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Thermoresponsive elastin-b-collagen-like peptide bioconjugate nanovesicles for targeted drug delivery to collagen-containing matrices Tianzhi Luo, Michael A. David, Lucas C. Dunshee, Rebecca A. Scott, Morgan A. Urello, Christopher Price, and Kristi L. Kiick Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.7b00686 • Publication Date (Web): 18 Jul 2017 Downloaded from http://pubs.acs.org on July 19, 2017
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Thermoresponsive elastin-b-collagen-like peptide bioconjugate nanovesicles for targeted drug delivery to collagen-containing matrices. Tianzhi Luoa, Michael A. Davidb, Lucas C. Dunsheec, Rebecca A. Scotta,d, Morgan A. Urelloc, Christopher Priceb, Kristi L. Kiicka,b,d,* a
Department of Materials Science and Engineering, University of Delaware, Newark, DE, 19716, USA b
c
Department of Biomedical Engineering, University of Delaware, Newark, DE, 19716, USA
Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, 19716, USA d
Delaware Biotechnology Institute, Newark, DE, 19711, USA.
Keywords Collagen-like
peptide,
elastin-like
peptide,
self-assembly,
thermoresponsive,
cytocompatiblility
ACS Paragon Plus Environment
drug
delivery,
Biomacromolecules
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Abstract
Over the past few decades, (poly)peptide block copolymers have been widely employed in generating well-defined nanostructures as vehicles for targeted drug delivery applications. We previously reported the assembly of thermoresponsive nanoscale vesicles from an elastin-b-collagen like peptide (ELPCLP). The vesicles were observed to dissociate at elevated temperatures, despite the LCST-like behavior of the tethered ELP domain, which is suggested to be triggered by the unfolding of the CLP domain. Here, the potential of using the vesicles as drug delivery vehicles for targeting collagen-containing matrices is evaluated. The sustained release of an encapsulated model drug was achieved over a period of three weeks, following which complete release could be triggered via heating. The ELP-CLP vesicles show strong retention on a collagen substrate, presumably through collagen triple helix interactions. Cell viability and proliferation studies using fibroblasts and chondrocytes suggest that the vesicles are highly cytocompatible. Additionally, essentially no activation of a macrophage-like cell line is observed, suggesting that the vesicles do not initiate an inflammatory response. Endowed with thermally controlled delivery, the ability to bind collagen, and excellent cytocompatibility, these ELP-CLP nanovesicles are suggested to have significant potential in the controlled delivery of drugs to collagencontaining matrices and tissues.
1. Introduction Collagen is the main component of the extracellular matrix (ECM) in humans. Largely found in tendon, ligament, skin, cartilage and bone, collagens have widespread functions not only as a structural element in tissues, but also in mediating cell adhesion, migration, tissue scaffolding and repair.1 Although the roles of the 29 identified collagens in vivo vary widely,2 they all share the same tertiary structure – collagen triple helix, which comprises three polyproline-II type helices twisted together in a
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right-handed form.3 Each strand of the helix consists of regularly repeated Gly-X-Y tripeptide motifs, with proline (Pro) and (4R)-hydroxyproline (Hyp) occupying the X and Y positions at the highest frequency. Short synthetic collagen-like peptides (CLPs) (or collagen-mimetic peptides (CMPs)) mimic the triple helical conformation of native collagens,4-6 although unlike native full-length collagens, the folding and unfolding of CLP triple helices are reversible as a result of their relatively low molecular mass (
