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Hyperthermia Sensitization and Proton Beam Triggered Liposomal Drug Release for Targeted Tumor Therapy

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Abstract

Purpose

The objectives of this study were to: 1) determine if mild hyperthermia (40–42°C) can sensitize tumor cells for more effective proton beam radiotherapy (PBRT); 2) characterize the survival fraction of cells exposed to PBRT; and 3) characterize release of the drug doxorubicin (Dox) from low temperature sensitive liposomes (LTSLs) without exposure to mild hyperthermia in combination with PBRT.

Methods

Dox was actively loaded in LTSLs. A549 monolayer cells were incubated with 100–200 nM of Dox-LTSL (±mild hyperthermia). Cell irradiation (0–6 Gy) was performed by placing the cell culture plates inside a solid water phantom and using a clinical proton treatment beam with energy of 150 MeV. End points were survival fraction, radiation-mediated Dox release, and reactive oxygen species (ROS) production.

Results

Hyperthermia effectively sensitized cells for PBRT and lowered the cell survival fraction (SF) by an average of 9.5%. The combination of 100 nM Dox-LTSL and PBRT (1–6 Gy) achieved additive to synergistic response at various dose combinations. At higher radiation doses (>3 Gy), the SF in the Dox and Dox-LTSL groups was similar (~20%), even in the absence of hyperthermia. In addition, 30% of the Dox was released from LTSLs and a 1.3–1.6 fold increase in ROS level occurred compared to LTSL alone therapy.

Conclusions

The combination of LTSLs and PBRT achieves additive to synergistic effect at various dose combinations in vitro. Concurrent PBRT and Dox-LTSL treatment significantly improved the cytotoxic outcomes of the treatment compared to PBRT and Dox chemotherapy without LTSLs. We hypothesize that PBRT may induce drug release from LTSL in the absence of hyperthermia.

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by a multidisciplinary team grant from the Center for Veterinary Health Sciences and the College of Arts and Sciences, Oklahoma State University, and a collaborative research agreement with ProCure Proton Therapy Center, Oklahoma City.

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Authors and Affiliations

  1. Laboratory of Nanomedicine and Targeted Therapy Department of Physiological Sciences Center for Veterinary Health Sciences, Oklahoma State University, 169 McElroy Hall, Stillwater, OK, 74078, United States of America

    R. Fernando, D. Maples, L. K. Senavirathna & A. Ranjan

  2. Procure Proton Therapy Center, Oklahoma City, OK, 73142, United States of America

    Y. Zheng

  3. Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, 21201, United States of America

    J. C. Polf

  4. Department of Physics, College of Arts and Sciences, Oklahoma State University, Stillwater, OK, 74078, United States of America

    E. R. Benton

  5. Department of Veterinary Clinical Sciences Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, 74078, United States of America

    K. E. Bartels

  6. School of Electrical and Computer Engineering College of Engineering, Architecture and Technology, Oklahoma State University, Stillwater, OK, 74078, United States of America

    D. Piao

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  1. R. Fernando
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  2. D. Maples
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  3. L. K. Senavirathna
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  4. Y. Zheng
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  5. J. C. Polf
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  8. D. Piao
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  9. A. Ranjan
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Corresponding author

Correspondence to A. Ranjan.

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Fernando, R., Maples, D., Senavirathna, L.K. et al. Hyperthermia Sensitization and Proton Beam Triggered Liposomal Drug Release for Targeted Tumor Therapy. Pharm Res 31, 3120–3126 (2014). https://doi.org/10.1007/s11095-014-1404-5

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  • DOI: https://doi.org/10.1007/s11095-014-1404-5

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