Hematology Unit, Clinical Pathology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
Molecules. 2019 Jun 3;24(11):2103. doi: 10.3390/molecules24112103.
The targeted nano-encapsulation of anticancer drugs can improve drug delivery and the selective targeting of cancer cells. Nuclear factor kappa B (NF-kB) is a regulator for different biological responses, including cell proliferation and differentiation. In acute myeloid leukemia (AML), constitutive NF-κB has been detected in more than 50% of cases, enabling leukemic cells to resist apoptosis and stimulate uncontrolled proliferation. We evaluated NF-kB expression in bone marrow samples from 103 patients with AML using quantitative real time polymerase chain reaction (RT-PCR) and found that expression was increased in 80.5% (83 out 103) of these patients with AML in comparison to the control group. Furthermore, overexpressed transmembrane glycoprotein (CD44) on leukemic cells in comparison to normal cells is known to play an important role in leukemic cell engraftment and survival. We designed poly lactide co-glycolide (PLGA) nanoparticles conjugated with antiCD44 and encapsulating parthenolide (PTL), a nuclear factor kappa B (NF-kB) inhibitor, in order to improve the selectivity and targeting of leukemic cells and to spare normal cells. In vitro, in leukemic cell lines Kasumi-1, KG-1a, and THP-1, proliferation was decreased by 40% (** < 0.01) with 5 µM PLGA-antiCD44-PTL nanoparticles in comparison to the same concentration of free PTL (~10%). The higher uptake of the nanoparticles by leukemic cells was confirmed with confocal microscopy. In conclusion, PLGA-antiCD44-PTL nanoparticles improved the bioavailability and selective targeting of leukemic cells, thus holding promise as a drug delivery system to improve the cure rate of AML.
载药纳米囊泡可以提高药物传递效率和肿瘤细胞的靶向性。核因子-κB（NF-κB）是细胞增殖和分化等多种生物学反应的调节因子。在急性髓系白血病（AML）中，超过 50%的病例中存在组成性 NF-κB，使白血病细胞能够抵抗凋亡并刺激不受控制的增殖。我们使用实时定量聚合酶链反应（RT-PCR）评估了 103 例 AML 患者骨髓样本中的 NF-κB 表达情况，发现与对照组相比，80.5%（83/103）的 AML 患者 NF-κB 表达增加。此外，与正常细胞相比，白血病细胞上过表达的跨膜糖蛋白（CD44）在白血病细胞植入和存活中发挥重要作用。我们设计了聚乳酸-羟基乙酸共聚物（PLGA）纳米粒，与抗 CD44 偶联并包载倍半萜内酯（PTL），即核因子-κB（NF-κB）抑制剂，以提高白血病细胞的选择性和靶向性，并保护正常细胞。在体外，在白血病细胞系 Kasumi-1、KG-1a 和 THP-1 中，与相同浓度的游离 PTL（~10%）相比，浓度为 5 μM 的 PLGA-antiCD44-PTL 纳米粒使细胞增殖减少了 40%（**<0.01）。共聚焦显微镜证实了纳米粒被白血病细胞的摄取增加。总之，PLGA-antiCD44-PTL 纳米粒提高了药物的生物利用度和白血病细胞的靶向性，因此有望作为一种药物传递系统，提高 AML 的治愈率。
