title: Magnetic resonance-guided regional gene delivery strategy using a tumor stroma-permeable nanocarrier for pancreatic cancer.
abstract: BACKGROUND
  Gene therapy is a very promising technology for treatment of pancreatic ductal adenocarcinoma (PDAC). However, its application has been limited by the abundant stromal response in the tumor microenvironment. The aim of this study was to prepare a dendrimer-based gene-free loading vector with high permeability in the tumor stroma and explore an imaging-guided local gene delivery strategy for PDAC to promote the efficiency of targeted gene delivery.
  
  
  METHODS
  The experimental protocol was approved by the animal ethics committee of Zhongshan Hospital, Fudan University. Third-generation dendrigraft poly-L-lysines was selected as the nanocarrier scaffold, which was modified by cell-penetrating peptides and gadolinium (Gd) chelates. DNA plasmids were loaded with these nanocarriers via electrostatic interaction. The cellular uptake and loaded gene expression were examined in MIA PaCa-2 cell lines in vitro. Permeability of the nanoparticles in the tumor stroma and transfected gene distribution in vivo were studied using a magnetic resonance imaging-guided delivery strategy in an orthotopic nude mouse model of PDAC.
  
  
  RESULTS
  The nanocarriers were synthesized with a dendrigraft poly-L-lysine to polyethylene glycol to DTPA ratio of 1:3.4:8.3 and a mean diameter of 110.9±7.7 nm. The luciferases were strictly expressed in the tumor, and the luminescence intensity in mice treated by Gd-DPT/plasmid luciferase (1.04×10(4)±9.75×10(2) p/s/cm(2)/sr) was significantly (P<0.05) higher than in those treated with Gd-DTPA (9.56×10(2)±6.15×10 p/s/cm(2)/sr) and Gd-DP (5.75×10(3)± 7.45×10(2) p/s/cm(2)/sr). Permeability of the nanoparticles modified by cell-penetrating peptides was superior to that of the unmodified counterpart, demonstrating the improved capability of nanoparticles for diffusion in tumor stroma on magnetic resonance imaging.
  
  
  CONCLUSIONS
  This study demonstrated that an image-guided gene delivery system with a stroma-permeable gene vector could be a potential clinically translatable gene therapy strategy for PDAC.
authors.affiliation: Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China ; Shanghai Institute of Medical Imaging, Fudan University, Shanghai, People's Republic of China.
authors.forename: Qingbing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Sai
authors.initials: S
authors.lastname: An
authors.affiliation: Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China ; Shanghai Institute of Medical Imaging, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D010190:Pancreatic Neoplasms / Q000378:metabolism*
keywords: cell-penetrating peptides; genetic therapy; interventional; magnetic resonance imaging; molecular imaging; pancreatic cancer