title: Evaluation of nanolipoprotein particles (NLPs) as an in vivo delivery platform.
abstract: Nanoparticles hold great promise for the delivery of therapeutics, yet limitations remain with regards to the use of these nanosystems for efficient long-lasting targeted delivery of therapeutics, including imparting functionality to the platform, in vivo stability, drug entrapment efficiency and toxicity. To begin to address these limitations, we evaluated the functionality, stability, cytotoxicity, toxicity, immunogenicity and in vivo biodistribution of nanolipoprotein particles (NLPs), which are mimetics of naturally occurring high-density lipoproteins (HDLs). We found that a wide range of molecules could be reliably conjugated to the NLP, including proteins, single-stranded DNA, and small molecules. The NLP was also found to be relatively stable in complex biological fluids and displayed no cytotoxicity in vitro at doses as high as 320 µg/ml. In addition, we observed that in vivo administration of the NLP daily for 14 consecutive days did not induce significant weight loss or result in lesions on excised organs. Furthermore, the NLPs did not display overt immunogenicity with respect to antibody generation. Finally, the biodistribution of the NLP in vivo was found to be highly dependent on the route of administration, where intranasal administration resulted in prolonged retention in the lung tissue. Although only a select number of NLP compositions were evaluated, the findings of this study suggest that the NLP platform holds promise for use as both a targeted and non-targeted in vivo delivery vehicle for a range of therapeutics.
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Fischer
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Dina R
authors.initials: DR
authors.lastname: Weilhammer
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Alexis
authors.initials: A
authors.lastname: Dunkle
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Mona
authors.initials: M
authors.lastname: Hwang
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Michele
authors.initials: M
authors.lastname: Corzett
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Cheri
authors.initials: C
authors.lastname: Lychak
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Wasima
authors.initials: W
authors.lastname: Mayer
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Salustra
authors.initials: S
authors.lastname: Urbin
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Collette
authors.affiliation: School of Natural Sciences, University of California Merced, Merced, California, United States of America.
authors.forename: Jiun
authors.initials: J
authors.lastname: Chiun Chang
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America; School of Natural Sciences, University of California Merced, Merced, California, United States of America.
authors.forename: Gabriela G
authors.initials: GG
authors.lastname: Loots
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Rasley
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors.forename: Craig D
authors.initials: CD
authors.lastname: Blanchette
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004269:DNA, Bacterial / Q000737:chemistry / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000378:metabolism*; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism; D004337:Drug Carriers; D004355:Drug Stability; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes; D008075:Lipoproteins, HDL / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity; D010316:Particle Size; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D052899:Pore Forming Cytotoxic Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000942:Antigens, Bacterial; D053327:Apolipoprotein E4; D004269:DNA, Bacterial; D004277:DNA, Single-Stranded; D004337:Drug Carriers; D005456:Fluorescent Dyes; C043908:LcrV protein, Yersinia; D008075:Lipoproteins, HDL; D010713:Phosphatidylcholines; D052899:Pore Forming Cytotoxic Proteins; D011994:Recombinant Proteins; C017251:1,2-oleoylphosphatidylcholine; D004134:Dimyristoylphosphatidylcholine