Selecting Improved Peptidyl Motifs for Cytosolic Delivery of Disparate Protein and Nanoparticle Materials
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- 作者：Kelly Boeneman ; James B. Delehanty ; Juan B. Blanco-Canosa ; Kimihiro Susumu ; Michael H. Stewart ; Eunkeu Oh ; Alan L. Huston ; Glyn Dawson ; Sampat Ingale ; Ryan Walters ; Miriam Domowicz ; Jeffrey R. Deschamps ; W. Russ Algar ; Stassi DiMaggio ; Janet Manono ; Christopher M. Spillmann ; Darren Thompson ; Travis L. Jennings ; Philip E. Dawson ; Igor L. Medintz
- 刊名：ACS Nano
- 出版年：2013
- 出版时间：May 28, 2013
- 年：2013
- 卷：7
- 期：5
- 页码：3778-3796
- 全文大小：1346K
- 年卷期：v.7,no.5(May 28, 2013)
- ISSN：1936-086X
文摘
Cell penetrating peptides facilitate efficient intracellular uptake of diverse materials ranging from small contrast agents to larger proteins and nanoparticles. However, a significant impediment remains in the subsequent compartmentalization/endosomal sequestration of most of these cargoes. Previous functional screening suggested that a modular peptide originally designed to deliver palmitoyl-protein thioesterase inhibitors to neurons could mediate endosomal escape in cultured cells. Here, we detail properties relevant to this peptide鈥檚 ability to mediate cytosolic delivery of quantum dots (QDs) to a wide range of cell-types, brain tissue culture and a developing chick embryo in a remarkably nontoxic manner. The peptide further facilitated efficient endosomal escape of large proteins, dendrimers and other nanoparticle materials. We undertook an iterative structure鈥揳ctivity relationship analysis of the peptide by discretely modifying key components including length, charge, fatty acid content and their order using a comparative, semiquantitative assay. This approach allowed us to define the key motifs required for endosomal escape, to select more efficient escape sequences, along with unexpectedly identifying a sequence modified by one methylene group that specifically targeted QDs to cellular membranes. We interpret our results within a model of peptide function and highlight implications for in vivo labeling and nanoparticle-mediated drug delivery by using different peptides to co-deliver cargoes to cells and engage in multifunctional labeling.