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Cancer Therapy: Preclinical

Efficacy, Biodistribution, and Pharmacokinetics of CD22-Targeted Pegylated Liposomal Doxorubicin in a B-cell Non–Hodgkin's Lymphoma Xenograft Mouse Model

Joseph M. Tuscano, Shiloh M. Martin, Yunpeng Ma, William Zamboni and Robert T. O'Donnell
Joseph M. Tuscano
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Shiloh M. Martin
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Yunpeng Ma
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William Zamboni
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Robert T. O'Donnell
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DOI: 10.1158/1078-0432.CCR-09-3199 Published May 2010
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    Fig. 1.

    In vitro cytotoxicity of PLD versus IL-PLD in various cell lines. Raji (A), Ramos (B), or Jurkat (C) cells were treated with PLD (filled symbol) or IL-PLD (open symbol) for 72 h, then assessed for viability as described in Materials and Methods. Viability is expressed as % of control (nontreated) cells.

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    Fig. 2.

    Plasma DXR clearance, myelotoxicity, and biodistribution of IL-PLD, PLD, and NL-DXR in xenograft-bearing mice. A, blood samples were taken from IL-PLD–treated (▪), PLD-treated (♦), and NL-DXR–treated (▴) mice (n = 4 per group); blood cells were pelleted; and plasma was collected. DXR was extracted from plasma and quantified. B, mice were treated with 10 mg/kg IL-PLD, PLD, NL-DXR, or PBS (n = 4 per group), and 24 hours later, mice were euthanized and bone marrow cells (BMC) were harvested and counted. C, xenograft-bearing mice were treated with 10 mg/kg IL-PLD (filled columns) or PLD (open columns; n = 4 per group), and 24 hours later, mice were euthanized and organs were harvested, washed, weighed, and the DXR was extracted and quantified.

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    Fig. 3.

    IL-PLD treatment produced a greater reduction of tumor volume than did PLD with comparable toxicity. Mice were treated with either a single dose of 8 mg/kg (▪), 12 mg/kg (▴), or 16 mg/kg (•) or were treated with three doses of 8 mg/kg (♦) PLD (solid line) or IL-PLD (dashed line; n = 8 per group). Tumor size was assessed twice weekly. All treatment groups were compared with PBS-treated control mice (+). Tumor volumes were compared in mice treated with the various single doses (A) or 8 mg/kg single versus three dose (B). Toxicity assessment included weekly measurements of WBC counts (C) and mice weights (D).

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    Fig. 4.

    IL-PLD produced more reduction in tumor volume and enhanced survival versus PLD- or HB22.7-conjugated empty liposomes (IL-null). Mice were treated with IL-PLD (♦), PLD (▴), PLD plus unconjugated HB22.7 (•), or IL-null (+) on day 1, 8, and 15 after tumor implantation (n = 8 per group). All groups were compared with PBS-treated control (▪). A, tumor volume. B, survival.

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  • Table 1.

    χ2 and P values for xenograft studies

    PLD vs IL-PLD dose-response study (Fig. 3)χ2P
    Ctrl vs 8 mg/kg PLD single dose0.14540.7029
    Ctrl vs 12 mg/kg PLD single dose2.4960.1141
    Ctrl vs 16 mg/kg PLD single dose7.5040.0062
    Ctrl vs 8 mg/kg 3 doses3.6460.0562
    Ctrl vs 8 mg/kg IL-PLD single dose4.7950.0285
    Ctrl vs 12 mg/kg IL-PLD single dose4.9220.0265
    Ctrl vs 16 mg/kg IL-PLD single dose7.5040.0062
    Ctrl vs 8 mg/kg IL-PLD 3 doses7.5040.0062
    PLD vs 8 mg/kg IL-PLD single dose6.80.0091
    PLD vs 12 mg/kg IL-PLD single dose0.72420.3948
    PLD vs 16 mg/kg IL-PLD single dose0.024250.8762
    PLD vs 8 mg/kg IL-PLD 3 doses7.3440.0067
    8 mg/kg PLD single dose vs 8 mg/kg PLD 3 doses4.7950.0285
    8 mg/kg IL-PLD single dose vs 8 mg/kg IL-PLD 3 doses4.2680.0388
    PLD vs IL-PLD vs IL-null study (Fig. 4)χ2P
    Ctrl vs PLD20.5<0.0001
    Ctrl vs IL-PLD26.5<0.0001
    Ctrl vs PLD + free HB22.710.790.001
    Ctrl vs IL-null11.480.0007
    IL-PLD vs PLD12.940.0003
    IL-PLD vs PLD + free HB22.714.870.0001
    IL-PLD vs IL-null9.8240.0017
    PLD vs PLD + free HB22.70.30520.5806
    PLD vs IL-null0.080970.776
    IL-null vs PLD + free HB22.70.15590.693

    NOTE: Data were analyzed using the modified Kaplan- Meier curves and the Log-rank test as described in Materials and Methods. Comparisons with significant P values (<0.05) are shown in bold.

    Abbreviation: Ctrl, control.

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    Clinical Cancer Research: 16 (10)
    May 2010
    Volume 16, Issue 10
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    Efficacy, Biodistribution, and Pharmacokinetics of CD22-Targeted Pegylated Liposomal Doxorubicin in a B-cell Non–Hodgkin's Lymphoma Xenograft Mouse Model
    Joseph M. Tuscano, Shiloh M. Martin, Yunpeng Ma, William Zamboni and Robert T. O'Donnell
    Clin Cancer Res May 15 2010 (16) (10) 2760-2768; DOI: 10.1158/1078-0432.CCR-09-3199

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    Efficacy, Biodistribution, and Pharmacokinetics of CD22-Targeted Pegylated Liposomal Doxorubicin in a B-cell Non–Hodgkin's Lymphoma Xenograft Mouse Model
    Joseph M. Tuscano, Shiloh M. Martin, Yunpeng Ma, William Zamboni and Robert T. O'Donnell
    Clin Cancer Res May 15 2010 (16) (10) 2760-2768; DOI: 10.1158/1078-0432.CCR-09-3199
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