Effective Locoregional Therapy with Small Molecule Tyrosine Kinase Inhibitors Employing In Situ Forming Drug Delivery Systems.

Background: In breast and other cancers, receptor tyrosine kinases (RTK), including the insulin-like growth factor 1 receptor (IGF-1R), play important roles in promoting the oncogenic process. These RTKs are therefore potential targets for developing new therapeutics. An initial screening of a chemical library against the IGF-1R in breast cancer cells identified two compounds as potent inhibitors of IGF-1R signaling, nordihydroguaiaretic acid (NDGA) and a diaryl urea compound (PQ401). Both compounds inhibit the growth of breast cancer cells in vitro and in vivo. However, their clinical potential may be limited because of their low solubility and bioavailability. A variety of drug delivery strategies have been examined to improve the solubility and efficacy of agents such as paclitaxel and camptothecin. In this study, we evaluated two in situ depot forming drug delivery systems (ISDDS) as the basis for local therapy with these tyrosine kinase inhibitors (TKI).Materials and Methods: The first ISDDS studied is based on the biodegradable, biocompatible co-polymer poly(lactic-co-glycolic acid) (PLGA). PLGA is soluble in various biocompatible solvents (eg. DMSO, glycofurol) but precipitates after injection into an aqueous environment and forms a solid implant in situ, entrapping co-administered drugs. PLGA along with TKI was dissolved in a biocompatible solvent, injected into PBS to form PLGA droplets, and in vitro release kinetics of the TKI were studied. The anti-tumor activity of TKI administered in the PLGA-based ISDDS was assessed in vivo using a mouse mammary carcinoma model. The second ISDDS is based on the surfactant F127, a block co-polymer with reverse therma gelling properties. At a concentration of 15% or greater, F127 is liquid at 4C, but gels at >23C. TKI were first solubilized in F127 via the formation of micelles. These TKI/micelles were tested for growth inhibition of breast cancer cells in vitro. The TKI/micelles were then formulated in 15% F127 and injected intratumorally into breast tumors in mice and tumor growth/regression was monitored.Results: In vitro release kinetics of TKI from PLGA demonstrated an initial burst (∼30% release within 3 hr) followed by slow release over several days. Intratumoral injection of the PLGA/TKI delivery system resulted in significant tumor regression compared to PLGA only or TKI only. TKI solubilized in F127 micelles showed in vitro growth inhibitory activity comparable to free drug. Intratumoral administration of TKI/micelles formulated in F127 resulted in significant tumor regression compared to F127 only or TKI only.Discussion: Two in situ depot forming drug delivery systems were tested for the locoregional therapy of breast cancer with tyrosine kinase inhibitors. Both systems demonstrated efficacy in a mouse breast cancer model and may prove useful in women with breast cancer for the local delivery of these and other agents with low solubility. Intratumoral injection of an ISDDS provides high local drug concentration while potentially preventing the systemic side effects associated with intravenous administration of chemotherapeutic agents. In addition, injection of an ISDDS at the site of tumor resection, may help prevent local recurrence. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6109.