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.
Highlights
Collateral damage to healthy tissues caused by therapeutic agent action remains a major problem for cancer therapy, limiting treatment efficacy and applicability, and compromising patient survival
Specificity can be enhanced via therapeutic agentcontaining nanocarriers equipped with ligands that bind receptors selectively overexpressed in cancer cells [1,2,3]
A steady state is virtually impossible to achieve in vivo, where natural biological cycles, homeostasis mechanisms, and the practicalities of drug-administration regulations all conspire against it. We explore these issues with an approach examining the kinetics of nanocarrier-ligand complexes binding to healthy and cancer cells so as to identify drug design strategies that maximize targeting specificity
Summary
Collateral damage to healthy tissues caused by therapeutic agent action remains a major problem for cancer therapy, limiting treatment efficacy and applicability, and compromising patient survival. Specificity can be enhanced via therapeutic agentcontaining nanocarriers equipped with ligands that bind receptors selectively overexpressed in cancer cells [1,2,3] This approach holds promise, with a number of drugs on the market [4] and ongoing research focusing on nanocarrier-ligand conjugates and on identifying viable receptors [5,6,7,8], the occurrence of side effects in nanocarrier-treated patients remains a limiting factor. In the context of high-specificity cancer cell targeting, it has been shown that multivalent nanocarriers equipped with low-affinity ligands can achieve much higher coverage on cells with modestly higher receptor densities under equilibrium conditions [3,16]. We find that both the magnitude of the endocytosis rate and its functional dependence on the number of bound ligands, which is governed by the molecular mechanism of endocytosis, have substantial effects on the specificity
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