Lysozyme dextran nanogels (NG) have great potential in vitro as a drug delivery platform, combining simple chemistry with rapid uptake and cargo release in target cells with “stealth” properties and low toxicity. In this work, we study for the first time the potential of targeted NG as a drug delivery platform in vivo to alleviate acute pulmonary inflammation in animal model of LPS-induced lung injury. NG are targeted to the endothelium via conjugation with an antibody (Ab) directed to Intercellular Adhesion Molecule-1(ICAM-NG), whereas IgG conjugated NG (IgG-NG) are used for control formulations. The amount of Ab conjugated to the NG and distribution in the body after intravenous (IV) injection have been quantitatively analyzed using a tracer isotope-labeled [125I]IgG. As a proof of concept, Ab-NG are loaded with dexamethasone, an anti-inflammatory therapeutic, and the drug uptake and release kinetics are measured by HPLC. In vivo studies in mice showed that: i) ICAM-NG accumulates in mouse lungs (~120% ID/g vs ~15% ID/g of IgG-NG); and, ii) DEX encapsulated in ICAM-NG, but not in IgG-NG practically blocks LPS-induced overexpression of pro-inflammatory cell adhesion molecules including ICAM-1 in the pulmonary inflammation.
References
[1]
Howard MD, Hood ED, Zern B, Shuvaev VV, Grosser T, et al. (2014) Nanocarriers for vascular delivery of anti-inflammatory agents. Annu Rev Pharmacol Toxicol 54: 205–226. doi: 10.1146/annurev-pharmtox-011613-140002
[2]
Cheng Z, Al Zaki A, Hui JZ, Muzykantov VR, Tsourkas A (2012) Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science 338: 903–910. doi: 10.1126/science.1226338
[3]
Buxton DB (2009) Nanomedicine for the management of lung and blood diseases. Nanomedicine (Lond) 4: 331–339. doi: 10.2217/nnm.09.8
[4]
Pan H, Myerson JW, Hu L, Marsh JN, Hou K, et al. (2013) Programmable nanoparticle functionalization for in vivo targeting. FASEB J 27: 255–264. doi: 10.1096/fj.12-218081
[5]
Simionescu M, Gafencu A, Antohe F (2002) Transcytosis of pla sma macromolecules in endothelial cells: a cell biological survey. Microsc Res Tech 57: 269–288. doi: 10.1002/jemt.10086
[6]
Cybulsky MI, Gimbrone MA Jr (1991) Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 251: 788–791. doi: 10.1126/science.1990440
[7]
Iiyama K, Hajra L, Iiyama M, Li H, DiChiara M, et al. (1999) Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res 85: 199–207. doi: 10.1161/01.res.85.2.199
[8]
Muro S, Muzykantov VR (2005) Targeting of antioxidant and anti-thrombotic drugs to endothelial cell adhesion molecules. Curr Pharm Des 11: 2383–2401. doi: 10.2174/1381612054367274
[9]
Charoenphol P, Mocherla S, Bouis D, Namdee K, Pinsky DJ, et al. (2011) Targeting therapeutics to the vascular wall in atherosclerosis-Carrier size matters. Atherosclerosis 217: 364–370. doi: 10.1016/j.atherosclerosis.2011.04.016
[10]
Greineder CF, Howard MD, Carnemolla R, Cines DB, Muzykantov VR (2013) Advanced drug delivery systems for antithrombotic agents. Blood 122: 1565–1575. doi: 10.1182/blood-2013-03-453498
[11]
Howard MD, Hood ED, Zern B, Shuvaev VV, Grosser T, et al.. (2014) Nanocarriers for Vascular Delivery of Anti-Inflammatory Agents. Annual Review of Pharmacology and Toxicology, Vol 54. pp. 205–226.
