A Novel DNA Tetrahedron Nanodrug Delivery System for Targeting Breast Cancer Cells
ZHANG Fang-hua, ZHANG Chao, YIN Ji-wei, HAN Meng-nan, WANG Xu-ming, LI Wei, DU Jie*, ZHANG Hong-lei*
Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China
Abstract：OBJECTIVE To design and develop a new affibody-engineered DNA nanostructure attached with nucleoside analogues to improve treatment efficacy and reduce their systemic toxicity. METHODS 5-Fluorodeoxyuridine (FUdR) was chosen as a typical nucleoside and derivatized to its phosphoramidite form. Four DNA strands were synthesized and 10 FUdR molecules were attached to 5' end of each DNA strand. An affibody molecule was connected to the end of polymeric FUdR through a linker in one of the four strands. A DNA tetrahedron was self-assembled through four DNA strands according to the principle of base complementary pairing. RESULTS This nano-drug has a size of 20 nm, and the drug-loading of 19.6% for FUdR in mole ratio was contained. The drug also have a good stability in plasma. The in vitro results showed that the nano-drug had high selectivity and inhibition (81.2%) for breast cancer cells BT474 overexpressing HER2 and low toxicity in MCF-7 cells with low HER2 expression. CONCULUSION The affibody-DNA tetrahedrons, as a simple and effective active targeting delivery nanocarrier, provide a new avenue for the transport of nucleoside antitumor drugs.
张芳华, 张超, 尹纪伟, 韩孟楠, 王旭明, 李玮, 杜洁, 张红蕾. 新型DNA四面体纳米载药系统靶向乳腺癌细胞的研究[J]. 中国药学杂志, 2021, 56(23): 1932-1940.
ZHANG Fang-hua, ZHANG Chao, YIN Ji-wei, HAN Meng-nan, WANG Xu-ming, LI Wei, DU Jie, ZHANG Hong-lei. A Novel DNA Tetrahedron Nanodrug Delivery System for Targeting Breast Cancer Cells. Chinese Pharmaceutical Journal, 2021, 56(23): 1932-1940.
GALMARINI C M, MACKEY J R, DUMONTET C, et al. Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol, 2002, 3(7): 415-424.
[2]
PARKER W B, et al. Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chem Rev, 2009, 109(7):2880-2893.
[3]
JORDHEIM L P, DURANTEL D, ZOULIM F, et al. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov, 2013, 12(6): 447-464.
[4]
HEIDELBERGER C, CHAUDHURI N K, DANNEBERG P, et al. Fluorinated pyrimidines, a new class of tumor-inhibitory compounds. Nature, 1957, 179(4561): 663-666.
[5]
LONGLEY D, HARKIN D P, JOHNSTON P G, et al. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer, 2003, 3(5): 330-338.
[6]
SEO H W, KIM D Y, KWON D Y, et al. Injectable intratumoral hydrogel as 5-fluorouracil drug depot. Biomaterials, 2013, 34(11): 2748-2757.
[7]
ELMESHAD A N, MORTAZAVI S M, MOZAFARI M R, et al. Formulation and characterization of nanoliposomal 5-fluorouracil for cancer nanotherapy. J Liposome Res, 2014, 24(1): 1-9.
[8]
ROTH S K, EPLEY C C, NOVAK J J, et al. Photo-triggered release of 5-fluorouracil from a MOF drug delivery vehicle. Chem Commun, 2018, 54(55): 7617-7620.
[9]
SHAYAN K, NOWROOZI A, et al. Boron nitride nanotubes for delivery of 5-fluorouracil as anticancer drug: a theoretical study. Appl Surf Sci, 2018, 428(15): 500-513.
[10]
WANG P, MEYER T A, PAN V, et al. The beauty and utility of DNA origami. Chem, 2017, 2(3): 359-382.
[11]
GOODMAN R P, SCHAAP I A T, TARDIN C F, et al. Rapid chiral assembly of rigid DNA building blocks for molecular nanofabrication. Science, 2005, 310(5754): 1661-1665.
[12]
GOODMAN R P, BERRY R M, TURBERFIELD A J, et al. The single-step synthesis of a DNA tetrahedron. Chem Commun, 2004, 21(12): 1372-1373.
[13]
KANG J H, KIM K R, LEE H, et al. In vitro and in vivo behavior of DNA tetrahedrons as tumor-targeting nanocarriers for doxorubicin delivery. Colloids Surf B, 2017, 157(2017): 424-431.
[14]
ZHANG G, ZHANG Z, YANG J, et al. DNA tetrahedron delivery enhances doxorubicin-induced apoptosis of HT-29 colon cancer cells. Nanoscale Res Lett, 2017, 12(1): 495-503.
[15]
ZHANG Y, JIANG S, ZHANG D, et al. DNA-affibody nanoparticles for inhibiting breast cancer cells overexpressing HER2. Chem Commun, 2017, 53(3): 573-576.
[16]
ZHANG C, ZHANG H L, HAN M N, et al. DNA-affibody nanoparticle delivery system for cisplatin-based breast cancer chemotherapy. RSC Adv, 2019, 9(10): 1982-1989.
[17]
SILVA E F, BAZONI R F, RAMOS E B, et al. DNA-doxorubicin interaction: new insights and peculiarities. Biopolymers, 2016, 107(3): 22998-23007.
[18]
STHL S, GRSLUND T, KARLSTRM A E, et al. Affibody molecules in biotechnological and medical applications. Trends Biotechnol, 2017, 35(8): 691-712.
[19]
EIGENBROT C, ULTSCH M, DUBNOVITSKY A, et al. Structural basis for high-affinity HER2 receptor binding by an engineered protein. Proc Natl Acad Sci USA, 2010, 107(34): 15039-15044.
2021, Vol. 56 
