Journal
ACS NANO
Volume 10, Issue 12, Pages 11548-11560Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.6b06182
Keywords
systemic administration; cancer gene therapy; oncolytic adenovirus; calcium phosphate (CaP); preexisting immunity; liver sequestration
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Funding
- National Natural Science Foundation of China [81472841, 81572999, 81502692]
- State Key Laboratory of Oncogenes and Related Genes [91-14-01, 91-15-08]
- Shanghai Municipal Health and Family Planning Commission Foundation [201440015]
- Science and Technology Commission foundation of Shanghai [14JC1492500]
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Oncolytic adenovirus (Onco(Ad)) is a promising therapeutic agent for treating cancer. However, the therapeutic potential of Onco(Ad) is hindered by hepatic sequestration and the host immune response in vivo. Here, we constructed a PEG/Lipids/calcium phosphate (CaP)-Onco(Ad) (PLC-Onco(Ad)) delivery system for ZD55-IL-24, an oncolytic adenovirus that carries the IL-24 gene. The negatively charged PLC-ZDS5-IL-24 were disperse and resisted serum-induced aggregation. Compared to naked ZDS5-IL-24, the systemic administration of PLC-ZD55-IL-24 in BALB/c mice resulted in reduced liver sequestration and systemic toxicity and evaded the innate immune response. In addition, masking the surface of OncoAd protected it from neutralization by pre-existing neutralizing antibody. PLC-Onco(Ad) achieved efficient targeted delivery in Huh-7-bearing nude mice, and intravenous administration of a high dose of PLC-ZD55-IL-24 increased therapeutic efficacy without inducing toxicity. The developed PLC-Onco(Ad) delivery system represents a promising improvement for oncolytic adenovirus-based cancer gene therapy in vivo.
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