INTRODUCTION Protein polymers are an emerging platform for engineering biodegradable cancer nanomedicines. A class of protein polymers, elastin-like-polypeptide (ELP) has tunable solubility that allows them to stabilize either the core or corona of monodisperse nanoparticles. We recently discovered two novel approaches to arm these nanoparticles: i) by decoration of their surface with the cognate protein target of Rapamycin (Rapa), which promotes specific and sustained release in vivo; and ii) to develop antibody-core protein polymer nanoparticles (APPNs) as multivalent CD20-targeted therapeutics. Rapamycin analogues are under clinical evaluation across a spectrum of cancers, while anti-CD20 therapies like Rituximab are approved for B-cell Lymphoma.  EXPERIMENTAL METHODS Synthetic ELP genes were fused with genes encoding for the FK506 binding protein, which binds Rapa (FSI-Rapa), and a single chain antibody (scFv) that binds CD20. Nanoparticles were optimized to assemble stable particles with diameters below 100 nm. FSI-Rapa was evaluated for release rate using HPLC and its anti-proliferative potential in a mTOR (mammalian target of rapamycin) sensitive cell line. Anti-CD20 APPNs were characterized for their binding specificity and apoptotic cell signaling. Both FSI-Rapa formulations and APPNs were evaluated for suppression of human xenograft models.RESULTS Both fusion proteins assemble protein nanoparticles with significant biological activity. FKBP decorated FSI nanoparticles have a 5-fold slower rate of Rapa release than free FKBP and 30-fold slower release than unmodified ELP nanoparticles. Drug-loaded nanoparticles reduced side-effects compared to free Rapa; furthermore, they halt tumor progression in vivo.The APPNs induce CD20 dependent apoptosis in a B-cell lymphoma in vitro and halt the in vivo growth of tumor xenografts better than Rituximab.CONCLUSIONS Protein polymer nanoparticles offer multiple opportunities to control assembly, presentation, and release of biologically functional molecules.FUNDING   NIH EB012281-02; USC Whittier Foundation; USC Ming Hsieh Institute; Stop Cancer Foundation; USC CTSI- NIH UL1RR031986-03.

Protein polymer nanoparticles with multivalent avidity for small molecules or cell-surface receptors

246th National Meeting (2013)

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