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Title: Lipid cross-linking of nanolipoprotein particles substantially enhances serum stability and cellular uptake [Lipid crosslinking enhances the stability of nanolipoprotein particles in serum by multiple orders of magnitude]

Abstract

Nanolipoprotein particles (NLPs) consist of a discoidal phospholipid lipid bilayer confined by an apolipoprotein belt. NLPs are a promising platform for a variety of biomedical applications due to their biocompatibility, size, definable composition, and amphipathic characteristics. However, poor serum stability hampers the use of NLPs for in vivo applications such as drug formulation. In this study, NLP stability was enhanced upon the incorporation and subsequent UV-mediated intermolecular cross-linking of photoactive DiynePC phospholipids in the lipid bilayer, forming cross-linked nanoparticles (X-NLPs). Both the concentration of DiynePC in the bilayer and UV exposure time significantly affected the resulting X-NLP stability in 100% serum, as assessed by size exclusion chromatography (SEC) of fluorescently labeled particles. Cross-linking did not significantly impact the size of X-NLPs as determined by dynamic light scattering and SEC. X-NLPs had essentially no degradation over 48 h in 100% serum, which is a drastic improvement compared to non-cross-linked NLPs (50% degradation by ~10 min). X-NLPs had greater uptake into the human ATCC 5637 bladder cancer cell line compared to non-cross-linked particles, indicating their potential utility for targeted drug delivery. X-NLPs also exhibited enhanced stability following intravenous administration in mice. Lastly, these results collectively support the potential utility of X-NLPs formore » a variety of in vivo applications.« less

Authors:
 [1];  [1];  [2];  [3];  [1];  [1];  [2];  [1];  [2]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  2. Univ. of California - Davis (UC David) and UC Davis Comprehensive Cancer Center, Sacramento, CA (United States)
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Santa Cruz, CA (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1342026
Report Number(s):
LLNL-JRNL-683565
Journal ID: ISSN 1944-8244; TRN: US1701786
Grant/Contract Number:
AC52-07NA27344
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
ACS Applied Materials and Interfaces
Additional Journal Information:
Journal Volume: 8; Journal Issue: 32; Journal ID: ISSN 1944-8244
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; cross-linking; DiynePC; drug delivery; nanoparticles; NLP; rHDL; serum stability

Citation Formats

Gilmore, Sean F., Blanchette, Craig D., Scharadin, Tiffany M., Hura, Greg L., Rasley, Amy, Corzett, Michele, Pan, Chong-xian, Fischer, Nicholas O., and Henderson, Paul T.. Lipid cross-linking of nanolipoprotein particles substantially enhances serum stability and cellular uptake [Lipid crosslinking enhances the stability of nanolipoprotein particles in serum by multiple orders of magnitude]. United States: N. p., 2016. Web. doi:10.1021/acsami.6b04609.
Gilmore, Sean F., Blanchette, Craig D., Scharadin, Tiffany M., Hura, Greg L., Rasley, Amy, Corzett, Michele, Pan, Chong-xian, Fischer, Nicholas O., & Henderson, Paul T.. Lipid cross-linking of nanolipoprotein particles substantially enhances serum stability and cellular uptake [Lipid crosslinking enhances the stability of nanolipoprotein particles in serum by multiple orders of magnitude]. United States. doi:10.1021/acsami.6b04609.
Gilmore, Sean F., Blanchette, Craig D., Scharadin, Tiffany M., Hura, Greg L., Rasley, Amy, Corzett, Michele, Pan, Chong-xian, Fischer, Nicholas O., and Henderson, Paul T.. 2016. "Lipid cross-linking of nanolipoprotein particles substantially enhances serum stability and cellular uptake [Lipid crosslinking enhances the stability of nanolipoprotein particles in serum by multiple orders of magnitude]". United States. doi:10.1021/acsami.6b04609. https://www.osti.gov/servlets/purl/1342026.
@article{osti_1342026,
title = {Lipid cross-linking of nanolipoprotein particles substantially enhances serum stability and cellular uptake [Lipid crosslinking enhances the stability of nanolipoprotein particles in serum by multiple orders of magnitude]},
author = {Gilmore, Sean F. and Blanchette, Craig D. and Scharadin, Tiffany M. and Hura, Greg L. and Rasley, Amy and Corzett, Michele and Pan, Chong-xian and Fischer, Nicholas O. and Henderson, Paul T.},
abstractNote = {Nanolipoprotein particles (NLPs) consist of a discoidal phospholipid lipid bilayer confined by an apolipoprotein belt. NLPs are a promising platform for a variety of biomedical applications due to their biocompatibility, size, definable composition, and amphipathic characteristics. However, poor serum stability hampers the use of NLPs for in vivo applications such as drug formulation. In this study, NLP stability was enhanced upon the incorporation and subsequent UV-mediated intermolecular cross-linking of photoactive DiynePC phospholipids in the lipid bilayer, forming cross-linked nanoparticles (X-NLPs). Both the concentration of DiynePC in the bilayer and UV exposure time significantly affected the resulting X-NLP stability in 100% serum, as assessed by size exclusion chromatography (SEC) of fluorescently labeled particles. Cross-linking did not significantly impact the size of X-NLPs as determined by dynamic light scattering and SEC. X-NLPs had essentially no degradation over 48 h in 100% serum, which is a drastic improvement compared to non-cross-linked NLPs (50% degradation by ~10 min). X-NLPs had greater uptake into the human ATCC 5637 bladder cancer cell line compared to non-cross-linked particles, indicating their potential utility for targeted drug delivery. X-NLPs also exhibited enhanced stability following intravenous administration in mice. Lastly, these results collectively support the potential utility of X-NLPs for a variety of in vivo applications.},
doi = {10.1021/acsami.6b04609},
journal = {ACS Applied Materials and Interfaces},
number = 32,
volume = 8,
place = {United States},
year = 2016,
month = 7
}

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  • Rats receiving a nutritionally deficient diet displayed markedly elevated serum free T3 levels but showed no increase in oxygen consumption. This was associated with greatly reduced ratios of hepatic cellular and nuclear /sub 125/I-T3 to serum /sub 125/I-T3. Kinetic data supported the conclusion that cellular uptake of T3 was decreased in the nutritionally deficient rats. The lack of metabolic effect, despite the elevated serum T3 levels, is attributable to reduced availability of serum T3 to tissue nuclear receptor sites.
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