Research Article

Progress in the development of Lipoplex and Polyplex modifi ed with Anionic Polymer for effi cient Gene Delivery

Yoshiyuki Hattori*

Published: 07/24/2017 | Volume 1 - Issue 1 | Pages: 003-018

ABSTRACT

Nucleic acid-based therapy has become an increasingly important strategy for treating a variety of human diseases. In systemic therapy, a therapeutic gene must be delivered efficiently to its target tissues without side effects. To deliver a therapeutic gene such as plasmid DNA (pDNA) or small interfering RNA (siRNA) to target tissues by systemic administration, cationic carriers such as cationic liposomes and polymers have been commonly used as a non-viral vector. However, the binary complex of therapeutic gene and cationic carrier must be stabilized in the blood circulation by avoiding agglutination with blood components, because electrostatic interactions between positively charged complexes and negatively charged erythrocytes can cause agglutination, and the agglutinates contribute to high entrapment of the therapeutic genes in the highly extended lung capillaries. One promising approach for overcoming this problem is modification of the surface of cationic complexes with anionic biodegradable polymers such as hyaluronic acid, chondroitin sulfate, or polyglutamic acid. As another approach, we recently developed a sequential injection method of anionic polymer and cationic liposome/therapeutic gene complex (cationic lipoplex) for delivery of a therapeutic gene into the liver or liver metastasis. In this review, we describe recent advances in the delivery of therapeutic genes by lipid- and polymer-based carrier systems using anionic polymers.

