Designing sub-20 nm self-assembled nanocarriers for small molecule delivery: Interplay among structural geometry, assembly energetics, and cargo release kinetics

Biological constraints in diseased tissues have motivated the need for small nanocarriers (10–30 nm) to achieve sufficient vascular extravasation and pervasive tumor penetration. This particle size limit is only an order of magnitude larger than molecules, such that cargo loading better described by co-assembly processes rather simple encapsulation. Understanding structural, kinetic, energetic contributions carrier-cargo thus critical molecular-level control towards predictable vivo behavior. These interconnected set properties were systematically examined using sub-20 nm self-assembled known as three-helix micelles (3HM). Both hydrophobicity “geometric packing parameter” dictate molecule compatibility with 3HM's alkyl tail core. Planar obelisk-like apomorphine doxorubicin (DOX) molecules intercalated well within 3HM core near core-shell interface, forming integral component co-assembly, corroborated small-angle X-ray neutron-scattering structural studies. DOX promoted crystalline ordering, which significantly increased (+63%) activation energy subunit exchange. Subsequently, 3HM-DOX displayed slow-release kinetics (t1/2 = 40 h) at physiological temperatures, ~50× greater preference micelle two drug partitioning coefficients (micellar core/shell Kp1 ~ 24, shell/bulk solvent Kp2 2). The geometric insights between nanocarrier their cargos developed here will aid broader efforts deconvolute carrier-drug co-assemblies. Adding this knowledge pharmacological immunological explorations expand our understanding nanomedicine behavior throughout all physical they are intended encounter.