A Combined Chemoimmunotherapy Approach Using a Plasmid-Doxorubicin Complex

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We report a combined chemoimmunotherapy vehicle consisting of plasmid loaded with doxorubicin and evaluate its efficacy in two different tumor models. A stable complex was formed with a 1300:1 ratio of doxorubicin bound to native plasmid via intercalation. Pharmacokinetics of the complex showed much slower clearance from plasma up to 3 h compared to 10 min for free doxorubicin. In mice bearing NCl-H358 xenografts, lower doses of complex (doxorubicin 0.5 mg/kg, plasmid 4 mg/kg) effectively reduced tumor growth compared to high doses (5 mg/kg) of free doxorubicin (68% versus 77%). Similar results were observed in mice bearing 4T1 murine allografts; the complex (doxorubicin 2 mg/kg, plasmid 8 mg/kg) was effective and caused similar reduction of tumor compared to free doxorubicin (4 mg/kg) (47% versus 46%). The complex showed no signs of severe systemic toxicity or cardiotoxicity compared to the free doxorubicin in mice as indicated by body weights and heart tissue histology. Elevated levels of cytokines (IL-12, IL-6, and IFN-gamma) were observed in serum as well as in tumor tissue after intravenous injection of complex when compared to plasmid or doxorubicin alone. This approach simultaneously delivers both chemotherapeutic and immunotherapeutic agents without time delay, improves pharmacokinetics of the free drug, lowers drug toxicity, upregulates a variety of cytokines, and is effective against different tumors.
Publisher
AMER CHEMICAL SOC
Issue Date
2009-05
Language
English
Article Type
Article
Keywords

CPG MOTIFS ENHANCE; CELL LUNG-CANCER; ANTITUMOR-ACTIVITY; BACTERIAL-DNA; ANTIBODY THERAPY; DAUNORUBICIN-DNA; IMMUNE-RESPONSE; BREAST-CANCER; IFN-GAMMA; CHEMOTHERAPY

Citation

MOLECULAR PHARMACEUTICS, v.6, no.3, pp.1019 - 1028

ISSN
1543-8384
URI
http://hdl.handle.net/10203/192413
Appears in Collection
BS-Journal Papers(저널논문)
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