Research ArticleBioengineering

An implantable microdevice to perform high-throughput in vivo drug sensitivity testing in tumors

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Science Translational Medicine  22 Apr 2015:
Vol. 7, Issue 284, pp. 284ra57
DOI: 10.1126/scitranslmed.3010564
  • Fig. 1. In vivo drug sensitivity assay.

    (A) The device is implanted by needle directly into tissue, and drugs diffuse from device reservoirs into confined regions of tumor. Each region is assayed independently to assess the tumor-specific response to a given drug, such as apoptosis or growth arrest. A second biopsy needle selectively retrieves a small column of tissue that immediately surrounds and includes the device. This tissue contains the regions of drug diffusion and is used for determination of drug efficacy. (B) Three methods for precise control over the release profile of a given drug are demonstrated: reservoir opening size affects the rate of transport; the formulation of a drug in a polymer matrix (for example, PEG slows release of sunitinib versus free doxorubicin); and hydrophilic expansive hydrogels (to achieve rapid tissue uptake of highly insoluble drugs, such as lapatinib). Scale bars, 300 μm.

  • Fig. 2. Anticancer drugs are delivered into confined regions of tumor.

    Devices were implanted into BT474 tumors, and drugs (table S1) were passively released. (A) Doxorubicin, sunitinib, and lapatinib autofluorescence were detected by microscopy. Cetuximab conjugated with Alexa 488. (B) Dasatinib and gemcitabine distribution detected by MALDI tissue imaging. (C) Three-dimensional reconstruction of drug release from adjacent reservoirs separated by 750 μm. (D and E) Combinations of drugs are co-delivered to a given region of tumor from one reservoir (red, doxorubicin; blue, lapatinib) (D) or from two adjacent reservoirs 250 μm apart (E). (F) Release of a microdose of sunitinib (50% in PEG-1450) at three time points, demonstrating expanded but confined region of tissue distribution even at longer time points. Scale bars, 300 μm.

  • Fig. 3. Pharmacokinetics of drug release from device reservoirs.

    (A) Intratumor transport distances for doxorubicin released from a device in BT474 tumors. Transport was measured as line profiles taken from the center of the reservoir-device interface, moving radially outward, at 4, 14, and 44 hours. Data are averages ± SD (n = 10 distinct reservoirs for each time point). Curves are averaged over 10 samples from five different tumors for each time point. (B and C) Representative tumor cross section showing local doxorubicin distribution at 20 hours after release of the pure drug (B) and drug diluted to 10% (w/w) in PEG-1450 matrix (C) from a device in BT474 tumors. (D) Intratumor doxorubicin distribution after systemic administration of drug (8 mg/kg) in BT474 tumor-bearing mice at 6 hours after injection. Scale bars, 300 μm (B to D). (E) Chart comparing the intratumor concentration of doxorubicin after release as 100% pure drug or 5% drug in PEG-1450 matrix. Device profiles were fit to polynomial curves and compared with systemic dosing. Maximal and average doses after systemic dosing are shown. (F) Drug concentrations for each tumor section in (G) to (I). Concentration profiles are measured as shown in insert. (G to I) Apoptosis after the release of 100% pure drug (F), 5% doxorubicin in PEG-1000 (G), and 1% doxorubicin in PEG-1000 (H). Sections are representative of A375 tumors stained for cleaved caspase-3 (CC3) (brown). Scale bars, 200 μm.

  • Fig. 4. Pharmacodynamics and heterogeneity of drug response based on reservoir.

    (A) Effect of drug exposure time on CC3 expression in A375 tumors. Tumors were implanted with devices releasing doxorubicin (40% in PEG-1450) and analyzed at 8, 14, and 20 hours. Scale bars, 300 μm. (B) Tissue cross sections stained for multiple biomarkers of drug efficacy: CC3 (apoptosis), Ki67 (cell proliferation), and survivin (apoptosis inhibitor). Images were taken 20 hours after doxorubicin (40% in PEG-1450) exposure and are representative of n = 12 A375 tumors. Scale bars, 200 μm. Individual rectangles represent 100 μm. (C) Panel of 16 distinct reservoirs from a single device, each eluting doxorubicin (40% in PEG-1450) in A375 tumors after 20 hours of implantation. Scale bar, 300 μm.

