Lanthanide-doped nanoparticles conjugated with an anti-CD33 antibody and a p53-activating peptide for acute myeloid leukemia therapy.
Lanthanide-doped nanoparticles conjugated with an anti-CD33 antibody and a p53-activating peptide for acute myeloid leukemia therapy.
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DOI：
10.1016/j.biomaterials.2018.03.025
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发表时间：
2018-06
期刊：
影响因子：
14
通讯作者：
Lu W
中科院分区：
文献类型：
--
作者：
Niu F;Yan J;Ma B;Li S;Shao Y;He P;Zhang W;He W;Ma PX;Lu W
大约三分之一的人类癌症可归因于肿瘤抑制蛋白p53通过其两种负调节剂MDM 2和MDMX的功能性抑制，使得MDM 2和MDMX的双特异性肽拮抗剂对于抗癌疗法具有高度吸引力的候选药物。然而，两个药理学障碍仍然是肽疗法发展的主要障碍：对体内蛋白水解降解的敏感性和不能穿过细胞膜。在这里，我们报告了一种基于荧光镧系氟氧化物纳米颗粒（LONP）的多功能肽药物递送系统的设计，用于潜在治疗急性髓性白血病（AML），该白血病通常含有野生型p53，高水平的MDM 2和/或MDMX，以及过表达的细胞表面受体CD 33。我们通过金属-硫醇盐键将MDM 2和MDMX的十二聚体肽拮抗剂（称为PMI）和靶向CD 33的人源化单克隆抗体缀合至LONP，以允许AML特异性细胞内递送稳定的PMI。所得纳米颗粒抗CD 33-LONp-PMI虽然对正常细胞无毒，但通过拮抗MDM 2和/或MDMX以激活p53途径诱导AML细胞系和从AML患者分离的原代白血病细胞的凋亡。荧光抗CD 33-LONp-PMI还实现了AML细胞中一系列凋亡事件的实时可视化，证明了可能的疾病跟踪和治疗反应监测的有用工具。我们的研究揭示了抗CD 33-LONp-PMI作为一类新型抗肿瘤药物的发展，如果进一步验证，可能有助于AML的靶向分子治疗。
Roughly one third of all human cancers are attributable to the functional inhibition of the tumor suppressor protein p53 by its two negative regulators MDM2 and MDMX, making dual-specificity peptide antagonists of MDM2 and MDMX highly attractive drug candidates for anticancer therapy. Two pharmacological barriers, however, remain a major obstacle to the development of peptide therapeutics: susceptibility to proteolytic degradation in vivo and inability to traverse the cell membrane. Here we report the design of a fluorescent lanthanide oxyfluoride nanoparticle (LONp)-based multifunctional peptide drug delivery system for potential treatment of acute myeloid leukemia (AML) that commonly harbors wild type p53, high levels of MDM2 and/or MDMX, and an overexpressed cell surface receptor, CD33. We conjugated to LONp via metal-thiolate bonds a dodecameric peptide antagonist of both MDM2 and MDMX, termed PMI, and a CD33-targeted, humanized monoclonal antibody to allow for AML-specific intracellular delivery of a stabilized PMI. The resultant nanoparticle antiCD33-LONp-PMI, while nontoxic to normal cells, induced apoptosis of AML cell lines and primary leukemic cells isolated from AML patients by antagonizing MDM2 and/or MDMX to activate the p53 pathway. Fluorescent antiCD33-LONp-PMI also enabled real-time visualization of a series of apoptotic events in AML cells, proving a useful tool for possible disease tracking and treatment response monitoring. Our studies shed light on the development of antiCD33-LONp-PMI as a novel class of antitumor agents, which, if further validated, may help targeted molecular therapy of AML.
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