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Drug Delivery Nanoparticles with Locally Tunable Toxicity Made Entirely from a Light-Activatable Prodrug of Doxorubicin

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Abstract

Purpose

A major challenge facing nanoparticle-based delivery of chemotherapy agents is the natural and unavoidable accumulation of these particles in healthy tissue resulting in local toxicity and dose-limiting side effects. To address this issue, we have designed and characterized a new prodrug nanoparticle with controllable toxicity allowing a locally-delivered light trigger to convert the payload of the particle from a low to a high toxicity state.

Methods

The nanoparticles are created entirely from light-activatable prodrug molecules using a nanoprecipitation process. The prodrug is a conjugate of doxorubicin and photocleavable biotin (DOX-PCB).

Results

These DOX-PCB nanoparticles are 30 times less toxic to cells than doxorubicin, but can be activated to release pure therapeutic doxorubicin when exposed to 365 nm light. These nanoparticles have an average diameter of around 100 nm and achieve the maximum possible prodrug loading capacity since no support structure or coating is required to prevent loss of prodrug from the nanoparticle.

Conclusions

These light activatable nanoparticles demonstrate tunable toxicity and can be used to facilitate future therapy development whereby light delivered specifically to the tumor tissue would locally convert the nanoparticles to doxorubicin while leaving nanoparticles accumulated in healthy tissue in the less toxic prodrug form.

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Abbreviations

DLS:

Dynamic light scattering

DMEM:

Dulbecco's Modified Eagle Medium

DMSO:

Dimethyl sulfoxide

DOX:

Doxorubicin

DOX-PCB:

Doxorubicin-Photocleavable Biotin

DPBS:

Dulbecco’s phosphate buffered saline

EDTA:

Ethylenediaminetetraacetic acid

ESI:

Electrospray ionization

FBS:

Fetal bovine serum

HPLC:

High pressure liquid chromatography

LC:

Liquid chromatography

LED:

Light emitting diode

MS:

Mass spectrometry

NP:

Nanoparticles

NTA:

Nanoparticle tracking analysis

PCB:

Photocleavable biotin

PEG:

Polyethylene glycol

RES:

Reticulo-endothelial system

SEM:

Scanning electron microscopy

SRM:

Selected reaction monitoring

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Acknowledgments and Disclosures

Support was provided by Grant Numbers T32 CA121938, R25 CA153915, and 5 U54 CA119335 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The authors also wish to thank Dr. Yongxuan Su and the Molecular Mass Spectrometry Facility at the University of California San Diego Department of Chemistry and Biochemistry for their work with the mass spectrometry analysis. The authors also wish to thank Linda Shi and Michelle Duquette-Huber for their assistance with the PTK2 cell data collection.

Author information

Authors and Affiliations

  1. Department of Bioengineering, University of California San Diego, 9500 Gilman Dr. MC 0412, La Jolla, California, 92093-0412, USA

    Carolyn Schutt & Michael Berns

  2. Moores Cancer Center, University of California San Diego, La Jolla, California, 92093, USA

    Stuart Ibsen

  3. Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, P.O. Box 19, 74100, Ness-Ziona, Israel

    Eran Zahavy

  4. Department of Chemistry, Nanotechnology Innovation Center of Kansas State, Kansas State University, Manhattan, Kansas, 66506, USA

    Santosh Aryal

  5. Department of Nanoengineering, University of California San Diego, La Jolla, California, 92093, USA

    Stacey Kuo, Selin Esener & Sadik Esener

Authors
  1. Carolyn Schutt
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  2. Stuart Ibsen
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  3. Eran Zahavy
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  4. Santosh Aryal
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  5. Stacey Kuo
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  6. Selin Esener
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  7. Michael Berns
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  8. Sadik Esener
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Correspondence to Carolyn Schutt.

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Schutt, C., Ibsen, S., Zahavy, E. et al. Drug Delivery Nanoparticles with Locally Tunable Toxicity Made Entirely from a Light-Activatable Prodrug of Doxorubicin. Pharm Res 34, 2025–2035 (2017). https://doi.org/10.1007/s11095-017-2205-4

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  • DOI: https://doi.org/10.1007/s11095-017-2205-4

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