Use of Apatinib-nanosponge conjugate to reduce post-radiation induced oral cavity and salivary fibrosis.

DELTAMED LLC is a startup company focused on developing delivery platforms for small molecule mitigators of fibrosis. Radiation induced fibrosis and lymphedema in head and neck cancer patients is a painful, debilitating and cosmetically disfiguring late side-effect following curative (chemo)radiotherapy. Currently, there are no FDA approved curative treatments, only therapies that mitigate fibrosis. These therapies target the TGFβ1R-p38-MK2 signaling axis that activate myofibroblasts thus driving fibrosis. Direct inhibition of MK2 can prevent myofibroblast development and subsequent fibrotic injury. In addition, soft tissue fibrosis in liver, bowel and lung occurs due to activation of pro-angiogenic signaling processes. We and others have shown that the small molecule Apatinib prevents MK2 activation. The polypeptide, MMI-0100, is an allosteric MK2 inhibitor originally designed to disrupt MK2 signaling but MMI-0100 suffers from having an exceptionally short plasma half-life. Currently, there are no FDA-approved MK2 inhibitors and early generation small molecule MK2 inhibitors lack “druggability”. Encapsulation of drug molecules in nanoparticles significantly extends plasma half life by reducing drug clearance. Thus, DELTAMED LLC proposes to employ a novel nanosponge prodrug delivery system for the MK2 inhibitors Apatinib/MMI-0100. T o e n a b l e t h i s , t h e c o m p a n y has teamed with Dr. Gregory Gan (KUMC), a leader in MK2 research and Dr. Stefan Bossmann the inventor of the novel drug delivery platform referred to as “nanosponge.” The DELTAMED LLC team will develop a series of small molecule-nanosponge linked compounds that can selectively release the active moiety target cells with high potency and selectivity. The immediate goal of this proposal is to use existing MK2 inhibitors and improve their circulation half-life and potential cumulative drug delivery i.e. to make them more druggable. In this Phase I STTR, DELTAMED LLC will link Apatinib and/or MMI-0100 to different nanosponge backbones via amide and esterase cleavable bond. Conjugated compounds will be iteratively developed and tested using in vitro cell and protein-based screens. Finally, one lead compound will be advanced to in vivo biologic studies to determine a maximum tolerated dose and pharmacokinetic and pharmacodynamic distribution.