Chemical modification with high molecular weight polyethylene glycol reduces transduction of hepatocytes and increases efficacy of intravenously delivered oncolytic adenovirus

Konstantin Doronin, Elena V. Shashkova, Shannon M. May, Sean E. Hofherr, Michael A Barry

Research output: Contribution to journalArticle

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Abstract

Oncolytic adenoviruses are anticancer agents that replicate within tumors and spread to uninfected tumor cells, amplifying the anticancer effect of initial transduction. We tested whether coating the viral particle with polyethylene glycol (PEG) could reduce transduction of hepatocytes and hepatotoxicity after systemic (intravenous) administration of oncolytic adenovirus serotype 5 (Ad5). Conjugating Ad5 with high molecular weight 20-kDa PEG but not with 5-kDa PEG reduced hepatocyte transduction and hepatotoxicity after intravenous injection. PEGylation with 20-kDa PEG was as efficient at detargeting adenovirus from Kupffer cells and hepatocytes as virus predosing and warfarin. Bioluminescence imaging of virus distribution in two xenograft tumor models in nude mice demonstrated that PEGylation with 20-kDa PEG reduced liver infection 19- to 90-fold. Tumor transduction levels were similar for vectors PEGylated with 20-kDa PEG and unPEGylated vectors. Anticancer efficacy after a single intravenous injection was retained at the level of unmodified vector in large established prostate carcinoma xenografts, resulting in complete elimination of tumors in all animals and long-term tumor-free survival. Anticancer efficacy after a single intravenous injection was increased in large established hepatocellular carcinoma xenografts, resulting in significant prolongation of survival as compared with unmodified vector. The increase in efficacy was comparable to that obtained with predosing and warfarin pretreatment, significantly extending the median of survival. Shielding adenovirus with 20-kDa PEG may be a useful approach to improve the therapeutic window of oncolytic adenovirus after systemic delivery to primary and metastatic tumor sites.

Original languageEnglish (US)
Pages (from-to)975-988
Number of pages14
JournalHuman Gene Therapy
Volume20
Issue number9
DOIs
StatePublished - Sep 1 2009

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Adenoviridae
Hepatocytes
Molecular Weight
Neoplasms
Heterografts
Intravenous Injections
Warfarin
Viruses
Kupffer Cells
Nude Mice
Intravenous Administration
Virion
Antineoplastic Agents
Prostate
Hepatocellular Carcinoma
Carcinoma
Liver
Infection

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Chemical modification with high molecular weight polyethylene glycol reduces transduction of hepatocytes and increases efficacy of intravenously delivered oncolytic adenovirus. / Doronin, Konstantin; Shashkova, Elena V.; May, Shannon M.; Hofherr, Sean E.; Barry, Michael A.

In: Human Gene Therapy, Vol. 20, No. 9, 01.09.2009, p. 975-988.

Research output: Contribution to journalArticle

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