A Targeted and Stable Polymeric Nanoformulation Enhances Systemic Delivery of mRNA to Tumors

被引:77
作者
Chen, Qixian [1 ,2 ]
Qi, Ruogu [3 ]
Chen, Xiyi [4 ]
Yang, Xi [5 ]
Wu, Sudong [6 ]
Xiao, Haihua [3 ]
Dong, Wenfei [1 ]
机构
[1] Suzhou Inst Biomed Engn, CAS Key Lab Biomed Diagnost, Suzhou 215163, Peoples R China
[2] MIT, Dept Chem, Cambridge, MA 02139 USA
[3] Chinese Acad Sci, State Key Lab Polymer Phys & Chem, Changchun Inst Appl Chem, Changchun 130022, Peoples R China
[4] Dalian Med Univ, Sch Publ Hlth, 9 West Sect Lvshun South Rd, Dalian 116044, Peoples R China
[5] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Neurosurg, Shanghai 200127, Peoples R China
[6] Chinese Acad Sci, Ningbo Inst Mat Technol & Engn, Ningbo 315201, Zhejiang, Peoples R China
基金
中国国家自然科学基金;
关键词
VIVO GENE-TRANSFER; POLYPLEX MICELLES; PANCREATIC TUMORS; EXPRESSION; PEPTIDE; CANCER; THERAPIES; CELLS; DNA;
D O I
10.1016/j.ymthe.2016.10.006
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
The high vulnerability of mRNA necessitates the manufacture of delivery vehicles to afford adequate protection in the biological milieu. Here, mRNA was complexed with a mixture of cRGD-poly(ethylene glycol) (PEG)-polylysine (PLys) (thiol) and poly(N-isopropylacrylamide) (PNIPAM)-PLys(thiol). The ionic complex core consisting of opposite-charged PLys and mRNA was crosslinked though redox-responsive disulfide linkage, thereby avoiding structural disassembly for exposure of mRNA to harsh biological environments. Furthermore, PNIPAM contributed to prolonged survival in systemic circulation by presenting a spatial barrier in impeding accessibility of nucleases, e.g., RNase, due to the thermo-responsive hydrophilic-hydrophobic transition behavior upon incubation at physiological temperature enabling translocation of PNIPAM from shell to intermediate barrier. Ultimately, the cRGD ligand attached to the formulation demonstrated improved tumor accumulation and potent gene expression, as manifested by virtue of facilitated cellular uptake and intracellular trafficking. These results indicate promise for the utility of mRNA as a therapeutic tool for disease treatment.
引用
收藏
页码:92 / 101
页数:10
相关论文
共 22 条
[1]   A peptide nucleic acid-nuclear localization signal fusion that mediates nuclear transport of DNA [J].
Brandén, LJ ;
Mohamed, AJ ;
Smith, CIE .
NATURE BIOTECHNOLOGY, 1999, 17 (08) :784-787
[2]   REQUIREMENT OF VASCULAR INTEGRIN ALPHA(V)BETA(3) FOR ANGIOGENESIS [J].
BROOKS, PC ;
CLARK, RAF ;
CHERESH, DA .
SCIENCE, 1994, 264 (5158) :569-571
[3]   Targeted Polymeric Micelles for siRNA Treatment of Experimental Cancer by Intravenous Injection [J].
Christie, R. James ;
Matsumoto, Yu ;
Miyata, Kanjiro ;
Nomoto, Takahiro ;
Fukushima, Shigeto ;
Osada, Kensuke ;
Halnaut, Julien ;
Pittella, Frederico ;
Kim, Hyun Jin ;
Nishiyama, Nobuhiro ;
Kataoka, Kazunori .
ACS NANO, 2012, 6 (06) :5174-5189
[4]   Optimized rod length of polyplex micelles for maximizing transfection efficiency and their performance in systemic gene therapy against stroma-rich pancreatic tumors [J].
Dirisala, Anjaneyulu ;
Osada, Kensuke ;
Chen, Qixian ;
Tockary, Theofilus A. ;
Machitani, Kaori ;
Osawa, Shigehito ;
Liu, Xueying ;
Ishii, Takehiko ;
Miyata, Kanjiro ;
Oba, Makoto ;
Uchida, Satoshi ;
Itaka, Keiji ;
Kataoka, Kazunori .
BIOMATERIALS, 2014, 35 (20) :5359-5368
[5]  
Furger KA, 2003, MOL CANCER RES, V1, P810
[6]   Targeted gene delivery by polyplex micelles with crowded PEG palisade and cRGD moiety for systemic treatment of pancreatic tumors [J].
Ge, Zhishen ;
Chen, Qixian ;
Osada, Kensuke ;
Liu, Xueying ;
Tockary, Theofilus A. ;
Uchida, Satoshi ;
Dirisala, Anjaneyulu ;
Ishii, Takehiko ;
Nomoto, Takahiro ;
Toh, Kazuko ;
Matsumoto, Yu ;
Oba, Makoto ;
Kano, Mitsunobu R. ;
Itaka, Keiji ;
Kataoka, Kazunori .
BIOMATERIALS, 2014, 35 (10) :3416-3426
[7]   Block copolymer micelles for delivery of gene and related compounds [J].
Kakizawa, Y ;
Kataoka, K .
ADVANCED DRUG DELIVERY REVIEWS, 2002, 54 (02) :203-222
[8]   State-of-the-art gene-based therapies: the road ahead [J].
Kay, Mark A. .
NATURE REVIEWS GENETICS, 2011, 12 (05) :316-328
[9]   Delivery of Nucleic Acid Drugs [J].
Lee, Yan ;
Kataoka, Kazunori .
NUCLEIC ACID DRUGS, 2012, 249 :95-134
[10]   Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges [J].
Mingozzi, Federico ;
High, Katherine A. .
NATURE REVIEWS GENETICS, 2011, 12 (05) :341-355