Effect of Basic Cell-Penetrating Peptides on the Structural, Thermodynamic, and Hydrodynamic Properties of a Novel Drug Delivery Vector, ELP[V5G3A2-150]

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• 作者：Daniel F. Lyons ; Vu Le ; Wolfgang H. Kramer ; Gene L. Bidwell ; III ; Edwin A. Lewis ; Drazen Raucher ; John J. Correia
• 刊名：Biochemistry
• 出版年：2014
• 出版时间：February 18, 2014
• 年：2014
• 卷：53
• 期：6
• 页码：1081-1091
• 全文大小：451K
• ISSN：1520-4995

文摘

Elastin-like polypeptides (ELPs) are large, nonpolar polypeptides under investigation as components of a novel drug delivery system. ELPs are soluble at low temperatures, but they desolvate and aggregate above a transition temperature (T_T). This aggregation is being utilized for targeting systemically delivered ELP鈥揹rug conjugates to heated tumors. We previously examined the structural, thermodynamic, and hydrodynamic properties of ELP[V₅G₃A₂-150] to understand its behavior as a therapeutic agent. In this study, we investigate the effect that adding basic cell-penetrating peptides (CPPs) to ELP[V₅G₃A₂-150] has on the polypeptide鈥檚 solubility, structure, and aggregation properties. CPPs are known to enhance the uptake of ELP into cultured cells in vitro and into tumor tissue in vivo. Interestingly, the asymmetric addition of basic residues decreased the solubility of ELP[V₅G₃A₂-150], although below the T_T we still observed a low level of self-association that increased with temperature. The 螖H of the aggregation process correlates with solubility, suggesting that the basic CPPs stabilize the aggregated state. This is potentially beneficial as the decreased solubility will increase the fraction aggregated and enhance drug delivery efficacy at a heated tumor. Otherwise, the basic CPPs did not significantly alter the biophysical properties of ELP. All constructs were monomeric at low temperatures but self-associate with increasing temperature through an indefinite isodesmic association. This self-association was coupled to a structural transition to type II 尾-turns. All constructs reversibly aggregated in an endothermic reaction, consistent with a reaction driven by the release of water.