Read Full Article HTMLDOI: 10.29328/journal.jgmgt.1001002Cite this Article

REFERENCES

  1. Collins M, Thrasher AA. Gene therapy: progress and predictions. Proc Biol Sci. 2015; 282. Ref.: https://goo.gl/MpvdAg
  2. Aagaard L, Rossi JJ. RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev. 2007; 59: 75-86. Ref.: https://goo.gl/w6Ljep
  3. He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004; 5: 522-531. Ref.: https://goo.gl/xtPsZE
  4. Wang H, Jiang Y, Peng H, Chen Y, Zhu P, et al. Recent progress in microRNA delivery for cancer therapy by non-viral synthetic vectors. Adv Drug Deliv Rev. 2015; 81: 142-160. Ref.: https://goo.gl/pr7ZdH
  5. Zhang Y, Wang Z, Gemeinhart RA. Progress in microRNA delivery. J Control Release. 2013; 172: 962-974. Ref.: https://goo.gl/ZFRb69
  6. Roberts TC, Ezzat K, El Andaloussi S, Weinberg MS. Synthetic SiRNA Delivery: Progress and Prospects. Methods Mol Biol. 2016; 1364: 291-310. Ref.: https://goo.gl/WDZAmf
  7. Young LS, Searle PF, Onion D, Mautner V. Viral gene therapy strategies: from basic science to clinical application, J Pathol. 2006; 208: 299-318. Ref.: https://goo.gl/uvg8Ay
  8. Kaiser J. Gene therapy. Seeking the cause of induced leukemias in X-SCID trial. Science. 2003; 299: 495. Ref.: https://goo.gl/nsHKvE
  9. Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, et al. Non-viral vectors for gene-based therapy. Nat Rev Genet. 2014; 15: 541-555. Ref.: https://goo.gl/zRNE5K
  10. Glover DJ, Lipps HJ, Jans DA. Towards safe, non-viral therapeutic gene expression in humans. Nat Rev Genet. 2005; 6: 299-310. Ref.: https://goo.gl/Dp8a7i
  11. Zhou J, Shum KT, Burnett JC, Rossi JJ. Nanoparticle-Based Delivery of RNAi Therapeutics: Progress and Challenges. Pharmaceuticals. 2013; 6: 85-107. Ref.: https://goo.gl/eXwyQM
  12. Zhang S, Zhi D, Huang L. Lipid-based vectors for siRNA delivery. J Drug Target. 2012; 20: 724-735. Ref.: https://goo.gl/QjH3mf
  13. Hwang SJ, Davis ME. Cationic polymers for gene delivery: designs for overcoming barriers to systemic administration. Curr Opin Mol Ther. 2001; 3: 183-191. Ref.: https://goo.gl/QXaq9z
  14. Goula D, Benoist C, Mantero S, Merlo G, Levi G, et al. Polyethylenimine-based intravenous delivery of transgenes to mouse lung. Gene Ther. 1998; 5: 1291-1295. Ref.: https://goo.gl/4Jkmpk
  15. Yeeprae W, Kawakami S, Suzuki S, Yamashita F, Hashida M. Physicochemical and pharmacokinetic characteristics of cationic liposomes. Pharmazie. 2006; 61: 102-105. Ref.: https://goo.gl/bFxs41
  16. Eliyahu H, Servel N, Domb AJ, Barenholz Y. Lipoplex-induced hemagglutination: potential involvement in intravenous gene delivery. Gene Ther. 2002; 9: 850-858. Ref.: https://goo.gl/npqi3U
  17. Simberg D, Weisman S, Talmon Y, Faerman A, Shoshani T, et al. The role of organ vascularization and lipoplex-serum initial contact in intravenous murine lipofection. J Biol Chem. 2003; 278: 39858-39865. Ref.: https://goo.gl/W8gqip
  18. 18 Y. Hattori. Delivery of plasmid DNA into tumors by intravenous injection of PEGylated cationic lipoplexes into tumor-bearing mice. Pharmacology & Pharmacy. 2016; 7.
  19. Gjetting T, Arildsen NS, Christensen CL, Poulsen TT, Roth JA, et al. In vitro and in vivo effects of polyethylene glycol (PEG)-modified lipid in DOTAP/cholesterol-mediated gene transfection. Int J Nanomedicine. 2010; 5: 371-383. Ref.: https://goo.gl/wLcjFt
  20. Bourguignon LY. Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin Cancer Biol. 2008; 18: 251-259. Ref.: https://goo.gl/9xxva6
  21. Cortes-Dericks L, Schmid RA. CD44 and its ligand hyaluronan as potential biomarkers in malignant pleural mesothelioma: evidence and perspectives. Respir Res. 2017; 18: 58. Ref.: https://goo.gl/6SvFda
  22. Toole BP. Hyaluronan-CD44 Interactions in Cancer: Paradoxes and Possibilities. Clin Cancer Res. 2009; 15: 7462-7468. Ref.: https://goo.gl/pcCFMU
  23. Xie F, Zhang L, Peng J, Li C1, Pu J, et al. Hepatic Carcinoma Selective Nucleic Acid Nanovector Assembled by Endogenous Molecules Based on Modular Strategy. Mol Pharm. 2017; 14: 1841-1851. Ref.: https://goo.gl/td4jGT
  24. Chen M, Zeng Z, Qu X, Tang Y, Long Q, et al. Biocompatible anionic polyelectrolyte for improved liposome based gene transfection. Int J Pharm. 2015; 490: 173-179. Ref.: https://goo.gl/bHhj68
  25. Lu HD, Zhao HQ, Wang K, Lv LL. Novel hyaluronic acid-chitosan nanoparticles as non-viral gene delivery vectors targeting osteoarthritis. Int J Pharm. 2011; 420: 358-365. Ref.: https://goo.gl/ynnqri
  26. Lu H, Lv L, Dai Y, Wu G, Zhao H, et al. Porous chitosan scaffolds with embedded hyaluronic acid/chitosan/plasmid-DNA nanoparticles encoding TGF-β1 induce DNA controlled release, transfected chondrocytes, and promoted cell proliferation. PloS one. 2013; 8. Ref.: https://goo.gl/rpgcwQ
  27. Raviña M, Cubillo E, Olmeda D, Novoa-Carballal R, Fernandez-Megia E, et al. Hyaluronic acid/chitosan-g-poly(ethylene glycol) nanoparticles for gene therapy: an application for pDNA and siRNA delivery. Pharm Res. 2010; 27: 2544-2555. Ref.: https://goo.gl/JMcnXV
