Comparison of pharmacokinetics, tissue distribution and pharmacodynamics of liposomal and free doxorubicin in tumour-bearing mice following intratumoral injection.
OBJECTIVE
The clinical application of doxorubicin (DOX) is limited by severe systemic side effects. The aim of this study was to develop a strategy that combined the liposomal DOX (LipDOX) and intratumoral injection to reduce the toxicity and enhance the antitumor efficiency.


METHODS
The pharmacokinetics, tissue distribution and pharmacodynamics of LipDOX compared with free DOX were investigated by intratumoral injection in murine H22 hepatoma-bearing mice at a dose of 20 mg/kg body weight. A sensitive HPLC-tandem mass spectrometry method was used to determine the DOX levels in plasma and tissues. The tumour volume and body weight of mice were measured every 3 days.


RESULTS
LipDOX administration resulted in 1.3-fold longer mean residence time (MRT) and 2.4-fold higher area under concentration (AUC)-time curve compared with free DOX administration in tumour. Free DOX caused higher peak plasma concentration (Cmax ) than LipDOX in plasma and major organs, which may result in significant mortality for acute cardiac toxicity. After successive 21 days treatment, the final volume of tumour treated by normal saline, free DOX and LipDOX was 5.0-, 1.3-fold higher and 1.6-fold lower than the initial tumour volume, respectively.


CONCLUSIONS
Our results indicated that the intratumoral injection of LipDOX is a promising approach with higher therapeutic efficacy and lower systemic toxicity than free DOX.
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
Shuangxia
S
Ren
Cuiyun
C
Li
Yu
Y
Dai
Ning
N
Li
Xin
X
Wang
Fengjie
F
Tian
Sufeng
S
Zhou
Zhixia
Z
Qiu
Yang
Y
Lu
Di
D
Zhao
Xijing
X
Chen
Dingding
D
Chen
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015552:Injections, Intralesional; D008081:Liposomes; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008813:Mice, Inbred ICR; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D008081:Liposomes; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
intratumoral injection; liposomal doxorubicin; pharmacodynamics; pharmacokinetics; tissue distribution