According to the American Cancer Society, half of all men and one-third of all women in the United States will develop cancer in their lifetime. While chemotherapy has dramatically improved the survival rate of cancer patients, it comes at the cost of severe toxicities and in some cases poor response rates. In certain cases, such as bone cancer, chemotherapy has very limited effectiveness. In order to address these shortcomings, drug delivery innovations are necessary to improve the success rate of these treatments and improve the quality of life for these patients. Drug delivery vehicles are needed that are stable t post-administration dilution, can avoid biological barriers (e.g. reticuloendothelial system (RES) uptake), and deliver drugs in response to a physiological stimuli encountered in solid tumor environment (i.e. change in the pH level). Polymer micelles formed by the assembly of amphiphilic block copolymers are a particular type of nanocarrier that are attractive due to their ability to confer water solubility to hydrophobic drugs by encapsulating them within the core of the micelle. In an effort to overcome the inherent instability of traditional micelles, a polymer micelle-based drug delivery system was developed that utilizes novel stabilizing technology. This stabilizing technology utilizes reversible, pH-dependent crosslinking chemistry that stabilizes the micelle at physiological pH, but releases the drug in response to lower pH environments, such as areas surrounding a tumor or within endosomes. Daunorubicin is part of a widely prescribed family of chemotherapeutic drugs, anthracyclines. Unfortunately, this class of drugs suffers from poor pharmacokinetic and biodistribution profiles and severe cardiotoxicity. While there are many reports of anthracycline-based nanocarriers in the literature, these nanocarriers are typically unstable in the bloodstream, which quickly revert back to the pharmacokinetic and toxicity profiles of the free drug. Accordingly, it would be highly desirable t have a stable, anthracycline-based nanoparticle for the treatment of cancer that demonstrates an improved safety profile with respect to cardiotoxicity. In this Phase I SBIR proposal, stabilized, daunorubicin-loaded micelles (termed IT-143) will be evaluated for antitumor activity in bone cancer xenograft models and cardiotoxicity in rabbits.
Specific Aim 1 will investigate the anti-tumor efficacy of IT-143 in four separate bone cancer models including Ewing Sarcoma and osteosarcoma models.
Specific Aim 2 will evaluate the cardiac toxicity of IT-143 in rabbits accompanied by supporting pharmacokinetics. Successful completion of these Phase I aims will provide essential preclinical data for the further advancement of IT-143. The Phase II SBIR proposal will focus on IND-enabling, GLP toxicology studies and GMP manufacture of IT-143.
Although chemotherapeutic drugs have dramatically improved the survival of patients suffering from cancer, innovations in drug delivery technologies are needed to improve delivery of the drug to the tumor and avoid unwanted side effects. We have developed a nanocarrier that is designed to deliver the chemotherapeutic drug doxorubicin specifically to the tumor. Further development and commercialization of this nanocarrier will result in improved patient treatments for cancer, and reduced side effects often associated with chemotherapy.
|Bakewell, Suzanne J; Carie, Adam; Costich, Tara L et al. (2017) Imaging the delivery of drug-loaded, iron-stabilized micelles. Nanomedicine 13:1353-1362|