[12]
Maruyama K, Holmberg E, Kennel SJ, Klibanov A, Torchilin VP, et al. (1990) Characterization of Invivo Immunoliposome Targeting to Pulmonary Endothelium. Journal of Pharmaceutical Sciences 79: 978–984. doi: 10.1002/jps.2600791107
[13]
Johnson ER, Matthay MA (2010) Acute Lung Injury: Epidemiology, Pathogenesis, and Treatment. Journal of Aerosol Medicine and Pulmonary Drug Delivery 23: 243–252. doi: 10.1089/jamp.2009.0775
[14]
Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, et al. (2005) Incidence and outcomes of acute lung injury. New England Journal of Medicine 353: 1685–1693. doi: 10.1056/nejmoa050333
[15]
Cliffel DE, Turner BN, Huffman BJ (2009) Nanoparticle-based biologic mimetics. Wiley Interdisciplinary Reviews-Nanomedicine and Nanobiotechnology 1: 47–59. doi: 10.1002/wnan.20
[16]
Mochalin VN, Shenderova O, Ho D, Gogotsi Y (2012) The properties and applications of nanodiamonds. Nature Nanotechnology 7: 11–23. doi: 10.1038/nnano.2011.209
[17]
Liu J, Weller GE, Zern B, Ayyaswamy PS, Eckmann DM, et al. (2010) Computational model for nanocarrier binding to endothelium validated using in vivo, in vitro, and atomic force microscopy experiments. Proc Natl Acad Sci U S A 107: 16530–16535. doi: 10.1073/pnas.1006611107
[18]
Muzykantov VR, Christofidou-Solomidou M, Balyasnikova I, Harshaw DW, Schultz L, et al. (1999) Streptavidin facilitates internalization and pulmonary targeting of an anti-endothelial cell antibody (platelet-endothelial cell adhesion molecule 1): a strategy for vascular immunotargeting of drugs. Proc Natl Acad Sci U S A 96: 2379–2384. doi: 10.1073/pnas.96.5.2379
[19]
Muzykantov VR, Atochina EN, Ischiropoulos H, Danilov SM, Fisher AB (1996) Immunotargeting of antioxidant enzyme to the pulmonary endothelium. Proc Natl Acad Sci U S A 93: 5213–5218. doi: 10.1073/pnas.93.11.5213
[20]
Christofidou-Solomidou M, Scherpereel A, Wiewrodt R, Ng K, Sweitzer T, et al. (2003) PECAM-directed delivery of catalase to endothelium protects against pulmonary vascular oxidative stress. American Journal of Physiology-Lung Cellular and Molecular Physiology 285: L283–L292.
[21]
Danilov SM, Muzykantov VR, Martynov AV, Atochina EN, Sakharov IY, et al. (1991) Lung Is the Target Organ for a Monoclonal-Antibody to Angiotensin-Converting Enzyme. Laboratory Investigation 64: 118–124.
[22]
Muro S, Garnacho C, Champion JA, Leferovich J, Gajewski C, et al. (2008) Control of endothelial targeting and intracellular delivery of therapeutic enzymes by modulating the size and shape of ICAM-1-targeted carriers. Molecular Therapy 16: 1450–1458. doi: 10.1038/mt.2008.127
[23]
Carnemolla R, Shuvaev VV, Muzykantov VR (2010) Targeting antioxidant and antithrombotic biotherapeutics to endothelium. Seminars in Thrombosis and Hemostasis 36: 332–342. doi: 10.1055/s-0030-1253455
[24]
Chittasupho C, Xie S-X, Baoum A, Yakovleva T, Siahaan TJ, et al. (2009) ICAM-1 targeting of doxorubicin-loaded PLGA nanoparticles to lung epithelial cells. European Journal of Pharmaceutical Sciences 37: 141–150. doi: 10.1016/j.ejps.2009.02.008
[25]
Rocksen D, Lilliehook B, Larsson R, Johansson T, Bucht A (2000) Differential anti-inflammatory and anti-oxidative effects of dexamethasone and N-acetylcysteine in endotoxin-induced lung inflammation. Clinical and Experimental Immunology 122: 249–256. doi: 10.1046/j.1365-2249.2000.01373.x
[26]
Everts M, Kok RJ, Asgeirsdottir SA, Melgert BN, Moolenaar TJM, et al. (2002) Selective intracellular delivery of dexamethasone into activated endothelial cells using an E-selectin-directed immunoconjugate. Journal of Immunology 168: 883–889. doi: 10.4049/jimmunol.168.2.883
Vinogradov SV, Bronich TK, Kabanov AV (2002) Nanosized cationic hydrogels for drug delivery: preparation, properties and interactions with cells. Advanced Drug Delivery Reviews 54: 135–147. doi: 10.1016/s0169-409x(01)00245-9
[31]
Ferrer MCC, Sobolewski P, Composto RJ, Eckmann DM (2013) Cellular uptake and intracellular cargo release from dextran based nanogel drug carriers. Journal of Nanotechnology in Engineering and Medicine 4 011002: 1–8. doi: 10.1115/1.4023246
Ferrer MCC, Ferrier RC Jr, Eckmann DM, Composto RJ (2013) A facile route to synthesize nanogels doped with silver nanoparticles. Journal of Nanoparticle Research 15: 1–7. doi: 10.1007/s11051-012-1323-5
[34]
Takei F (1985) Inhibition of Mixed Lymphocyte-Response by a Rat Monoclonal-Antibody to a Novel Murine Lymphocyte-Activation Antigen (Mala-2). Journal of Immunology 134: 1403–1407.
