Anti-CD33修饰的多肽纳米粒 (aCD33-KNSN) 细胞核靶向传递喜树碱对急性骨髓性白血病的治疗效果

Therapeutic Effect of Anti-CD33 Modified Peptide Nanoparticles (Anti-CD33-KNSN) on Acute Myeloid Leukemia by Targeted Delivery of Camptothecin to the Nucleus

关键词:  喜树碱  细胞核定位  aCD33-NKSN  急性骨髓性白血病  抗肿瘤活性

Key words:  Camptothecin  aCD33-NKSN  Nucleus-targeted  Acute Myeloid Leukemia  Antitumor activity

摘要:

目的 为了增强喜树碱细胞核靶向治疗效果,本研究合成了一种新的纳米递送载体 (aCD33-NKSN),其由CD33抗体 (aCD33)、核定位信号 (NLS)、基因融合肽 (KALA) 和硬脂酸 (SA) 四部分组成,用于CD33靶向和核定位传递喜树碱治疗急性骨髓性白血病 (AML)。方法 采用透析法制备载喜树碱aCD33-NKSN纳米粒 (CPT/aCD33-NKSN),检测其理化性质并考察其抗肿瘤活性。结果 CPT/aCD33-NKSN纳米粒为球形,平均尺寸为 96.4±7.8nm,zeta电位为 28.5±4.6 mV。CPT/aCD33-NKSN纳米粒的包封率和载药量分别达到 92.4% 和15.2%,并具有持续释药行为。组织分布和细胞摄取研究表明,CPT/aCD33-NKSN主要分布在Kasumi-1荷瘤小鼠的肿瘤部位,载香豆素-6 (C6) aCD33-NKSN纳米粒(C6/aCD33-NKSN) 能够定位到Kasumi-1细胞核。细胞凋亡和抗肿瘤活性研究表明,与游离CPT相比,CPT/aCD33-NKSN能更明显地诱导Kasumi-1细胞凋亡,CPT/aCD33-NKSN比游离CPT更有效地抑制Kasumi-1荷瘤小鼠体内肿瘤的生长,且毒性较轻。结论 CPT/aCD33-NKSN纳米粒系统可以增强包封药物的抗肿瘤效果,减少组织毒性,这可能归因于aCD33靶向性和核定位能力。该纳米递药系统构建为急性骨髓性白血病临床治疗提供一种新的治疗策略。

Abstract:

ABSTRACT: OBJECTIVE To enhance the effect of nuclear targeted therapy with camptothecin, in this study, a new nano-delivery carrier (aCD33-NKSN) was synthesized, which was composed of CD33 antibody (aCD33), nuclear localization signal (NLS), fusion peptide (KALA) and stearic acid (SA), It was used for CD33 targeting and nuclear localization delivery of camptothecin in the treatment of acute myeloid leukemia (AML). METHODS Camptothecin-loaded aCD33-NKSN nanoparticles (CPT/aCD33-NKSN) were prepared by dialysis, and their physical and chemical properties were tested and their antitumor activities were investigated in the treatment of acute myeloid leukemia (AML). RESULTS The CPT/aCD33-NKSN nanoparticles assumed a spherical morphology. Their average diameter measured 96.4±7.8 nm. Additionally, the zeta potential of these nanoparticles was determined to be 28.5±4.6 mV. The CPT/aCD33-NKSN nanoparticles were above 92.4% and 15.2% in entrapment ef?ciency and drug loading capacity, and had sustained drug release behavior. Biodistribution and cellular uptake study exhibited that CPT/aCD33-NKSN mainly distributed in tumor site of Kasumi-1-bearing mice, and coumarin-6 (C6) loaded aCD33-NKSN nanoparticle (C6/NKSN) was predominantly accumulated in the nucleus of Kasumi-1 cells. Cell apoptosis and antitumor activity study showed that CPT/aCD33-NKSN could more obviously induce apoptosis of Kasumi-1 cells compared with free CPT, CPT/aCD33-NKSN inhibited the growth of tumor in Kasumi-1 tumor-bearing mice more effectively than free CPT, and the toxicity was less obvious. CONCLUSION CPT/aCD33-NKSN nanoparticle system could enhance the anti-tumor effect of encapsulated drugs and reduce tissue toxicity, which may be attributed to the targeting of aCD33 and the ability of nuclear localization. Development of this nano drug delivery system could offer a fresh approach for the clinical treatment of AML.