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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Large Molecule Therapeutics

Paclitaxel-Loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy

Lorena Simón-Gracia, Hedi Hunt, Pablo D. Scodeller, Jens Gaitzsch, Gary B. Braun, Anne-Mari A. Willmore, Erkki Ruoslahti, Giuseppe Battaglia and Tambet Teesalu
Lorena Simón-Gracia
Laboratory of Cancer Biology, Institute of Biomedicine, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
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Hedi Hunt
Laboratory of Cancer Biology, Institute of Biomedicine, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
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Pablo D. Scodeller
Laboratory of Cancer Biology, Institute of Biomedicine, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Jens Gaitzsch
Department of Chemistry, University College London, London, United Kingdom.Department of Chemistry, University of Basel, Basel, Switzerland.
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Gary B. Braun
Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Anne-Mari A. Willmore
Laboratory of Cancer Biology, Institute of Biomedicine, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
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Erkki Ruoslahti
Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California.
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Giuseppe Battaglia
Department of Chemistry, University College London, London, United Kingdom.
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  • For correspondence: tambet.teesalu@ut.ee g.battaglia@ucl.ac.uk
Tambet Teesalu
Laboratory of Cancer Biology, Institute of Biomedicine, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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  • For correspondence: tambet.teesalu@ut.ee g.battaglia@ucl.ac.uk
DOI: 10.1158/1535-7163.MCT-15-0713-T Published April 2016
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    Figure 1.

    Characterization of empty polymersomes (PS) and paclitaxel (PTX)-loaded polymersomes (PS–PTX). A, TEM images of freshly prepared empty and paclitaxel-polymersomes. Polymersome samples were deposited on copper grids and stained with phosphotungstic acid at pH 7.4. B, DLS determination of hydrodynamic diameter and PDI values of empty and paclitaxel-polymersomes after incubation for indicated time and temperature.

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    Figure 2.

    In vitro assessment of cytotoxicity of free and encapsulated paclitaxel (PTX) to MKN-45P, CT26, and SKOV-3 cells. Cytotoxicity measured by MTT assay of the indicated formulations at 0.5 μmol/L of paclitaxel after 24 hours of incubation. PS, polymersomes; PS–PTX, paclitaxel-loaded polymersomes. Statistical analysis was performed by ANOVA. N = 4; error bars, mean + SEM; ***, P < 0.001; **, P < 0.01; *, P < 0.05.

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    Figure 3.

    Intraperitoneally administered fluorescent polymersomes home to peritoneal tumors in vivo. Mice bearing disseminated MKN-45P (A) or CT26 (B) tumors were injected with polymersomes labeled with fluorescein and the mice were perfused after 24 hours. C, fluorescence intensity of tumors and different organs from ex vivo imaging was quantified with ImageJ. Results are normalized for tissue area. D, confocal micrographs of peritoneal tumor sections after 24 hours of FAM-polymersomes injection in MKN-45P- and CT26-bearing mice. Blue, DAPI; green, FAM; red, CD31. The white arrow indicates the colocalization of green and red fluorescence and the pink arrow indicates only the green fluorescence. Representative fields from multiple sections of three independent mice are shown. Tu, tumor; Ki, kidney; He, heart; Li, liver; Lu, lung; Sp, spleen. N = 4 for MKN-45 tumor model and n = 3 for CT26 tumor model. Error bars, mean + SEM. Scale bar, 50 μm.

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    Figure 4.

    Experimental therapy of MKN-45P tumor-bearing mice. Mice bearing disseminated peritoneal tumors induced with MKN-45P-Luc cells were injected with indicated formulations (1 mg PTX/kg) every other day. A, tumor growth was monitored by measurement of luciferase activity. Days after MKN-45P-Luc cells injection are plotted on the x-axis. On the y-axis are the photons recovered from region of interest. The arrows indicate treatment injections. B, quantification of metastatic nodules after the treatment. N = 5 in each group. PS, polymersomes; PS-PTX, paclitaxel-loaded polymersomes. Statistical analyses, ANOVA; error bars, mean + SEM; ***, P < 0.001; **, P < 0.01.

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    • Supplementary data: Figures 1-10 - Figure S1: Structure of the co-polymer POEGMA-PDPA; Figure S2: Quantification of paclitaxel loading into polymersomes (PS-PTX) and PTX release from the vesicles; Figure S3: z-potential measurements; Figure S4: In vitro cellular internalization and drug release of polymersomes; Figure S5: Viability and proliferation and of MKN-45P and CT-26 cells; Figure S6: Fluorescence in control organs; Figure S7: In vivo imaging of rhodamine-labeled polymersomes; Figure S8: Homing of fluorescein-labeled polymersomes to organs; Figure S9: Subcutaneous tumor homing of polymersomes; Figure S10: Peritoneal tumor homing of polymersomes after IP and IV injection.
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Molecular Cancer Therapeutics: 15 (4)
April 2016
Volume 15, Issue 4
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Paclitaxel-Loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy
Lorena Simón-Gracia, Hedi Hunt, Pablo D. Scodeller, Jens Gaitzsch, Gary B. Braun, Anne-Mari A. Willmore, Erkki Ruoslahti, Giuseppe Battaglia and Tambet Teesalu
Mol Cancer Ther April 1 2016 (15) (4) 670-679; DOI: 10.1158/1535-7163.MCT-15-0713-T

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Paclitaxel-Loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy
Lorena Simón-Gracia, Hedi Hunt, Pablo D. Scodeller, Jens Gaitzsch, Gary B. Braun, Anne-Mari A. Willmore, Erkki Ruoslahti, Giuseppe Battaglia and Tambet Teesalu
Mol Cancer Ther April 1 2016 (15) (4) 670-679; DOI: 10.1158/1535-7163.MCT-15-0713-T
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