Design of High-Specificity Nanocarriers by Exploiting Non-Equilibrium Effects in Cancer Cell Targeting

Abstract

Although targeting of cancer cells using drug-delivering nanocarriers holds promise for improving therapeutic agent specificity, the strategy of maximizing ligand affinity for receptors overexpressed on cancer cells is suboptimal. To determine design principles that maximize nanocarrier specificity for cancer cells, we studied a generalized kinetics-based theoretical model of nanocarriers with one or more ligands that specifically bind these overexpressed receptors. We show that kinetics inherent to the system play an important role in determining specificity and can in fact be exploited to attain orders of magnitude improvement in specificity. In contrast to the current trend of therapeutic design, we show that these specificity increases can generally be achieved by a combination of low rates of endocytosis and nanocarriers with multiple low-affinity ligands. These results are broadly robust across endocytosis mechanisms and drug-delivery protocols, suggesting the need for a paradigm shift in receptor-targeted drug-delivery design.

Figure 1. Schematic of model kinetics and endocytosis profiles.

(A) Nanocarrier (gold) with two of four ligands bound on receptors (green). (B) Mapping to a 1D random walk with constant, sigmoidal, and linear profiles dictating rates of endocytosis in each ligand binding state .

Figure 2. The endocytosis profile is a major determinant of specificity behavior.

(A–C) Surface maps of specificity under the steady-state drug-delivery protocol with constant (A), linear (B), and sigmoidal endocytosis with (C). (D) Maximum specificity under steady-state drug delivery and sigmoidal endocytosis for various threshold values. In all cases, the total number of ligands is , , and .

Figure 3. The drug-delivery protocol is also a major determinant of specificity behavior.

(A–C) Specificity for a constant endocytosis profile under steady-state (A), single-dose (B), and pretargeted drug-delivery protocols (C). For the pretargeted drug-delivery protocol, the collection time window is from 200 to 300 seconds. (D) Maximum specificity under the pretargeted drug-delivery protocol and constant endocytosis for various values of . In all cases and .

Figure 4. Specificity can be widely varied depending on parameter selection.

(A) The combination of pretargeted drug-delivery protocol and sigmoidal endocytosis exhibits the highest specificity of all combinations examined. , , threshold at . (B) Maximum specificity across all combinations. , , for sigmoidal endocytosis, and from 200 to 300 sec for pretargeted drug-delivery protocol. Solid lines correspond to and . (C) Effects of the overexpression factor on specificity across drug-delivery protocols for constant endocytosis profile at , . The specificity rises sharply at . (D) Effects of the endocytosis rate (normalized by ) across drug-delivery protocols for constant endocytosis profile at , , .