[35]
Li J, Yu SY, Yao P, Jiang M (2008) Lysozyme-dextran core-shell nanogels prepared via a green process. Langmuir 24: 3486–3492. doi: 10.1021/la702785b
Zern BJ, Chacko A-M, Liu J, Greineder CF, Blankemeyer ER, et al. (2013) Reduction of Nanoparticle Avidity Enhances the Selectivity of Vascular Targeting and PET Detection of Pulmonary Inflammation. Acs Nano 7: 2461–2469. doi: 10.1021/nn305773f
[38]
Shuvaev VV, Han J, Yu KJ, Huang S, Hawkins BJ, et al. (2011) PECAM-targeted delivery of SOD inhibits endothelial inflammatory response. Faseb Journal 25: 348–357. doi: 10.1096/fj.10-169789
[39]
Armstrong JK, Wenby RB, Meiselman HJ, Fisher TC (2004) The hydrodynamic radii of macromolecules and their effect on red blood cell aggregation. Biophysical Journal 87: 4259–4270. doi: 10.1529/biophysj.104.047746
[40]
Mittal V, Matsko NB (2012) Analytical imaging techniques for soft matter. Berlin Heidelberg: Springer-Verlag.
[41]
Arruebo M, Valladares M, Gonzalez-Fernandez A (2009) Antibody-Conjugated Nanoparticles for Biomedical Applications. Journal of Nanomaterials 2009: 1–24. doi: 10.1155/2009/439389
[42]
Liu J, Weller GER, Zern B, Ayyaswamy PS, Eckmann DM, et al. (2010) Computational model for nanocarrier binding to endothelium validated using in vivo, in vitro, and atomic force microscopy experiments. Proceedings of the National Academy of Sciences of the United States of America 107: 16530–16535. doi: 10.1073/pnas.1006611107
[43]
Henzi I, Walder B, Tramer MR (2000) Dexamethasone for the prevention of postoperative nausea and vomiting: A quantitative systematic review. Anesthesia and Analgesia 90: 186–194. doi: 10.1097/00000539-200001000-00038
[44]
Eberhart LHJ, Morin AM, Georgieff M (2000) Dexamethasone for prophylaxis of postoperative nausea and vomiting - A meta-analysis of randomised controlled studies. Anaesthesist 49: 713–720.
[45]
El Azab SR, Rosseell PMJ, de Lange JJ, Groeneveld ABJ, van Strik R, et al. (2002) Dexamethasone decreases the pro- to anti-inflammatory cytokine ratio during cardiac surgery. British Journal of Anaesthesia 88: 496–501. doi: 10.1093/bja/88.4.496
[46]
Chen C-C, Siddiqui FJ, Chen T-L, Chan ES-Y, Tam K-W (2012) Dexamethasone for Prevention of Postoperative Nausea and Vomiting in Patients Undergoing Thyroidectomy: Meta-analysis of Randomized Controlled Trials. World Journal of Surgery 36: 61–68. doi: 10.1007/s00268-011-1343-9
[47]
De Jong WH, Borm PJA (2008) Drug delivery and nanoparticles: Applications and hazards. International Journal of Nanomedicine 3: 133–149. doi: 10.2147/ijn.s596
[48]
Hua S (2013) Targeting sites of inflammation: intercellular adhesion molecule-1 as a target for novel inflammatory therapies. Front Pharmacol 4: 127. doi: 10.3389/fphar.2013.00127
