On the design of precision nanomedicines

Abstract

TeaserWe proposed the design of nanomedicines that target cells phenotypically enabling binding only when a precise receptor(s) composition is present. AbstractTight control on the selectivity of nanoparticles' interaction with biological systems is paramount for the development of targeted therapies. However, the large number of synthetically tunable parameters makes it difficult to identify optimal design ``sweet spots'' without rational guiding principles. Here we address this problem combining super-selectivity theory (SST) with analytical models from soft matter and polymer physics into a unified theoretical framework. Starting from an archetypal polymersome functionalized with targeting ligands, we use our model to identify the most selective combination of parameters in terms of particle size, brush polymerization degree and grafting density, as well as tether length, binding affinity and ligands number. We further show how to combine multivalent interactions into multiplexed systems which act holistically as a function of the density of more than one receptor type, so as to achieve binding only when multiple receptors are expressed above a threshold density. We show that theory can be used to effectively fit experimental data and, hence confirming its suitability. We thus propose the design of "barcoding" targeting approach that can be tailor-made to unique cell populations enabling personalized therapies.

Determinants of ligand-functionalized DNA nanostructure-cell interactions

“…4,5 Incorporation of multiple ligands onto nanoparticles results in a higher avidity towards target receptors as a result of multivalency 6,7 , and facilitates local delivery which increases drug accumulation in the site of interest, enhancing therapeutic efficiency and reducing off-target effects. Optimization of the synthesis and formulation of nanomedicines has revealed several parameters that modulate targeting efficiency and cellular uptake 8 , which include the orientation 9 , mobility 10 , and surface density of ligands on the nanoparticle. [11][12][13] In addition, nanoparticle size, shape, and aspect ratio also influence their uptake and therapeutic effectiveness.…”