Carolyn Schutt1, Stuart Ibsen2, Eran Zahavy3, Santosh Aryal4, Stacey Kuo5, Selin Esener5, Michael Berns6, Sadik Esener5. 1. Department of Bioengineering, University of California San Diego, 9500 Gilman Dr. MC 0412, La Jolla, California, 92093-0412, USA. carolyn.schutt@gmail.com. 2. Moores Cancer Center, University of California San Diego, La Jolla, California, 92093, USA. 3. Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, P.O. Box 19, 74100, Ness-Ziona, Israel. 4. Department of Chemistry, Nanotechnology Innovation Center of Kansas State, Kansas State University, Manhattan, Kansas, 66506, USA. 5. Department of Nanoengineering, University of California San Diego, La Jolla, California, 92093, USA. 6. Department of Bioengineering, University of California San Diego, 9500 Gilman Dr. MC 0412, La Jolla, California, 92093-0412, USA.
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.
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.
Entities:
Keywords:
DNA intercalation; Doxorubicin; Light-activatable; Nanoparticle drug delivery vehicle; Prodrug