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.

在所有人类癌症中，大约有三分之一归因于其两个负调控因子MDM2和MDMX对肿瘤抑制蛋白p53的功能抑制，从而使MDM2和MDMX的双特异性肽拮抗剂成为抗癌治疗的极具吸引力的候选药物。然而，两个药理学障碍仍然是肽治疗剂发展的主要障碍：对体内蛋白水解降解的敏感性和无法穿越细胞膜的能力。在这里，我们报告基于荧光镧系元素氧氟化物纳米颗粒（LONp）的多功能肽药物输送系统的设计，以进行潜在治疗通常包含野生型p53，高水平的MDM2和/或MDMX以及过度表达的细胞表面受体CD33的急性髓细胞白血病（AML）。我们通过金属硫醇盐键与LONp缀合，称为MMI的MDM2和MDMX的十二聚体肽拮抗剂和靶向CD33的人源化单克隆抗体，以允许AML特异性的细胞内递送稳定的PMI。所得的抗CD33-LONp-PMI纳米颗粒虽然对正常细胞无毒，但通过拮抗MDM2和/或MDMX激活p53途径，诱导了AML细胞株和从AML患者分离的原代白血病细胞的凋亡。荧光抗CD33-LONp-PMI还可以实时显示AML细胞中一系列凋亡事件，从而证明了可能的疾病追踪和治疗反应监测的有用工具。我们的研究揭示了抗CD33-LONp-PMI作为一类新型抗肿瘤药的发展，如果进一步验证，它可能有助于AML的靶向分子治疗。