Investigating Three-Helix Micelles Transport and Accumulation in Tumors

Long-circulating three-helix micelles (3HM) developed in our lab has been found to selectively accumulate & penetrate through several solid tumor models in vivo. However, the underlying 3HM transport mechanism has yet to be fully understood. In solid tumors, while leaky blood vessels permit nanoparticle extravasation, high interstitial pressure prevents convective transport to the necrotic core. Additionally, dense tumor extracellular matrix presents a size-exclusion barrier to large nanoparticles (e.g. 100 nm liposomes) penetrating through the tumor. We hypothesize that 3HM tumor transport is mainly governed by Fick's laws of diffusion, advantageous to its small size (sub-20 nm) and long plasma half-life (~30 hours in mice). Solving diffusive flux for particle extravasation yields an equation that links the observed 3HM tumor accumulation to its plasma elimination time constant, with respect to tumor vessel permeability. Additionally, we have found that 3HM in vivo tumor penetration agrees with mathematical modeling of non-steady state diffusion profile. As such, 3HM represents a prime example of a small and stable nanoparticle with high diffusivity that is well-suited for passive tumor targeting.