(56h) Precision Nanomedicines to Deliver Kinase Inhibitors to the Tumor Microenvironment

Therapy based on personalized medicine—the genomic context of a patient’s disease—has become a leading strategy to treat cancer. Small molecule drugs such as kinase inhibitors, which target key effectors of cancer signaling pathways, constitute a major component of this strategy. However, such drugs can affect the same signaling pathways in healthy tissues, which often leads to dose-limiting toxicity (on-pathway toxicity), while imperfect selectivity for the therapeutic target can also limit dosing (off-pathway toxicity). In addition, the anti-tumor effects of kinase inhibitors are often diminished by the activation of compensatory or parallel pathways as a mechanism of resistance. Increasing the therapeutic index of targeted therapies, used as monotherapies or combinations, would greatly improve their effectiveness.

We developed and validated a nanoscale formulation technology to incorporate high drug loadings of kinase inhibitors. The resulting nanoparticles obviate dose-limiting toxicities of kinase inhibitors and thereby improve therapeutic index in solid tumors. We developed a polysaccharide-based nanoformulation platform which targets kinase inhibitors to P-selectin on tumor vasculature. P-selectin is expressed endogenously in certain tumors, but it can be greatly induced by radiation therapy. Our data shows striking efficacy with MEK and PI3K inhibitors and the abrogation of dose-limiting toxicities, such as skin rash and hyperglycemia, to greatly improve therapeutic index. Moreover, measurements of tumor tissue show prolonged inhibition of downstream effectors in the signaling pathways, constituting a significant modulation of drug pharmacodynamics.