Linearized oncolytic adenoviral plasmid DNA delivered by bioreducible polymers.
As an effort to overcome limits of adenovirus (Ad) as a systemic delivery vector for cancer therapy, we developed a novel system using oncolytic Ad plasmid DNA with two bioreducible polymers: arginine-grafted bioreducible poly(disulfide amine)polymer (ABP) and PEG5k-conjugated ABP (ABP5k) in expectation of oncolytic effect caused by progeny viral production followed by replication. The linearized Ad DNAs for active viral replication polyplexed with each polymer were able to replicate only in human cancer cells and produce progeny viruses. The non-immunogenic polymers delivering the DNAs markedly elicited to evade the innate and adaptive immune response. The biodistribution ratio of the polyplexes administered systemically was approximately 99% decreased in liver when compared with naked Ad. Moreover, tumor-to-liver ratio of the Ad DNA delivered by ABP or ABP5k was significantly elevated at 229- or 419-fold greater than that of naked Ad, respectively. The ABP5k improved the chance of the DNA to localize within tumor versus liver with 1.8-fold increased ratio. In conclusion, the innovative and simple system for delivering oncolytic Ad plasmid DNA with the bioreducible polymers, skipping time-consuming steps such as generation and characterization of oncolytic Ad vectors, can be utilized as an alternative approach for cancer therapy.
Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Jaesung
J
Kim
Pyung-Hwan
PH
Kim
Hye Yeong
HY
Nam
Jung-Sun
JS
Lee
Chae-Ok
CO
Yun
Sung Wan
SW
Kim
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001120:Arginine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D010957:Plasmids; D011073:Polyamines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution
D004279:DNA, Viral; D015850:Interleukin-6; D011073:Polyamines; C534803:arginine-grafted bioreducible poly(disulfide amine)polymer; D011092:Polyethylene Glycols; D001120:Arginine