title: Glycosaminoglycan-functionalized poly-lactide-co-glycolide nanoparticles: synthesis, characterization, cytocompatibility, and cellular uptake.
abstract: The efficient delivery of chemotherapeutics to the tumor via nanoparticle (NP)-based delivery systems remains a significant challenge. This is compounded by the fact that the tumor is highly dynamic and complex environment composed of a plurality of cell types and extracellular matrix. Since glycosaminoglycan (GAG) production is altered in many diseases (or pathologies), NPs bearing GAG moieties on the surface may confer some unique advantages in interrogating the tumor microenvironment. In order to explore this premise, in the study reported here poly-lactide-co-glycolide (PLGA) NPs in the range of 100-150 nm bearing various proteoglycans were synthesized by a single-step nanoprecipitation and characterized. The surface functionalization of the NPs with GAG moieties was verified using zeta potential measurements and X-ray photoelectron spectroscopy. To establish these GAG-bearing NPs as carriers of therapeutics, cellular toxicity assays were undertaken in lung epithelial adenocarcinoma (A549) cells, human pulmonary microvascular endothelial cells (HPMEC), and renal proximal tubular epithelial cells. In general NPs were well tolerated over a wide concentration range (100-600 μg/mL) by all cell types and were taken up to appreciable extents without any adverse cell response in A549 cells and HPMEC. Further, GAG-functionalized PLGA NPs were taken up to different extents in A459 cells and HPMEC. In both cell systems, the uptake of heparin-modified NPs was diminished by 50%-65% in comparison to that of unmodified PLGA. Interestingly, the uptake of chondroitin sulfate NPs was the highest in both cell systems with 40%-60% higher uptake when compared with that of PLGA, and this represented an almost twofold difference over heparin-modified NPs. These findings suggest that GAG modification can be explored as means of changing the uptake behavior of PLGA NPs and these NP systems have potential in cancer therapy.
authors: Institute for Macromolecular Chemistry, University of Freiburg, Freiburg, Germany.
authors: Surya P
authors: SP
authors: Lamichhane
authors: Institute for Macromolecular Chemistry, University of Freiburg, Freiburg, Germany ; Helmholtz Virtual Institute on "Multifunctional Biomaterials for Medicine", University of Freiburg, Freiburg, Germany.
authors: Neha
authors: N
authors: Arya
authors: Laboratory for Process Technology, Department of Microsystems Engineering, University of Freiburg, Freiburg, Germany.
authors: Nirdesh
authors: N
authors: Ojha
authors: Institute for Macromolecular Chemistry, University of Freiburg, Freiburg, Germany.
authors: Esther
authors: E
authors: Kohler
authors: Institute for Macromolecular Chemistry, University of Freiburg, Freiburg, Germany ; Helmholtz Virtual Institute on "Multifunctional Biomaterials for Medicine", University of Freiburg, Freiburg, Germany ; Centre for Biological Signaling Studies (BIOSS), University of Freiburg, Freiburg, Germany.
authors: V Prasad
authors: VP
authors: Shastri
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006025:Glycosaminoglycans / Q000737:chemistry*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry*; D056951:Photoelectron Spectroscopy; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: D006025:Glycosaminoglycans; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase
keywords: nanocarriers; passive targeting; polysaccharides; proteoglycans; tumor microenvironment
references: Int J Nanomedicine. 2008;3(1):21-9
references: 18488413
references: Biomaterials. 2007 Jun;28(18):2876-84
references: 17363053
references: Part Fibre Toxicol. 2009 Jan 09;6:1
references: 19134195
references: Nat Rev Drug Discov. 2008 Sep;7(9):771-82
references: 18758474
references: Int J Pharm. 2013 Oct 1;454(2):686-94
references: 23747506
references: Am J Physiol. 1998 Aug;275(2 Pt 1):L203-22
references: 9700080
references: Biochem Biophys Res Commun. 1997 Apr 7;233(1):1-5
references: 9144384
references: J Biol Chem. 2007 Feb 2;282(5):2785-97
references: 17145755
references: Pharm Res. 2013 Oct;30(10):2512-22
references: 23314933
references: Int J Cancer. 2007 Jun 15;120(12):2527-37
references: 17390371
references: Am J Physiol. 1998 May;274(5 Pt 1):L810-9
references: 9612297
references: Ageing Res Rev. 2013 Jan;12(1):376-90
references: 23123177
references: Nanotechnol Sci Appl. 2012 Aug 15;5:61-71
references: 24198497
references: Small. 2008 Jan;4(1):26-49
references: 18165959
references: Int J Cancer. 2006 Jul 1;119(1):41-8
references: 16450384
references: Pharm Res. 2007 Aug;24(8):1405-14
references: 17393074
references: Kidney Int. 1999 Jul;56(1):41-51
references: 10411678
references: Nat Rev Cancer. 2008 Nov;8(11):875-9
references: 18948997
references: Langmuir. 2005 Sep 13;21(19):8852-7
references: 16142970
references: Nanoscale. 2013 Apr 7;5(7):2818-29
references: 23443459
references: CA Cancer J Clin. 2013 Jan;63(1):11-30
references: 23335087
references: Drug Discov Today. 2003 Mar 15;8(6):259-66
references: 12623240
references: Eur Respir J Suppl. 1990 Oct;11:482s-484s
references: 2278607
references: Langmuir. 2007 Nov 20;23(24):12275-9
references: 17963413
references: Small. 2009 Jan;5(1):126-34
references: 19051182
references: Chem Biol Interact. 2006 Mar 10;160(1):1-40
references: 16430879
references: Adv Drug Deliv Rev. 2011 Mar 18;63(3):131-5
references: 20304019
references: Cancer Res. 1994 Mar 1;54(5):1381-7
references: 7509720
references: J Control Release. 2010 May 10;143(3):374-82
references: 20109508
references: J Biomed Mater Res B Appl Biomater. 2005 Feb 15;72(2):292-8
references: 15486967
references: Blood. 1997 Aug 1;90(3):1150-9
references: 9242547
references: Nat Rev Cancer. 2002 Jul;2(7):521-8
references: 12094238