Crystallization of the Multi-Receptor Tyrosine Kinase Inhibitor Sorafenib for Controlled Long-Term Drug Delivery Following a Single Injection.

Abstract

A major challenge in cancer medicine is the safe and effective delivery of drugs to the right tissue at the right time. Despite being designed for greater target specificity, many drugs still result in side effects and lack of safety in patients following global dissemination. Therefore, to develop new, more effective formulations capable of improving specificity and reducing off-target effects, here we describe formulation of drug crystals, from even a very hydrophobic and otherwise difficult to solubilize small molecule chemical compound, capable of providing constant drug release for weeks following a single injection. We chose to utilize the multi-tyrosine kinase inhibitor and multi-modal (anti-angiogenic and tumor cell cytotoxic) agent sorafenib, to combat aberrant angiogenesis and tumor growth which contribute to metastasis, ultimately responsible for poor patient outcomes. We tuned crystal size (surface area:volume ratios), imaged by SEM, to display controllability of drug delivery kinetics in in vitro drug release assays. Single and powder crystal X-ray diffraction (XRD) established that all crystals were the same polymorph and drug form. When utilized against an orthotopic triple negative breast cancer (TNBC) mouse model (4T1 in syngeneic BALB/c mice), we established anti-tumor activity from a single local, subcutaneous injection of crystalline sorafenib. From our findings, we support that engineering crystalline drug delivery systems has implications in the treatment of cancer or other diseases where high enough constitutive drug levels are needed to maintain target saturation and inhibition while also preventing emergence of drug resistance, which is a consequence often seen with suboptimal dosing. The online version contains supplementary material available at 10.1007/s12195-021-00708-6.