A duplex oligodeoxynucleotide-dendrimer bioconjugate as a novel delivery vehicle for doxorubicin in in vivo cancer therapy.
We designed a bioconjugate between duplex oligodeoxynucleotides (dODNs) and a dendrimer (DEN) and demonstrate its feasibility as a novel delivery system for doxorubicin (Dox) in animal tumor models and against cancer cells in vitro. The dODNs-DEN conjugates formed stable complexes with Dox (~184 Dox molecules per conjugate) and the resulting Dox-loaded conjugate exhibited a sustained drug release pattern both in vitro and in vivo. Pharmacokinetic studies showed that Dox-loaded dODNs-DEN conjugates were cleared from plasma much more slowly (up to 5.3h) than was free Dox (0.65h). Furthermore, tumors retained a higher amount of Dox in mice treated with the conjugate group compared to that of free Dox-treated group at the same dosage. In mice bearing 4T1 murine breast tumor allografts, the dendrimer conjugate, at a Dox concentration of 1mg/kg, was more effective than the equivalent concentration of free Dox and tumor size reduction was equivalent to that seen using 4mg/kg free Dox. We observed no severe systemic toxicity or cardiotoxicity in mice treated with the conjugate, as indicated by body weight change and heart tissue histology. These findings indicate that dODNs-DEN conjugates can be used to administer Dox with improved pharmacokinetics, lower toxicity, and an increased ability to concentrate drugs in tumors, compared with free drug, and that such conjugates are effective against tumors in vivo.
Lee
In-Hyun
IH
Cell Dynamics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, 261 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, Republic of Korea.
Yu
Mi Kyung
MK
Kim
In Hwa
IH
Lee
Jae-Hyuk
JH
Park
Tae Gwan
TG
Jon
Sangyong
S
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*
D000903:Antibiotics, Antineoplastic; D050091:Dendrimers; D004337:Drug Carriers; D009838:Oligodeoxyribonucleotides; D004317:Doxorubicin