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

Jung, Benson T.; Lim, Marc; Jung, Katherine; Li, Michael; Dong, He; Dube, Nikhil; Xu, Ting

doi:10.1016/j.jconrel.2020.09.037

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

Journal Article · Tue Sep 22 00:00:00 EDT 2020 · Journal of Controlled Release

DOI:https://doi.org/10.1016/j.jconrel.2020.09.037· OSTI ID:1840938

Jung, Benson T. ^[1];

^[1]; Jung, Katherine ^[1]; Li, Michael ^[1]; Dong, He ^[2]; Dube, Nikhil ^[1];

^[3]

Univ. of California, Berkeley, CA (United States)
Univ. of California, Berkeley, CA (United States); Univ. of Texas, Arlington, TX (United States)
Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

Biological constraints in diseased tissues have motivated the need for small nanocarriers (10–30 nm) to achieve sufficient vascular extravasation and pervasive tumor penetration. Here, this particle size limit is only an order of magnitude larger than small molecules, such that cargo loading is better described by co-assembly processes rather than simple encapsulation. Understanding the structural, kinetic, and energetic contributions of carrier-cargo co-assembly is thus critical to achieve molecular-level control towards predictable in vivo behavior. These interconnected set of properties were systematically examined using sub-20 nm self-assembled nanocarriers known as three-helix micelles (3HM). Both hydrophobicity and the “geometric packing parameter” dictate small molecule compatibility with 3HM's alkyl tail core. Planar obelisk-like apomorphine and doxorubicin (DOX) molecules intercalated well within the 3HM core and near the core-shell interface, forming an integral component to the co-assembly, as corroborated by small-angle X-ray and neutron-scattering structural studies. DOX promoted crystalline alkyl tail ordering, which significantly increased (+63%) the activation energy of 3HM subunit exchange. Subsequently, 3HM-DOX displayed slow-release kinetics (t_1/2 = 40 h) at physiological temperatures, with ~50× greater cargo preference for the micelle core as described by two drug partitioning coefficients (micellar core/shell K_p1 ~ 24, and shell/bulk solvent K_p2 ~ 2). The geometric and energetic insights between nanocarrier and their small molecule cargos developed here will aid in broader efforts to deconvolute the interconnected properties of carrier-drug co-assemblies. Adding this knowledge to pharmacological and immunological explorations will expand our understanding of nanomedicine behavior throughout all the physical and in vivo processes they are intended to encounter.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1840938

Journal Information:: Journal of Controlled Release, Vol. 329; ISSN 0168-3659

Publisher:: Controlled Release SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
Sub-20 nm nanocarrier
Drug delivery
Small molecule encapsulation
Molecular geometry
Release kinetics
Structural characterization

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

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