Research ArticleDrug Delivery

Local iontophoretic administration of cytotoxic therapies to solid tumors

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Science Translational Medicine  04 Feb 2015:
Vol. 7, Issue 273, pp. 273ra14
DOI: 10.1126/scitranslmed.3009951
  • Fig. 1. Iontophoretic devices used for the delivery of cytotoxic agents to solid tumors.

    (A) Front and side images of the implantable and transdermal devices. (B) Device components and assemblies. (C) Device treatment setups in the pancreatic (implanted device) and breast (transdermal device) cancer models where the drug is supplied to the device, using a syringe pump and electrical current via a DC power supply. Positive and negative leads connect to the device and counter electrode, respectively. (D) Device parameters of drug concentration (at constant current and time) and applied current (at constant concentration and time) were evaluated in mice with patient-derived pancreatic cancer xenografts. Data are means ± SD (n = 5). P values were determined by one-way ANOVA with unpaired t test. (E) Role of current on drug transport in ex vivo tumor and human skin tissue. Gemcitabine transport through PDX tumor tissue was evaluated by applying a current of 2 or 0 mA for 10 min and comparing drug transport into tumor. Data are means ± SD (n = 6). Cisplatin transport into human skin was evaluated by applying a current of 1 or 0 mA for 25 min and comparing drug transport into and through the skin. Data are means ± SD (n = 5). P values were determined by unpaired t test. NS, not significant.

  • Fig. 2. PK of gemcitabine and cisplatin delivered by iontophoretic devices in mouse models of human pancreatic and breast cancers.

    Iontophoretic device delivery was compared with IV delivery. PK of gemcitabine (20 mg/ml) delivered by device compared to IV was evaluated in an orthotopic PDX model of pancreatic cancer. Mice were administered a single treatment of gemcitabine through the device. Organs were collected from each animal at various times, and total gemcitabine concentrations were analyzed. Data are means ± SD (n = 3 to 5 animals per group). The limit of gemcitabine quantitation was 1 μg/ml. P values were determined by unpaired t test. PK of cisplatin delivered by device compared to IV and device + IV was evaluated in SUM149 orthotopic xenografts of breast cancer. Mice were administered a single treatment of cisplatin. Organs were collected from each animal at various times, and total platinum concentrations were analyzed. Data are means ± SD (n = 5 animals per group). The limit of platinum quantitation was 5 ng/ml. P values were determined by one-way ANOVA with unpaired t test comparing device cisplatin and device + IV cisplatin.

  • Fig. 3. Therapeutic effect of gemcitabine delivered iontophoretically in a pancreatic cancer PDX model.

    (A) Efficacy of device gemcitabine, IV gemcitabine, device saline, and IV saline in PDX mice treated twice per week for 7 weeks. Data are fold change in tumor volume (log2) (n = 7 for IV and device gemcitabine, n = 5 to 6 for IV and device saline). (B) Histological staining of representative tumors in (A) for Ki-67. Ki-67 staining was quantified according to H-score. P values were determined by one-way ANOVA with unpaired t test.

  • Fig. 4. Therapeutic effect of cisplatin delivered iontophoretically in mouse tumor xenograft and syngeneic models of breast cancer.

    (A) Treatment schedule according to mouse model. (B) Efficacy and survival of animals treated with device cisplatin, IV cisplatin (5 mg/kg), device + IV cisplatin (5 mg/kg), device saline, and IV saline. SUM149 tumor xenografts were treated once per week for a total of four doses (n = 8 to 9 per treatment group). T11 syngeneic tumors were treated once per week for a total of two doses (n = 9 per treatment group). The study endpoint was time to tumor progression to 2.0 cm in one dimension. Volume data are means ± SD. (C) Representative images of murine skin before and after 4 weeks of transdermal device treatment. (D) γH2AX staining of tumors harvested from SUM149 xenografts 24 hours after a single treatment. γH2AX staining was quantified according to H-score. P values were determined by one-way ANOVA with unpaired t test. (E) Efficacy and survival of animals with T11 syngeneic tumors after a single treatment of radiation (dose), device cisplatin, device cisplatin + radiation, IV cisplatin (dose), IV cisplatin (dose) + radiation, device + IV cisplatin, or device + IV cisplatin + radiation. Data are mean tumor volumes ± SEM (n = 8 per treatment group). P values for tumor growth inhibition were determined by one-way ANOVA with unpaired t test; P values for survival determined by log-rank test.

  • Fig. 5. Evaluation of single device treatments in dogs.

    (A) Device to be implanted directly onto the canine pancreas. (B) Plasma PK of gemcitabine during the single device (10 or 40 mg/ml) or IV (1 g/m2) treatment. (C) Organs were removed 1 hour after the initiation of treatment, and gemcitabine content was quantified in the pancreas of dogs after the administration of a single treatment. (D) Distance of gemcitabine transport away from the device and into the pancreatic tissue. Data are means ± SD (n = 5). P values were determined by Wilcoxon rank sum tests.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/7/273/273ra14/DC1

    Materials and Methods

    Fig. S1. Gemcitabine transport into PDX tumors after a single device treatment.

    Fig. S2. Drug transport through freshly excised murine skin.

    Fig. S3. Role of gemcitabine concentration in drug transport in vitro.

    Fig. S4. PK of cisplatin delivered transdermally by iontophoretic devices.

    Fig. S5. Body weight changes in response to chemotherapy.

    Fig. S6. Change in laboratory values after the device gemcitabine treatment schedule.

    Fig. S7. Short-term renal toxicity after a single cisplatin treatment in mice.

  • Supplementary Material for:

    Local iontophoretic administration of cytotoxic therapies to solid tumors

    James D. Byrne,* Mohammad R. N. Jajja,* Adrian T. O'Neill, Lissett R. Bickford, Amanda W. Keeler, Nabeel Hyder, Kyle Wagner, Allison Deal, Ryan E. Little, Richard A. Moffitt, Colleen Stack, Meredith Nelson, Christopher R. Brooks, William Lee, J. Chris Luft, Mary E. Napier, David Darr, Carey K. Anders, Richard Stack, Joel E. Tepper, Andrew Z. Wang, William C. Zamboni, Jen Jen Yeh,* Joseph M. DeSimone*

    *Corresponding author. E-mail: jen_jen_yeh{at}med.unc.edu (J.J.Y.); desimone{at}unc.edu (J.M.D.)

    Published 4 February 2015, Sci. Transl. Med. 7, 273ra14 (2015)
    DOI: 10.1126/scitranslmed.3009951

    This PDF file includes:

    • Materials and Methods
    • Fig. S1. Gemcitabine transport into PDX tumors after a single device treatment.
    • Fig. S2. Drug transport through freshly excised murine skin.
    • Fig. S3. Role of gemcitabine concentration in drug transport in vitro.
    • Fig. S4. PK of cisplatin delivered transdermally by iontophoretic devices.
    • Fig. S5. Body weight changes in response to chemotherapy.
    • Fig. S6. Change in laboratory values after the device gemcitabine treatment schedule.
    • Fig. S7. Short-term renal toxicity after a single cisplatin treatment in mice.

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