Self-Assembled Polymer Nanomedicines for Synergistic and Synthetic Lethal Drugging of Breast and Ovarian Tumors

Synergistic and synthetic lethal drug delivery to solid tumors can be difficult to achieve using traditional pharmaceutical excipients and nanotechnologies. Ideally, these strategies not only require that drug compounds with vastly differing size, charge, and hydrophobicity be co-delivered to tumor cells, but also that delivery (i) targets multiple cell populations within a heterogeneous tumor, (ii) is non-toxic to healthy tissues, and (iii) circumvents known mechanisms of resistance. Here, we describe recent progress in our laboratory utilizing self-assembled polymer drug carriers to address these difficult challenges. (i) We report the development of a nanoscale drug carrier based on Layer-by-Layer (LbL) polymer self-assembly that is capable of simultaneously targeting both cancer stem cells and the hypoxic tumor microenvironment in vitro and in vivo. (ii) We also describe the discovery of a novel DNA damage signal effector whose loss is synthetic lethal in ovarian cancer cells that lack functional tumor suppressor protein, p53, and the development of a series of lipid-like peptide co-polymers capable of co-delivering combinations of small interfering RNA and platinum therapy to ovarian tumors. (iii)  We present a novel nanoscale combination therapy of molecularly-targeted inhibitors that horizontally block oncogene-addicted and resistance-associated signaling in triple negative breast and non-small cell lung cancers in vitro and in vivo. These strategies are part of a comprehensive effort to directly address unmet clinical needs in the therapy of breast and ovarian carcinoma.