[PEGylated polyamidoamine dendrimer/methotrexate complex: pharmacokinetics and anti-tumor activity in normal and tumor-bearing rodents].
Generation 4 polyamidoamine (PAMAM) dendrimer was PEGylated with polyethylene glycol (PEG) at an average molecular weight 5 000 via amide bond. PAMAM and PEGylated PAMAM (PAMAM-PEG) dendrimer were used as drug nanocarriers. Methotrexate (MTX), an antineoplastic agent, was selected as a model drug. PAMAM/MTX and PAMAM-PEG/MTX complexes were prepared. The pharmacokinetic characters and anti-tumor activity of the PAMAM-PEG/MTX complex were studied as compared with MTX injection and PAMAM/MTX complex by intravenous injection in rats and S180 tumor bearing mice, separately. The plasma samples from normal rats were analyzed by HPLC method, and concentration-time data were analyzed using a non-compartmental analysis. Their anti-tumor effects in vivo were evaluated against S180 solid tumors in mice by measuring average tumor weight and calculating the inhibitory rate of tumor on day 17 after successive injections. The results showed that both plasma half-life and mean retention time (MRT) of the complexes were longer than that of MTX injection (P<0.01), while the area under the plasma concentration vs time curve (AUC) of PAMAM-PEG/MTX was the largest as compared with that of free drug and PAMAM/MTX complex (P<0.01). The inhibitory rate of tumor of PAMAM-PEG/MTX complex enhanced 2.1 and 1.8 times over that of free drug and PAMAM/MTX complex, respectively, indicating that PAMAM-PEG/MTX exhibited the highest antitumor activity. In summary, PEGylated PAMAM could be useful as a potential drug delivery carrier.
School of Pharmacy, Fudan University, Shanghai 200032, China.
Shu-yi
SY
Kong
Guo-tao
GT
Tang
Yuan-ying
YY
Pei
Yan-yan
YY
Jiang
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004337:Drug Carriers; D005260:Female; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D009368:Neoplasm Transplantation; D009757:Nylons / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012510:Sarcoma 180 / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D050091:Dendrimers; D004337:Drug Carriers; D009757:Nylons; C520550:PAMAM-G4; D011092:Polyethylene Glycols; D008727:Methotrexate