Tsekouras Konstantinos, Goncharenko Igor, Colvin Michael E, Huang Kerwyn Casey, Gopinathan Ajay
Department of Physics, University of California Merced, Merced, California, United States of America.
PLoS One. 2013 Jun 26;8(6):e65623. doi: 10.1371/journal.pone.0065623. Print 2013.
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.
尽管使用载药纳米载体靶向癌细胞有望提高治疗剂的特异性，但最大化配体与癌细胞上过表达受体的亲和力的策略并不理想。为了确定使纳米载体对癌细胞具有最大特异性的设计原则，我们研究了一个基于动力学的通用理论模型，该模型涉及具有一种或多种特异性结合这些过表达受体的配体的纳米载体。我们表明，系统固有的动力学在确定特异性方面起着重要作用，实际上可以利用它来实现特异性的数量级提高。与当前的治疗设计趋势相反，我们表明，这些特异性的提高通常可以通过低内吞率和具有多个低亲和力配体的纳米载体的组合来实现。这些结果在广泛的内吞作用机制和药物递送方案中都具有很强的稳健性，这表明在受体靶向药物递送设计中需要进行范式转变。
