Radiation-Activated Release of Active Drug from Nontoxic Nanoparticle Prodrugs

Background

The concept of restricting toxic chemotherapeutics to tumor tissue is not new. In a contemporary version of the approach, a nontoxic, inactive caged drug is selectively delivered to a tumor and low dose radiation is delivered to convert prodrug to active, toxic drug. In 2008, UC inventors attempted to improve on the approach by using nanoparticles. However, technical limitations severely compromised absorption of the excitation radiation and radiation was also quenched by tissue oxygen. Both of these problems have been solved by developing unique compositions, which pave the way for finely localized delivery of therapeutics, in terms of anatomy and timing, that might otherwise be “undruggable”.

Technology Description

UC inventors have developed compositions and methods for targeting tumors with very high doses of nanoparticle-caged prodrug, which is locally released as active drug by either localized or wide field/total body, low dose radiation. The prodrug is comprised of a nanoparticle and drug (e.g. Doxorubicin) and is nontoxic until activated by radiation.  The inclusion of ligands can facilitate crossing the blood-brain-barrier.

Applications

For the treatment of cancer, a radiation activated prodrug may significantly improve the management of solid, invasive tumors with a minimum of side effects. The 100 nm size of the nano-prodrugs enables them to exit from leaky tumor vessels. However, normal tissues are protected from damage by the nontoxic nature of the prodrug and by localized activation.  The prodrug is otherwise cleared by the liver and kidneys. In addition, because the radiation dose is low, patients can be treated every few days and there is an increased probability that small metastatic sites, which might escape conventional therapies, will be treated by the radiation activated drug. 

Advantages

State Of Development

·         Core/shell structures have been synthesized and demonstrate robust efficiency.

·         Animal models and the design of the radiation activated nanoparticle-prodrug platform have been developed.

·         Fifty two compositions, which have been developed, are activated by low dose, low energy radiation.

Intellectual Property Info

Worldwide rights available; pending patents available under confidentiality.

Related Materials

• Jung, J. Y., et al., Identification and Development of Nanoscintillators for Biotechnology Applications, Journal of Luminescence, 154:569–57, 2014 - 06/06/2014
• Murphy, E. A.; et al., Targeted nanogels: a versatile platform for drug delivery to tumors. Mol Cancer Ther 2011, 10 (6), 972-82
• Zordoky B, et al., Acute Doxorubicin Toxicity Differentially Alters Cytochrome P450 Expression and Arachidonic Acid Metabolism in Rat Kidney and Liver. Drug Metab Dispos. 39(8),1440-50, 2011.
• Ibsen S,, et al., A Novel Doxorubicin Prodrug with Controllable Photolysis; Activation for Cancer Chemotherapy. Pharm Res. 27:1848–1860, 2010.

Patent Status