In recent years, proteins involved in regulating gene expression and signal transduction pathways have generated tremendous enthusiasm as promising targets for treating resistant cancers. There are encouraging preclinical data revealing that these newer drug candidates can selectively target tumor cells through novel mechanisms of action, e.g. suberoylanilide hydroxamic acid (SAHA) and geldanamycin (GA). Separately each drug exerts astonishing antitumor activity in vitro, but the combination of SAHA and GA demonstrates superior tumor-kill. Despite their selective methods of action on molecular targets, these new antitumor agents are characterized by high liver toxicities, wide distributions, and rapid eliminations when injected IV. There is therefore a clear need to improve the technology for combination therapy of these exciting new drugs through means of a multifunctional carrier. From a practical point of view, this may reduce the therapeutic dosage required for pharmacological intervention along with a potentially lower dose- limiting toxicity. It is significant to note that accumulation of a single drug at a tumor site is extremely challenging, and becomes even more so when a separate carrier or drug is administered for combination therapy. Although not all drug combinations demand simultaneous delivery (timing may play a critical role), the superior antitumor efficacy of SAHA and GA suggests that greater cellular co-localization may play a critical role in biological tumor-kill. To test our hypothesis, we propose four broad specific aims: (1) to synthesize and characterize poly(asp-g-ADA)-b-PCL and poly(bCD-PEG)-b-PCL for GAp encapsulation (caged micelle) and SAHA solubilization, respectively, and to verify the presence of a crosslinked bCD-ADA shell as a diffusion barrier to SAHA dissociations from bCD cavities, (2) to study the loading and in vitro release kinetics of GAp and SAHA under varying environmental conditions using established methods for measuring controlled release of poorly-water soluble compounds, (3) to study the in vitro antitumor efficacy of GAp and SAHA co-delivery using transferrin-targeted caged micelles in MCF-7 (breast) and PC-3 (prostate) cells, and (4) to study the in vivo biological antitumor efficacy of GAp and SAHA using transferrin- targeted caged micelles in tumor-bearing mice. The current proposal is the first of its kind to investigate co-delivery of SAHA in combination with GA via means of a targeted biocompatible multifunctional carrier for effective combination therapy, with the ultimate long-term goal of improving chemotherapeutic regression of aggressive tumors in cancer patients. ? ? ?
