Li Xiangyu, Fu Huaxia, Wang Jing, Liu Wei, Deng Hao, Zhao Peng, Liao Wei, Yang Yuchuan, Wei Hongyuan, Yang Xia, Chen Yue
Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, China; Institute of Nuclear Physics and Chemistry, China Academy of Engineering Physics, 621900 Mianyang, China.
Institute of Nuclear Physics and Chemistry, China Academy of Engineering Physics, 621900 Mianyang, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu, Higher Education Institutions, 215123 Suzhou, China; Key Laboratory of Nuclear Medicine and Molecular Imaging of Sichuan Province, 621999 Mianyang, China.
Eur J Pharm Sci. 2021 Jun 1;161:105775. doi: 10.1016/j.ejps.2021.105775. Epub 2021 Feb 25.
Hyaluronan (HA) is a negatively charged linear polysaccharide that can interact with cluster determinant 44 (CD44) overexpressed cancers. However, HA can also bind to excess substrates in the human body leading to the lower specificity of tumor targeting. Conjugation of other targeting group to HA could enhance the uptake by cancer cell comparing to that of native HA. In this study, we develop the multi-functionalized HA (Lu-DOTA/Alexa647-HA100-N) for malignant tumor targeting. An asparagine-glycine-arginine (NGR) based peptide was selected for HA functionalization. The peptide is known to target CD13 receptor that is overexpressed in malignant tumors with abundant blood vessels, such as lung cancer. Furthermore, the fluorescent probe Alexa Fluor 647 for ex vivo/in vivo tracking and the radionuclide Lu for radioactive therapy were both labeled on the material. The functionalized HA could be bound by lung cancer cells and breast cancer cells. In vivo fluorescent imaging showed that the material could accumulate in the tumor site for more than 96 h. The Lu labeling of functionalized HA was stable for more 48 h at physiological conditions. The accumulation of Lu-DOTA/Alexa647-HA100-N in the tumor of lung cancer (NCI-H292) bearing mice was 1.91±0.97%ID/g, and it was about 17 times higher than the value in blood. Conclusion: The multimodality labeled functional HA was successfully prepared and could be fluorescent trackable ex vivo and in vivo. It showed high potential to be used for malignant cancer radiotherapy for its specific targeting property to tumors and radiotoxicity from the labeled Lu radionuclide.
透明质酸（HA）是一种带负电荷的线性多糖，可与过表达簇分化抗原44（CD44）的癌症相互作用。然而，HA也可与人体内的过量底物结合，导致肿瘤靶向的特异性降低。与天然HA相比，将其他靶向基团与HA偶联可增强癌细胞对其的摄取。在本研究中，我们开发了用于恶性肿瘤靶向的多功能化HA（Lu-DOTA/Alexa647-HA100-N）。选择基于天冬酰胺-甘氨酸-精氨酸（NGR）的肽对HA进行功能化。已知该肽靶向在血管丰富的恶性肿瘤（如肺癌）中过表达的CD13受体。此外，用于体外/体内追踪的荧光探针Alexa Fluor 647和用于放射治疗的放射性核素镥均标记在该材料上。功能化的HA可被肺癌细胞和乳腺癌细胞结合。体内荧光成像显示该材料可在肿瘤部位积聚超过96小时。功能化HA的镥标记在生理条件下48小时以上保持稳定。Lu-DOTA/Alexa647-HA100-N在荷肺癌（NCI-H292）小鼠肿瘤中的蓄积量为1.91±0.97%ID/g，约为血液中该值的17倍。结论：成功制备了多模态标记的功能化HA，其在体外和体内均可进行荧光追踪。因其对肿瘤的特异性靶向特性和标记的镥放射性核素的放射毒性，显示出用于恶性肿瘤放射治疗的巨大潜力。