  • Fig. 5. Local and systemic sensitivity to doxorubicin in three human tumor models.

    (A) Differential response of three human cell line tumor models to pure doxorubicin as measured by CC3+ cells. Data are averages ± SD (n = 18 to 22 unique reservoirs from 12 tumors for each model). Scale bars, 250 μm. (B) Apoptosis induction (CC3+ cells) after systemic administration of doxorubicin in A375, BT474, and PC3 tumors. Representative sections of tumors are shown 24 hours after treatment with doxorubicin (8 mg/kg) or control (saline injection). Data are averages ± SD CC3 expression from 12 sections scored per tumor model (4 sections each from three tumors for each model), and were scored in a blinded manner. Scale bars, 250 μm.

  • Fig. 6. Differential drug sensitivity in human tumor models.

    (A to C) Differential apoptotic response of human tumors to vemurafenib (50%), gemcitabine (60%), and topotecan (30%), all in PEG-1450, released from the device and assessed by CC3 expression after 20 to 24 hours. Data are averages ± SD [n = 12 spatially distinct reservoirs (biological replicates) from at least four tumors for each drug/tumor combination]. Scale bars, 200 μm. (D and E) Enhancement of apoptotic response by addition of targeted agents lapatinib and sunitinib to doxorubicin in the same device reservoir at 24 hours. Data are averages ± SD [n = 10 spatially distinct reservoirs (biological replicates) from at least four tumors for each drug/tumor combination]. Scale bars, 200 μm. P values were determined using Student’s t test for all graphs. n.s., not significant.

  • Fig. 7. Efficacy of five drugs in a patient-derived TNBC tumor model.

    (Top) Differential response of TNBC PDX tumor model to five commonly used drugs. AI was calculated from the number of CC3+ cells divided by total cells. Data are averages ± SD (n = 16 unique reservoirs from 8 tumors for device studies, 8 animals for systemic studies). (Bottom) Representative images of TNBC tumor sections removed 24 hours after exposure to microdose of each drug from the device or after systemic injections. Device formulations (w/w) in PEG-1450 are in table S1. Systemic doses: paclitaxel, 16 mg/kg; doxorubicin, 8 mg/kg; cisplatin, 20 mg/kg; gemcitabine, 30 mg/kg; lapatinib, 50 mg/kg. Scale bars, 200 μm.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/7/284/284ra57/DC1

    Materials and Methods

    Fig. S1. Removal of drug-exposed tumor region by a coring needle.

    Fig. S2. Visibility of device for in vivo imaging with ultrasound and CT.

    Fig. S3. Device/tissue cross sections stained for multiple drug sensitivity markers.

    Table S1. Solvents and concentrations of drug-polymer mixtures for device reservoirs.

  • Supplementary Material for:

    An implantable microdevice to perform high-throughput in vivo drug sensitivity testing in tumors

    Oliver Jonas, Heather M. Landry, Jason E. Fuller, John T. Santini Jr., Jose Baselga, Robert I. Tepper, Michael J. Cima, Robert Langer*

    *Corresponding author. E-mail: rlanger{at}mit.edu

    Published 22 April 2015, Sci. Transl. Med. 7, 284ra57 (2015)
    DOI: 10.1126/scitranslmed.3010564

    This PDF file includes:

    • Materials and Methods
    • Fig. S1. Removal of drug-exposed tumor region by a coring needle.
    • Fig. S2. Visibility of device for in vivo imaging with ultrasound and CT.
    • Fig. S3. Device/tissue cross sections stained for multiple drug sensitivity markers.
    • Table S1. Solvents and concentrations of drug-polymer mixtures for device reservoirs.

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