Hypothesis: Silicate prodrugs of taxane antitumor agents, customized to have proper hydrophobicity and hydrolytic lability, can be formulated with amphiphilic block copolymers into nanoparticles that are effective drugs and that have advantages over Taxol(R), Abraxane(R), and Taxotere(R). To test the essential issues underlying this hypothesis, we have assembled a team of University of Minnesota Investigators with diverse and complementary expertise in synthetic chemistry (co-I Hoye), materials science (PI Macosko), and pharmacology (co-I Panyam). The specific experiments discussed will be those using paclitaxel (the active agent in Taxol(R) and Abraxane(R)), but the approach is entirely analogous to that for docetaxel (the active agent in Taxotere(R)) as well as other taxane derivatives. Our hypothesis is guided by the innovation that silicate ester derivatives of drugs [i.e., DRUG-O- Si(OR)3] can function as prodrugs. This idea is new and unexplored. The silicate moiety can be tailored to dictate, independently, both the hydrophobicity of the prodrug as well as its rate of hydrolysis. These silicate prodrugs will be co-precipitated with biocompatible block copolymers (BCPs), using flash nanoprecipitation (FNP), to produce nanoparticles (NPs) in a size regime ideal for exploiting the enhanced permeation and retention (EPR) effect (ca. 100 nm diameter) for localization of particles at solid tumor sites. More specifically, we postulate that: i) the ability to alter the hydrophobic character of the prodrug allows control of a) the loading efficiency of the prodrug into NPs derived from amphiphilic block copolymers;b) the stability of the prodrug-loaded NPs;and c) the release rate of drug from the NPs. ii) The ability to alter the rate of hydrolysis of the prodrug, in a pH sensitive manner, allows control of the rate of conversion to free drug and the release rate of drug from the NPs. iii) The block size (both absolute and relative) and the amount (load ratio) of the BCP influences essential properties of the loaded NPs: size, stability, drug loading levels, and release rate of drug. iv) properly harnessed, this approach provides taxane-based drug formulations that are superior to those currently in clinical use [higher drug loading and less excipient, more selective accumulation, more selective drug release at (the more acidic) tumor sites, and fewer side effects]. Our goal is to be able to judge, objectively, at the end of this two-year R21 project whether a more comprehensive plan for full preclinical development through an R01 application and project is warranted. Chart I. Summary of the disciplinary expertise assembled to meet project Aims. Cross-disciplinary feedback will inform the integrated studies throughout. I. Silicate Prodrug and BCP Synthesis (Chemistry) prodrug hydrophobicity and hydrolysis/release rates;prodrug hydrophobicity and lability optimization particle formation (FNP), size, and stability II. Prodrug-Loaded BCP Nanoparticles (Materials Science) drug load levels;nanoparticle biodistribution;particle size and stability optimization III. Drug Delivery;Biological Efficacy (Pharmacology)

Public Health Relevance

A Silicate Prodrug Strategy for Enhancing Nanoparticle Delivery of Taxanes Taxol(R), Abraxane(R), and Taxotere(R) are important chemotherapeutics for cancer patients. We propose to develop improved forms of these drugs by formulating the active anticancer agents (the 'taxanes') into very small particles that will selectively accumulate at tumors and then release their active payload at those sites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB011671-02
Application #
8143529
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Peterson, Karen P
Project Start
2010-09-15
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$211,051
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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