Na Jin Hee, Koo Heebeom, Lee Sangmin, Han Seung Jin, Lee Kyung Eun, Kim Sunjin, Lee Haeshin, Lee Seulki, Choi Kuiwon, Kwon Ick Chan, Kim Kwangmeyung
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST) , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine , 601 North Caroline Street, Baltimore, Maryland 21287, United States.
Mol Pharm. 2016 Nov 7;13(11):3700-3711. doi: 10.1021/acs.molpharmaceut.6b00507. Epub 2016 Oct 3.
Herein, we elucidated the mechanisms and key factors for the tumor-targeting ability of nanoparticles that presented high targeting efficiency for liver tumor. We used several different nanoparticles with sizes of 200-300 nm, including liposome nanoparticles (LNPs), polystyrene nanoparticles (PNPs) and glycol chitosan-5β-cholanic acid nanoparticles (CNPs). Their sizes are suitable for the enhanced permeation and retention (EPR) effect in literature. Different in vitro characteristics, such as the particle structure, stability, and bioinertness, were carefully analyzed with and without serum proteins. Also, pH-dependent tumor cell uptakes of nanoparticles were studied using fluorescence microscopy. Importantly, CNPs had sufficient stability and bioinertness to maintain their nanoparticle structure in the bloodstream, and they also presented prolonged circulation time in the body (blood circulation half-life T = about 12.2 h), compared to the control nanoparticles. Finally, employing liver tumor bearing mice, we also observed that CNPs had excellent liver tumor targeting ability in vivo, while LNPs and PNPs demonstrated lower tumor-targeting efficiency due to the nonspecific accumulation in normal liver tissue. Liver tumor models were produced by laparotomy and direct injection of HT29 tumor cells into the left lobe of the liver of athymic nude mice. This study provides valuable information concerning the key factors for the tumor-targeting ability of nanoparticles such as stability, bioinertness, and rapid cellular uptake at targeted tumor tissues.
在此，我们阐明了对肝肿瘤具有高靶向效率的纳米颗粒的肿瘤靶向能力的机制和关键因素。我们使用了几种不同尺寸为200 - 300 nm的纳米颗粒，包括脂质体纳米颗粒（LNPs）、聚苯乙烯纳米颗粒（PNPs）和乙二醇壳聚糖 - 5β - 胆酸纳米颗粒（CNPs）。它们的尺寸在文献中适合增强渗透与滞留（EPR）效应。在有无血清蛋白的情况下，仔细分析了不同的体外特性，如颗粒结构、稳定性和生物惰性。此外，使用荧光显微镜研究了纳米颗粒的pH依赖性肿瘤细胞摄取。重要的是，与对照纳米颗粒相比，CNPs具有足够的稳定性和生物惰性，能够在血流中维持其纳米颗粒结构，并且它们在体内的循环时间也延长了（血液循环半衰期T = 约12.2小时）。最后，在荷肝肿瘤小鼠中，我们还观察到CNPs在体内具有出色的肝肿瘤靶向能力，而LNPs和PNPs由于在正常肝组织中的非特异性积累，表现出较低的肿瘤靶向效率。肝肿瘤模型是通过剖腹手术并将HT29肿瘤细胞直接注射到无胸腺裸鼠肝脏左叶中产生的。本研究提供了有关纳米颗粒肿瘤靶向能力的关键因素的有价值信息，如稳定性、生物惰性以及在靶向肿瘤组织处的快速细胞摄取。
