| Posted: Mar 27, 2018 |
Cell-penetrating 'nanodrills' show promise for intracellular drug delivery
(Nanowerk News) Researchers at Oregon State University and Oregon Health & Science University have created new nanomaterials able to cross cell membranes, establishing a novel platform for the intracellular delivery of molecular drugs and other cargo.
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The researchers explored how to tune the size, shape and morphology of materials known as cell-penetrating self-assembling peptide nanomaterials, or CSPNs.
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They used sequential ligation of peptide building blocks to create CSPNs that formed distinct shapes resembling a drill bit, and these “nanodrills” showed a strong capacity for encapsulating guest molecules for therapy or imaging.
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Findings were published in the Journal of Controlled Release, and a provisional patent application has been filed with the U.S. Patent and Trademark Office.
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“CSPNs represent a new modular drug delivery platform that can be programmed into exquisite structures through sequence-specific fine-tuning of amino acids,” said corresponding author Gaurav Sahay, assistant professor of pharmaceutical sciences at the OSU/OHSU College of Pharmacy. “The fine-tuning of amino acids imparted versatile properties like flexibility, self-assembly, higher drug loading, biodegradability and biocompatibility for effective intracellular delivery of CSPNs.”
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The Sahay lab team and collaborators, including researchers from the OHSU School of Medicine and the University of California San Diego, generated five different CSPNs, conjugating Tat peptides to a (RADA)2 linker and adding different numbers of phenylalanine residues.
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“We chose (RADA)2 because it contains alternating amino acids that repel water and mix with water; that imparted the property of self-assembly,” said first author Ashwani Narayana, postdoctoral scholar in the College of Pharmacy. “We demonstrated the transition of secondary structure in these CSPNs, which in turn played a vital role in self-assembly and drug delivery potential. The in-vivo efficacy of these nanodrills will extend the frontiers beyond intracellular delivery.”
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CSPNs with two, three or four phenylalanine residues self-assembled into nanodrills displaying a coarse-twisted, non-twisted or fine-twisted morphology, respectively.
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“These nanodrills had a high capacity to encapsulate hydrophobic guest molecules,” Narayana said. “The coarse-twisted nanodrills in particular demonstrated higher internalization and were able to localize rapamycin in the liver in a mouse model.”
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Rapamycin is an antifungal metabolite of the Streptomyces hygroscopicus bacterium and among its many properties is the ability to induce autophagy – the regulated, orderly degradation and recycling of cellular components.
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“Defects in autophagy lead to accumulation of toxic materials in various disease conditions ranging from infectious diseases to neurodegenerative disorders,” Sahay said. “These modular CSPNs could be a new platform for delivering molecules across biological barriers thought to be impenetrable. And minute changes can direct self-assembly into myriad defined nanostructures, making them ideal hosts for a range of different molecules.”
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