title: Complement C3 mediated targeting of liposomes to granulocytic myeloid derived suppressor cells.
abstract: In cancer patients, granulocytic myeloid derived suppressor cells (G-MDSCs) expand in number, infiltrating tumor and lymphatic tissues where they suppress an anti-tumor immune response. We report here the development of a liposomal drug delivery system that selectively targets G-MDSCs. The liposomes form a disulfide bond with activated complement C3 after intravenous injection and are taken up by G-MDSCs, which express the receptor for activated C3. In vitro experiments utilizing serum from a C3 knockout mouse demonstrate that G-MDSCs take up these liposomes in a C3-dependent manner. After systemic administration to tumor bearing mice, liposomes were incorporated by 22% of G-MDSCs in the blood and were also present in a percentage of G-MDSCs in the tumor (11%), spleen (22%), liver (35%) and lungs (26%). This liposomal system offers a versatile means of targeted drug delivery to G-MDSCs and could be an important tool for restoring anti-tumor immunity in cancer patients.
  
  
  BACKGROUND
  It has been shown that the presence of granulocytic myeloid derived suppressor cells (G-MDSCs) in cancer patients suppress the tumor immune response of T cells. Many drugs can be used to reverse this process. In this article, the authors describe the development of a liposomal drug delivery system for targeted drug delivery to G- MDSCs. This system may prove to be useful adjunct in immunotherapy in the fight against cancers.
authors.affiliation: WWAMI Biomedical Program, University of Alaska Anchorage, Anchorage, AK, United States. Electronic address: mpkullberg@uaa.alaska.edu.
authors.forename: Max
authors.initials: M
authors.lastname: Kullberg
authors.affiliation: WWAMI Biomedical Program, University of Alaska Anchorage, Anchorage, AK, United States.
authors.forename: Holly
authors.initials: H
authors.lastname: Martinson
authors.affiliation: WWAMI Biomedical Program, University of Alaska Anchorage, Anchorage, AK, United States.
authors.forename: Kristine
authors.initials: K
authors.lastname: Mann
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Anchordoquy
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000494:pharmacology*; D006098:Granulocytes / Q000378:metabolism*; D007167:Immunotherapy; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000628:therapy
chemical_list: D003176:Complement C3; D008081:Liposomes
keywords: Cancer; Complement C3; Immunotherapy; Liposome; MDSC; Myeloid derived suppressor cells
references.citation: Leuk Res. 1994 Aug;18(8):587-96
references.pmid: 8065160
references.citation: Biochim Biophys Acta. 2008 Apr;1778(4):854-63
references.pmid: 18211818
references.citation: Cancer Immunol Immunother. 2009 Jan;58(1):49-59
references.pmid: 18446337
references.citation: J Immunol Methods. 2008 Aug 20;337(1):49-54
references.pmid: 18572187
references.citation: Int J Cancer. 2014 Jun 15;134(12):2853-64
references.pmid: 24259296
references.citation: Cancer Res. 2006 Sep 15;66(18):9299-307
references.pmid: 16982775
references.citation: Cancer Chemother Pharmacol. 2013 Aug;72(2):417-27
references.pmid: 23797686
references.citation: Med Microbiol Immunol. 2010 Aug;199(3):273-81
references.pmid: 20376485
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13236-40
references.pmid: 21788512
references.citation: J Control Release. 2008 Feb 18;126(1):50-8
references.pmid: 18068849
references.citation: Front Oncol. 2013 Mar 15;3:49
references.pmid: 23508517
references.citation: Mol Pharm. 2012 Jul 2;9(7):2000-8
references.pmid: 22621404
references.citation: J Immunol. 2001 May 1;166(9):5398-406
references.pmid: 11313376
references.citation: Nat Rev Immunol. 2009 Mar;9(3):162-74
references.pmid: 19197294
references.citation: Ann Biomed Eng. 2012 Oct;40(10):2131-9
references.pmid: 22532323
references.citation: J Pharm Pharm Sci. 2003 May-Aug;6(2):292-301
references.pmid: 12935441
references.citation: Cancer Res. 2003 Aug 1;63(15):4441-9
references.pmid: 12907617
references.citation: Curr Opin Pharmacol. 2009 Aug;9(4):470-81
references.pmid: 19616475
references.citation: Leuk Lymphoma. 2014 Dec;55(12):2893-900
references.pmid: 24625328
references.citation: Int Immunopharmacol. 2011 Jul;11(7):783-8
references.pmid: 21406269
references.citation: Curr Pharm Des. 2004;10(24):2981-9
references.pmid: 15379663
references.citation: Adv Drug Deliv Rev. 2013 Oct;65(10):1284-98
references.pmid: 24018362
references.citation: Immunol Cell Biol. 2013 Sep;91(8):493-502
references.pmid: 23797066
references.citation: J Control Release. 2012 Jul 20;161(2):175-87
references.pmid: 21945285
references.citation: Prog Lipid Res. 2003 Nov;42(6):463-78
references.pmid: 14559067
references.citation: Int J Cancer. 2012 Nov 15;131(10):2402-10
references.pmid: 22362271
references.citation: Cancer Res. 2014 Sep 15;74(18):5091-102
references.pmid: 25224959
references.citation: Immunobiology. 2015 Feb;220(2):236-42
references.pmid: 25178934