Doxorubicin loaded pH-sensitive micelle targeting acidic extracellular pH of human ovarian A2780 tumor in mice - PubMed (original) (raw)

Doxorubicin loaded pH-sensitive micelle targeting acidic extracellular pH of human ovarian A2780 tumor in mice

Z G Gao et al. J Drug Target. 2005 Aug.

Abstract

The purpose of this study was to examine the efficacy of a chemotherapeutic drug, doxorubicin (DOX), loaded in pH-sensitive micelles poly(l-histidine) (M(n):5K)-b-PEG (M(n):5K) micelles. The micelles were designed to target the acidic extracellular pH of solid tumors. Studies of pH-dependent cytotoxicity, growth rate of the tumor, pharmacokinetics and biodistribution were conducted. In vitro DOX uptake upon A2780 cells by incubating the cells in a pH 6.8 complete medium at a concentration of 20 microg DOX/ml in the micelle formulation was more than five times that of pH 7.4 condition for initial 20 min. In vivo pharmacokinetic data showed that AUC (area under concentration curve) and half life time (t(1/2)) (plasma half life) of DOX in the pH sensitive micelles increased about 5.8- and 5.2-fold of free DOX in phosphate buffered saline (PBS), respectively. It appeared that DOX in the pH-sensitive micelles preferentially accumulated in the tumor site. The distributions at 12 h post injection in other organs including liver, kidney, spleen, lung and heart were not significantly different from those of DOX in PBS at a 6 mg DOX/kg dose. The in vivo test of anti-tumor activity was performed with human ovarian carcinoma A2780 which was subcutaneously xenografted in female nu/nu athymic mice. The pH-sensitive micelle formulation significantly retarded tumor growth rate without serious body weight loss. The triggered drug release by the reduced tumor pH is believed to be a major mechanism of the observed efficacy after passive accumulation of the micelles by EPR effect. This may have resulted in a local high dose of drug in the tested solid tumor.

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Figures

Figure 1

Figure 1

(A) Fluorescence histograms of A2780 cells incubated with free DOX or DOX loaded in polyHis/PEG pH-sensitive micelles. The DOX concentration in the incubation media was maintained constant at 20 μg/ml. For the micelle formulation, DOX (20 μg) was incorporated in 125 μg polyHis/PEG micelles/ml solution. Cells incubated in pH 6.8 medium (bold lines), pH 7.4 medium (dotted lines) and control plain medium without DOX (for fluorescence background, regular lines). All cells were incubated for 20 min after adding the formulations; (B) The cytotoxicity of DOX PBS and DOX polyHis/PEG micelles at pH 7.4 and 6.8 after 48 h incubation with varying the concentration of DOX and the block polymer.

Figure 2

Figure 2

The blood concentration-time profiles of DOX after i.v. administration of DOX PBS and the DOX micelles. Each formulation was administered to mice (female, n = 3) at a DOX dose of 6 mg/kg.

Figure 3

Figure 3

Fluorescence histograms of (A) tumor; (B) liver; (C) kidney; (D) spleen; (E) lung and (F) heart cells in mice post 12 h after i.v. injection of the formulations. DOX PBS (regular lines), DOX micelles (bold lines) and control (dotted lines). The DOX dose size of each formulation was 6 mg/kg.

Figure 4

Figure 4

(A) Effects of the DOX micelles and DOX PBS on the growth of A2780 ovarian carcinoma s.c. transplanted in nu/nu mice (female, n = 7). Each formulation was administered four times at three-day intervals (arrows) at a dose of 6 mg/kg; (B) Body weight changes of A2780 tumor bearing nu/nu mice (female, n = 7) treated with saline, DOX PBS, and DOX micelle. Each formulation was administered four times at three-day intervals (arrows) at a dose of 6 mg/kg DOX.

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