The Heller lab at MSKCC has discovered that poorly soluble kinase inhibitors mixed with specific indocyanine dye excipients will spontaneously form nanoparticles with very high (90% by mass) drug loadings, and that these dyes specifically target certain tumors while maintaining high blood stability. These nanoparticles offer the potential for avoiding both off- and on-pathway toxicities while delivering high quantities of targeted kinase inhibitors directly to tumors.
MECHANISM OF NANOPARTICLE FORMATION
Using the GPU-accelerated OpenPathSampling framework we developed in collaboration with the Bolhuis and Noé laboratories, we are studying the kinetic mechanism of nanoparticle formation to understand how critical nucleation events occur.
TUNING DYE ENCAPSULATION AND STABILITY
We are working with the Heller lab to tune both which drugs can be encapsulated and modulate blood stability and release properties through the synthesis of indocyanine dye derivatives. To do this, we are using alchemical free energy calculations to compute transfer free energies between various phases (pure drug, nanoparticle, and buffer), and coupling these approaches with constant-pH and counterion sampling methodologies.
Daniel Heller (MSKCC): Experimental nanoparticle synthesis
Shamay Y, Shah J, Tschaharganeh DF, Roxbury D, Budhathoki-Uprety J, Isik M, Mizrachi A, Nawaly K, Sugarman JL, Baut E, Neiman MR, Johnson DC, Sridharan R, Chu KL, Rajasekhar VK, Chodera JD, Lowe SW, and Heller DA
Quantitative self-assembly prediction yields targeted nanoparticles.