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. 2008 Sep;24(6):475-82.
doi: 10.1080/02656730701854767.

Tumor microvascular permeability is a key determinant for antivascular effects of doxorubicin encapsulated in a temperature sensitive liposome

Qing Chen  1 , Ava Krol, Alex Wright, David Needham, Mark W Dewhirst, Fan Yuan
Affiliations

Tumor microvascular permeability is a key determinant for antivascular effects of doxorubicin encapsulated in a temperature sensitive liposome

Qing Chen et al. Int J Hyperthermia. 2008 Sep.

Abstract

Previous data have demonstrated that doxorubicin (DOX) released from a lysolecithin-containing thermosensitive liposome (LTSL) can shut down blood flow in a human tumor xenograft (FaDu) in mice when the treatment is combined with hyperthermia (HT), suggesting that LTSL-DOX is a potential antivascular agent. To further understand mechanisms of the treatment, we investigated effects of LTSL-DOX (5 mg/kg body weight) plus HT (42 degrees C, 1 h) on microcirculation in another tumor (a murine mammary carcinoma, 4T07) implanted in mouse dorsal skin-fold chambers and dose responses of tumor (FaDu and 4T07) and endothelial cells to LTSL-DOX or free DOX with or without HT. We observed that LTSL-DOXHT could significantly reduce blood flow and microvascular density in 4T07 tumors. The antivascular efficacy of LTSLDOX- HT could be enhanced through increasing tumor microvascular permeability of liposomes by using platelet activating factor (PAF). We also observed that the dose responses of FaDu and 4T07 to DOX in vitro were similar to each other and could be enhanced by HT. Taken together, these data suggested that tumor microvascular permeability was more critical than the sensitivity of tumor cells to DOX in determining the antivascular efficacy of LTSL-DOX-HT treatment.

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Figures

Figure 1
Figure 1
Average RBC velocities in 4T07 tumors treated with LTSL-DOX-HT (n=7) and LTSL-HT (n=5). The velocity was measured at 0.5 hr before, at 0, 6 and 24 hrs after the treatment. Error bars, SEM; *, p<0.05, when comparing data between LTSL-DOX-HT and LTSL-HT groups. In addition, the velocities at 0, 6, and 24 hrs were significantly less than that before the treatment in the LTSL-DOX-HT group (p<0.05), whereas the decrease in RBC velocity after the treatment was statistically significant (i.e., p<0.05) only at 24 hrs in the LTSL-HT group.
Figure 2
Figure 2
Tumor microvascular permeability in FaDu and 4T07 tumors treated with (HT) or without hyperthermia (NT) (n=7 in each group), PAF alone or PAF plus HT (n=5 in each group). Error bars, SEM; a, p<0.05, FaDu NT vs. 4T07 NT; b, p<0.01, FaDu HT vs. FaDu NT and 4T07 HT; c, p<0.01, 4T07 PAF vs. 4T07 NT; d, p<0.05, 4T07 PAF vs. FaDu NT; e, p<0.01, 4T07 HT+PAF vs. 4T07 NT, 4T07 HT or FaDu NT.
Figure 3
Figure 3
Typical images of tumor surfaces in (A) control and (B) LTSL-DOX-HT treated groups. In each group, the images show the network of tumor vasculature at (a) 0.5 hr before treatment, and at (b) 0 hr, (c) 6 hrs, (d) 24 hrs, and (e) 72 hrs after treatment.
Figure 4
Figure 4
Microvascular density in 4T07 tumors treated with LTSL-DOX-HT (n=7), LTSL-HT (n=5), and PAF-LTSL-DOX-HT (n=5). Error bars, SEM; *, p<0.05, when comparing data between PAF-LTSL-DOX-HT and LTSL-HT or LTSL-DOX-HT groups at 0 and 6 hrs. In addition, the difference in data at 24 hrs between LTSL-HT and LTSL-DOX-HT or PAF-LTSL-DOX-HT groups was statistically significant (p<0.05).
Figure 5
Figure 5
Cytotoxicity of DOX and LTSL-DOX to tumor cells and HUVEC. FaDu and 4T07 cells as well as HUVEC were treated with DOX or LTSL-DOX at a range of exponentially increasing DOX concentrations or equivalent DOX concentrations between 0.001 μM and 100 μM at 37°C (NT) or 42°C (HT) for 1 hr. Then, the cells were incubated in fresh medium for 24 hrs, followed by the cytotoxicity assay. The percentage of viable cells was calculated relative to untreated cells. All assays were performed in triplicate. IC50 values were calculated from the dose–response curves by curve fitting the data. Error bars, SEM; a, p<0.01, DOX-HT vs. DOX-NT; b, p<0.05, LTSL-DOX-HT vs. LTSL-DOX-NT; c, p<0.05, LTSL-DOX-HT vs. DOX-HT; d, p<0.05, LTSL-DOX-HT from 4T07 group vs. LTSL-DOX-HT from FaDu group; e, p<0.05, DOX-NT vs. LTSL-DOX-NT.
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References

    1. Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Matthay K, Huang SK, et al. Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci U S A. 1991;88(24):11460–4. - PMC - PubMed
    1. Ranson M, Howell A, Cheeseman S, Margison J. Liposomal drug delivery. Cancer Treat Rev. 1996;22(5):365–79. - PubMed
    1. Tardi PG, Boman NL, Cullis PR. Liposomal doxorubicin. J Drug Target. 1996;4(3):129–40. - PubMed
    1. Gregoriadis G. Liposome Technology. CRC press; Boca Raton: 1993.
    1. Lasic DD, Papahadjopoulos D. Liposomes revisited. Science. 1995;267(5202):1275–1276. - PubMed

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