PMID- 30874432
OWN - NLM
STAT- MEDLINE
DCOM- 20200217
LR  - 20240210
IS  - 1520-4812 (Electronic)
IS  - 1043-1802 (Linking)
VI  - 30
IP  - 4
DP  - 2019 Apr 17
TI  - Polyvalent Diazonium Polymers Provide Efficient Protection of Oncolytic 
      Adenovirus Enadenotucirev from Neutralizing Antibodies while Maintaining 
      Biological Activity In Vitro and In Vivo.
PG  - 1244-1257
LID - 10.1021/acs.bioconjchem.9b00189 [doi]
AB  - Oncolytic viruses offer many advantages for cancer therapy when administered 
      directly to confined solid tumors. However, the systemic delivery of these 
      viruses is problematic because of the host immune response, undesired 
      interactions with blood components, and inherent targeting to the liver. Efficacy 
      of systemically administered viruses has been improved by masking viral surface 
      proteins with polymeric materials resulting in modulation of viral 
      pharmacokinetic profile and accumulation in tumors in vivo. Here we describe a 
      new class of polyvalent reactive polymer based on poly( 
      N-(2-hydroxypropyl)methacrylamide) (polyHPMA) with diazonium reactive groups and 
      their application in the modification of the chimeric group B oncolytic virus 
      enadenotucirev (EnAd). A series of six copolymers with different chain lengths 
      and density of reactive groups was synthesized and used to coat EnAd. Polymer 
      coating was found to be extremely efficient with concentrations as low as 1 mg/mL 
      resulting in complete (>99%) ablation of neutralizing antibody binding. Coating 
      efficiency was found to be dependent on both chain length and reactive group 
      density. Coated viruses were found to have reduced transfection activity both in 
      vitro and in vivo, with greater protection against neutralizing antibodies 
      resulting in lower transgene production. However, in the presence of neutralizing 
      antibodies, some in vivo transgene expression was maintained for coated virus 
      compared to the uncoated control. The decrease in transgene expression was found 
      not to be solely due to lower cellular uptake but due to reduced unpackaging of 
      the virus within the cells and reduced replication, indicating that the polymer 
      coating does not cause permanent inactivation of the virus. These data suggest 
      that virus activity may be modulated by the appropriate design of coating 
      polymers while retaining protection against neutralizing antibodies.
FAU - Francini, Nora
AU  - Francini N
AD  - School of Pharmacy , University of Nottingham , Nottingham NG7 2RD , U.K.
FAU - Cochrane, Daniel
AU  - Cochrane D
AD  - PsiOxus Therapeutics Limited , 4-10, The Quadrant, Abingdon Science Park , 
      Abingdon , Oxfordshire OX14 3YS , U.K.
FAU - Illingworth, Sam
AU  - Illingworth S
AD  - PsiOxus Therapeutics Limited , 4-10, The Quadrant, Abingdon Science Park , 
      Abingdon , Oxfordshire OX14 3YS , U.K.
FAU - Purdie, Laura
AU  - Purdie L
AD  - School of Pharmacy , University of Nottingham , Nottingham NG7 2RD , U.K.
FAU - Mantovani, Giuseppe
AU  - Mantovani G
AUID- ORCID: 0000-0002-0837-0351
AD  - School of Pharmacy , University of Nottingham , Nottingham NG7 2RD , U.K.
FAU - Fisher, Kerry
AU  - Fisher K
AD  - PsiOxus Therapeutics Limited , 4-10, The Quadrant, Abingdon Science Park , 
      Abingdon , Oxfordshire OX14 3YS , U.K.
AD  - Department of Oncology , Old Road Campus Research Building , Roosevelt Drive , 
      Oxford OX3 7DQ , U.K.
FAU - Seymour, Leonard W
AU  - Seymour LW
AD  - Department of Oncology , Old Road Campus Research Building , Roosevelt Drive , 
      Oxford OX3 7DQ , U.K.
FAU - Spain, Sebastian G
AU  - Spain SG
AUID- ORCID: 0000-0001-7241-5713
AD  - Department of Chemistry , University of Sheffield , Sheffield S3 7HF , U.K.
FAU - Alexander, Cameron
AU  - Alexander C
AD  - School of Pharmacy , University of Nottingham , Nottingham NG7 2RD , U.K.
LA  - eng
GR  - 29106/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190327
PL  - United States
TA  - Bioconjug Chem
JT  - Bioconjugate chemistry
JID - 9010319
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Diazonium Compounds)
RN  - 0 (Polymers)
RN  - 0 (enadenotucirev)
SB  - IM
MH  - Adenoviridae/*immunology
MH  - Antibodies, Neutralizing/*immunology
MH  - Cell Line, Tumor
MH  - Diazonium Compounds/chemistry/*pharmacology
MH  - Genetic Vectors
MH  - Humans
MH  - *Oncolytic Virotherapy
MH  - Polymers/chemistry/*pharmacology
MH  - Transfection
EDAT- 2019/03/16 06:00
MHDA- 2020/02/18 06:00
CRDT- 2019/03/16 06:00
PHST- 2019/03/16 06:00 [pubmed]
PHST- 2020/02/18 06:00 [medline]
PHST- 2019/03/16 06:00 [entrez]
AID - 10.1021/acs.bioconjchem.9b00189 [doi]
PST - ppublish
SO  - Bioconjug Chem. 2019 Apr 17;30(4):1244-1257. doi: 
      10.1021/acs.bioconjchem.9b00189. Epub 2019 Mar 27.