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Bioorg Med Chem Lett. 2016 Mar 15;26(6):1618-1623. doi: 10.1016/j.bmcl.2016.01.079. Epub 2016 Feb 4.

Synthesis of linear and cyclic peptide-PEG-lipids for stabilization and targeting of cationic liposome-DNA complexes.

Author information

1
Department of Materials, University of California, Santa Barbara, CA 93106, United States; Department of Physics, University of California, Santa Barbara, CA 93106, United States; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106, United States. Electronic address: ewert@mrl.ucsb.edu.
2
Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, United States.
3
Department of Materials, University of California, Santa Barbara, CA 93106, United States; Department of Physics, University of California, Santa Barbara, CA 93106, United States; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106, United States.
4
Department of Materials, University of California, Santa Barbara, CA 93106, United States; Department of Physics, University of California, Santa Barbara, CA 93106, United States; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106, United States; Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, United States.
5
Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, United States; Center for Nanomedicine and Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106, United States; Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia.
6
Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, United States; Center for Nanomedicine and Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106, United States.
7
Department of Materials, University of California, Santa Barbara, CA 93106, United States; Department of Physics, University of California, Santa Barbara, CA 93106, United States; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106, United States. Electronic address: safinya@mrl.ucsb.edu.

Abstract

Because nucleic acids (NAs) have immense potential value as therapeutics, the development of safe and effective synthetic NA vectors continues to attract much attention. In vivo applications of NA vectors require stabilized, nanometer-scale particles, but the commonly used approaches of steric stabilization with a polymer coat (e.g., PEGylation; PEG=poly(ethylene glycol)) interfere with attachment to cells, uptake, and endosomal escape. Conjugation of peptides to PEG-lipids can improve cell attachment and uptake for cationic liposome-DNA (CL-DNA) complexes. We present several synthetic approaches to peptide-PEG-lipids and discuss their merits and drawbacks. A lipid-PEG-amine building block served as the common key intermediate in all synthetic routes. Assembling the entire peptide-PEG-lipid by manual solid phase peptide synthesis (employing a lipid-PEG-carboxylic acid) allowed gram-scale synthesis but is mostly applicable to linear peptides connected via their N-terminus. Conjugation via thiol-maleimide or strain-promoted (copper-free) azide-alkyne cycloaddition chemistry is highly amenable to on-demand preparation of peptide-PEG-lipids, and the appropriate PEG-lipid precursors are available in a single chemical step from the lipid-PEG-amine building block. Azide-alkyne cycloaddition is especially suitable for disulfide-bridged peptides such as iRGD (cyclic CRGDKGPDC). Added at 10 mol% of a cationic/neutral lipid mixture, the peptide-PEG-lipids stabilize the size of CL-DNA complexes. They also affect cell attachment and uptake of nanoparticles in a peptide-dependent manner, thereby providing a platform for preparing stabilized, affinity-targeted CL-DNA nanoparticles.

KEYWORDS:

Heterobifunctional poly(ethylene glycol); Homing peptides; Lipid synthesis; Nanoparticles; Nonviral gene delivery; Peptide–PEG–lipids; Poly(ethylene glycol)

PMID:
26874401
PMCID:
PMC4775344
DOI:
10.1016/j.bmcl.2016.01.079
[Indexed for MEDLINE]
Free PMC Article

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