julia Y.
中科院分区：
文献类型：
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作者：
Ding, Hui;Inoue, Satoshi;Ljubimova, Julia Y.
有效治疗阿尔茨海默病、多发性硬化症或肿瘤等脑神经疾病应该是可能的，通过血脑屏障(BBB)或血脑肿瘤屏障(BTB)给药，并通过药物释放到细胞质中靶向特定类型的脑细胞。以可生物降解、无毒、非免疫原性的聚马来酸为载体的聚合物纳米生物偶联药物用于静脉注射纳米药物的设计和合成。脑瘤的治疗。利用针对BTB和肿瘤细胞的串联单抗，该聚合物药物通过BTB和肿瘤细胞膜。聚合物药物作用的下一步是通过结合反义寡核苷酸(AON)特异性地阻断肿瘤新生血管三聚体蛋白LN-411的合成来抑制肿瘤血管生成。AON通过pH激活的三亮氨酸释放到靶细胞胞浆中，三亮氨酸是一种内体逃逸部分。研究了该纳米生物聚合物的脑瘤给药和释药机制。与pH非依赖性亮氨酸酯相比，三亮氨酸内体逃逸单位的引入显著增加了AON对肿瘤细胞的递送，抑制了层粘连蛋白-411的合成，特异性地积聚在脑肿瘤中，并抑制了脑胶质瘤的生长。一种系统活性的聚合物药物输送系统的可用性，它通过BTB，靶向肿瘤细胞，并抑制胶质瘤的生长，为成功的胶质瘤治疗策略带来了希望。这种药物释放到大脑特定细胞类型的递送系统可能对治疗各种脑部疾病有用。
Effective treatment of brain neurological disorders such as Alzheimer's disease, multiple sclerosis, or tumors should be possible with drug delivery through blood-brain barrier (BBB) or blood-brain tumor barrier (BTB) and targeting specific types of brain cells with drug release into the cell cytoplasm. A polymeric nanobioconjugate drug based on biodegradable, nontoxic, and nonimmunogenic polymalic acid as a universal delivery nanoplatform was used for design and synthesis of nanomedicine drug for i.v. treatment of brain tumors. The polymeric drug passes through the BTB and tumor cell membrane using tandem monoclonal antibodies targeting the BTB and tumor cells. The next step for polymeric drug action was inhibition of tumor angiogenesis by specifically blocking the synthesis of a tumor neovascular trimer protein, laminin-411, by attached antisense oligonucleotides (AONs). The AONs were released into the target cell cytoplasm via pH-activated trileucine, an endosomal escape moiety. Drug delivery to the brain tumor and the release mechanism were both studied for this nanobiopolymer. Introduction of a trileucine endosome escape unit resulted in significantly increased AON delivery to tumor cells, inhibition of laminin-411 synthesis in vitro and in vivo, specific accumulation in brain tumors, and suppression of intracranial glioma growth compared with pH-independent leucine ester. The availability of a systemically active polymeric drug delivery system that passes through the BTB, targets tumor cells, and inhibits glioma growth gives hope for a successful strategy of glioma treatment. This delivery system with drug release into the brain-specific cell type could be useful for treatment of various brain pathologies.