Targeted nanoparticle-mediated LHPP for melanoma treatment
Targeted nanoparticle-mediated LHPP for melanoma treatment
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靶向纳米粒子介导的 LHPP 用于黑色素瘤治疗
DOI：
10.2147/ijn.s196374
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发表时间：
2019-05
影响因子：
8
通讯作者：
Maling Gou
中科院分区：
文献类型：
--
作者：
Qianqian Zhang;Meimei Xiong;Jinlu Liu;Shuai Wang;Ting Du;Tianyi Kang;Yu Liu;Hao Cheng;Meijuan Huang;Maling Gou
背景：磷酸赖氨酸磷酸组氨酸无机焦磷酸磷酸酶（LHPP）是一种新型的肿瘤抑制因子。然而，LHPP是否对黑色素瘤有效还没有研究。基因治疗为黑色素瘤的治疗提供了新的策略。目前，它缺乏安全有效的基因递送系统。研究方法：制备CRGDKGPDC肽（iRGD）修饰的杂合单甲氧基聚（乙二醇）-聚（D，L-丙交酯）纳米颗粒（iDPP）并与LHPP质粒复合，形成iDPP/LHPP纳米复合物。iDPP/LHPP纳米复合物的特征在于粒径分布，zeta电位，形态，细胞毒性和转染效率。在体外和体内研究了纳米复合物对黑色素瘤的抗肿瘤功效。此外，评价了iDPP/LHPP纳米复合物诱导的黑色素瘤中的潜在表观遗传变化。结果：iDPP/LHPP纳米复合物具有高转染效率和低毒性。此外，该纳米复合物显示中性电荷，可以满足静脉注射用于靶向基因治疗的要求。体外和体内实验表明，iDPP/LHPP纳米复合物显著抑制黑色素瘤生长，而不引起显著的不良反应。我们还发现LHPP在表观遗传学中起着重要作用。它主要在转录水平上调控细胞增殖和凋亡相关基因的表达。总结：这项工作表明，iDPP纳米颗粒递送的LHPP基因通过调节与表观遗传学相关的基因在黑色素瘤治疗中具有潜在的应用。
Background: Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a novel tumor suppressor. However, whether LHPP is effective to melanoma has not been investigated. Gene therapy provides a new strategy for the treatment of melanoma. Currently, it suffers from the lack of safe and effective gene delivery systems. Methods: A CRGDKGPDC peptide (iRGD) modified hybrid monomethoxy poly(ethylene glycol)-poly(D,L-lactide) nanoparticle (iDPP) was prepared and complexed with a LHPP plasmid, forming an iDPP/LHPP nanocomplex. The iDPP/LHPP nanocomplex was characterized by particle size distribution, zeta potential, morphology, cytotoxicity, and transfection efficiency. The antitumor efficacy of the nanocomplex against melanoma was studied both in vitro and in vivo. Further, the potential epigenetic changes in melanoma induced by iDPP/LHPP nanocomplex were evaluated. Results: The iDPP/LHPP nanocomplex showed high transfection efficiency and low toxicity. Moreover, the nanocomplex displayed a neutral charge that can meet the requirement of intravenous injection for targeted gene therapy. In vitro and in vivo experiments indicated that the iDPP/LHPP nanocomplex significantly inhibited the melanoma growth without causing notable adverse effects. We also found that LHPP played an important role in epigenetics. It regulated the expression of genes related to the proliferation and apoptosis chiefly at the level of transcription. Conclusion: This work demonstrates that the iDPP nanoparticle-delivered LHPP gene has a potential application in melanoma therapy through regulation of the genes associated with epigenetics.
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