CD44-Targeted Hyaluronic Acid-Coated Redox-Responsive Hyperbranched Poly(amido amine)/Plasmid DNA Ternary Nanoassemblies for Efficient Gene Delivery.
Hyaluronic acid (HA), which can specifically bind to CD44 receptor, is a specific ligand for targeting to CD44-overexpressing cancer cells. The current study aimed to develop ternary nanoassemblies based on HA-coating for targeted gene delivery to CD44-positive tumors. A novel reducible hyperbranched poly(amido amine) (RHB) was assembled with plasmid DNA (pDNA) to form RHB/pDNA nanoassemblies. HA/RHB/pDNA nanoassemblies were fabricated by coating HA on the surface of the RHB/pDNA nanoassembly core through electrostatic interaction. After optimization, HA/RHB/pDNA nanoassemblies were spherical, core-shell nanoparticles with nanosize (187.6 ± 11.4 nm) and negative charge (-9.1 ± 0.3 mV). The ternary nanoassemblies could efficiently protect the condensed pDNA from enzymatic degradation by DNase I, and HA could significantly improve the stability of nanoassemblies in the sodium heparin solution or serum in vitro. As expected, HA significantly decreased the cytotoxicity of RHB/pDNA nanoassemblies due to the negative surface charges. Moreover, it revealed that HA/RHB/pDNA nanoassemblies showed higher transfection activity than RHB/pDNA nanoassemblies in B16F10 cells, especially in the presence of serum in vitro. Because of the active recognition between HA and CD44 receptor, there was significantly different transfection efficiency between B16F10 (CD44+) and NIH3T3 (CD44-) cells after treatment with HA/RHB/pDNA nanoassemblies. In addition, the cellular targeting and transfection activity of HA/RHB/pDNA nanoassemblies were further evaluated in vivo. The results indicated that the interaction between HA and CD44 receptor dramatically improved the accumulation of HA/RHB/pDNA nanoassemblies in CD44-positive tumor, leading to higher gene expression than RHB/pDNA nanoassemblies. Therefore, HA/RHB/pDNA ternary nanoassemblies may be a potential gene vector for delivery of therapeutic genes to treat CD44-overexpressing tumors in vivo.
Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, PR China.|Laboratory for Drug Delivery and Biomaterials, Faculty of Pharmacy, University of Manitoba , 750 McDermot Avenue, Winnipeg, Manitoba R3E 0T5, Canada.
Jijin
J
Gu
Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, PR China.
Xinyi
X
Chen
Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, PR China.
Xiaoqing
X
Ren
Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, PR China.
Xiulei
X
Zhang
Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, PR China.
Xiaoling
X
Fang
Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, PR China.
Xianyi
X
Sha
D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D065546:Drug Liberation; D004355:Drug Stability; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry*; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D053758:Nanoparticles / Q000737:chemistry*; D010084:Oxidation-Reduction; D010957:Plasmids / Q000235:genetics*; D011073:Polyamines / Q000737:chemistry*; D014162:Transfection
D004337:Drug Carriers; D018960:Hyaluronan Receptors; C531249:Poly(amidoamine); D011073:Polyamines; D006820:Hyaluronic Acid; D004247:DNA