title: Bio-inspired polymer envelopes around adenoviral vectors to reduce immunogenicity and improve in vivo kinetics.
abstract: Adenoviral vectors have attracted substantial interest for systemic tumor gene therapy, but further work is needed to reduce their immunogenicity and alter their biodistribution before they can be used in the clinic. Here we describe a bio-inspired, cleavable PEGylated β-cyclodextrin-polyethyleneimine conjugate (CDPCP) that spontaneously coats adenovirus in solution. This cleavable PEG coating reduces the innate and adaptive immunogenicity of adenovirus particles, as well as improves their biodistribution away from the liver and into the tumor. Insertion of a matrix metalloproteinase substrate sequence into the conjugate allows PEG cleavage at the tumor site, simultaneously reducing liver biodistribution and increasing transgene expression in tumors, thereby avoiding the "PEG dilemma". Cationic β-cyclodextrin-PEI not only provides electrostatic attraction to promote envelope attachment to the viral capsid, but it also improves vector internalization and transduction after PEG cleavage. These results suggest that CDPCP may help expand the use of adenoviral vectors in cancer gene therapy.
  
  
  CONCLUSIONS
  The synthesized β-cyclodextrin-PEI-MMP-cleavable-PEG polymer (CDPCP), held great potential for gene therapy when applied for adenovirus coating. The β-cyclodextrin-PEI provided a powerful electrostatic attraction to attach the whole polymer onto the viral capsid, while the MMPs-cleavable PEG reduced innate and adaptive immunogenicity and improved the biodistribution of adenovirus vectors due to the tumor-specific enzyme triggered PEG cleavage. More importantly, an ingenious cooperation between the two components could solve the PEG dilemma. The CDPCP/Ad complexes exhibited a comprehensive and valued profile to be a candidate vector for future tumor gene therapy, we believe the current investigation on this kind of biomaterial may be of particular interest to the readership of Acta biomaterialia.
authors.affiliation: Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Gerui
authors.initials: G
authors.lastname: Fan
authors.affiliation: Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Fan
authors.affiliation: Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.affiliation: Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: xunsun22@gmail.com.
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
mesh_terms: D000256:Adenoviridae / Q000737:chemistry / Q000276:immunology; D000818:Animals; D045744:Cell Line, Tumor; D020099:Coated Materials, Biocompatible / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology
chemical_list: D020099:Coated Materials, Biocompatible; D009944:Organoplatinum Compounds; C530333:cis-diammine(pyridine)chloroplatinum(II)
keywords: Adenovirus; Cleavable PEG; Gene therapy; PEI; β-Cyclodextrin