  28. Ito T, Koyama Y, Otsuka M, et al. Analysis of the surface structure of DNA/polycation/hyaluronic acid ternary complex by Raman microscopy. J Pharm Biomed Anal. 2010; 51: 268-272. Ref.: https://goo.gl/8TTMxc
  29. Ito T, Koyama Y, Otsuka M. Preparation of calcium phosphate nanocapsule including deoxyribonucleic acid-polyethyleneimine-hyaluronic acid ternary complex for durable gene delivery. J Pharm Sci. 2014; 103: 179-184. Ref.: https://goo.gl/tevmrh
  30. Koyama Y, Sugiura K, Yoshihara C, Inaba T, Ito T. Highly Effective Non-Viral Antitumor Gene Therapy System Comprised of Biocompatible Small Plasmid Complex Particles Consisting of pDNA, Anionic Polysaccharide, and Fully Deprotected Linear Polyethylenimine. Pharmaceutics. 2015; 7: 152-164. Ref.: https://goo.gl/J2CNsp
  31. Li Y, Zhang J, Wang B, Shen Y, Ouahab A. Co-delivery of siRNA and hypericin into cancer cells by hyaluronic acid modified PLGA-PEI nanoparticles. Drug Dev Ind Pharm. 2016; 42: 737-746. Ref.: https://goo.gl/T1JGhu
  32. Zhao MD, Cheng JL, Yan JJ, Chen FY, Sheng JZ, et al. Hyaluronic acid reagent functional chitosan-PEI conjugate with AQP2-siRNA suppressed endometriotic lesion formation. Int J Nanomedicine. 2016; 11: 1323-1336. Ref.: https://goo.gl/5LQk7N
  33. Chen CJ, Zhao ZX, Wang JC, Zhao EY, Gao LY, et al. A comparative study of three ternary complexes prepared in different mixing orders of siRNA/redox-responsive hyperbranched poly (amido amine)/hyaluronic acid. Int J Nanomedicine. 2012; 7: 3837-3849. Ref.: https://goo.gl/FEtQ2n
  34. Gu J, Chen X, Ren X, Zhang X, Fang X, et al. CD44-Targeted Hyaluronic Acid-Coated Redox-Responsive Hyperbranched Poly(amido amine)/Plasmid DNA Ternary Nanoassemblies for Efficient Gene Delivery. Bioconjug Chem. 2016; 27: 1723-1736. Ref.: https://goo.gl/WA48jv
  35. Kim EJ, Shim G, Kim K, Kwon IC, Oh YK, et al. Hyaluronic acid complexed to biodegradable poly L-arginine for targeted delivery of siRNAs. The J Gene Med. 2009; 11: 791-803. Ref.: https://goo.gl/2cmfJb
  36. Surace C, Arpicco S, Dufaÿ-Wojcicki A, Marsaud V, Bouclier C, et al. Lipoplexes targeting the CD44 hyaluronic acid receptor for efficient transfection of breast cancer cells. Mol Pharm. 2009; 6: 1062-1073. Ref.: https://goo.gl/rTUoFA
  37. Dufaÿ Wojcicki A, Hillaireau H, Nascimento TL, Arpicco S, Taverna M, et al. Hyaluronic acid-bearing lipoplexes: physico-chemical characterization and in vitro targeting of the CD44 receptor. J Control Release. 2012; 162: 545-552. Ref.: https://goo.gl/DEP7mL
  38. Leite Nascimento T, Hillaireau H, Vergnaud J, Rivano M, Deloménie C, et al. Hyaluronic acid-conjugated lipoplexes for targeted delivery of siRNA in a murine metastatic lung cancer model. Int J Pharm. 2016; 514: 103-111. Ref.: https://goo.gl/Ztr3q5
  39. Nascimento TL, Hillaireau H, Noiray M, Bourgaux C, Arpicco S, et al. Supramolecular Organization and siRNA Binding of Hyaluronic Acid-Coated Lipoplexes for Targeted Delivery to the CD44 Receptor. Langmuir. 2015; 31: 11186-11194. Ref.: https://goo.gl/QwyYoY
  40. Taetz S, Bochot A, Surace C, Arpicco S, Renoir JM, et al. Hyaluronic acid-modified DOTAP/DOPE liposomes for the targeted delivery of anti-telomerase siRNA to CD44-expressing lung cancer cells. Oligonucleotides. 2009; 19: 103-116. Ref.: https://goo.gl/4XksiJ
  41. Yang X, Iyer AK, Singh A, Milane L, Choy E, et al. Cluster of Differentiation 44 Targeted Hyaluronic Acid Based Nanoparticles for MDR1 siRNA Delivery to Overcome Drug Resistance in Ovarian Cancer. Pharm Res. 2015; 32: 2097-2109. Ref.: https://goo.gl/Vamt93
  42. Jiang G, Park K, Kim J, Kim KS, Oh EJ, et al. Hyaluronic acid-polyethyleneimine conjugate for target specific intracellular delivery of siRNA. Biopolymers. 2008; 89: 635-642. Ref.: https://goo.gl/D7PuEF
  43. Park K, Lee MY, Kim KS, Hahn SK. Target specific tumor treatment by VEGF siRNA complexed with reducible polyethyleneimine-hyaluronic acid conjugate. Biomaterials. 2010; 31: 5258-5265. Ref.: https://goo.gl/GwUTLX
  44. Ganesh S, Iyer AK, Morrissey DV, Amiji MM. Hyaluronic acid based self-assembling nanosystems for CD44 target mediated siRNA delivery to solid tumors. Biomaterials. 2013; 34: 3489-3502. Ref.: https://goo.gl/5NYVTw
  45. Han SE, Kang H, Shim GY, Kim SJ, Choi HG, et al. Cationic derivatives of biocompatible hyaluronic acids for delivery of siRNA and antisense oligonucleotides. J Drug Target. 2009; 17: 123-132. Ref.: https://goo.gl/FysFvE
  46. Tran TH, Rastogi R, Shelke J, Amiji MM. Modulation of Macrophage Functional Polarity towards Anti-Inflammatory Phenotype with Plasmid DNA Delivery in CD44 Targeting Hyaluronic Acid Nanoparticles. Sci Rep. 2015; 5: 16632. Ref.: https://goo.gl/DXrNH8
  47. Tran TH, Krishnan S, Amiji MM. MicroRNA-223 Induced Repolarization of Peritoneal Macrophages Using CD44 Targeting Hyaluronic Acid Nanoparticles for Anti-Inflammatory Effects. PloS one. 2016; 11. Ref.: https://goo.gl/yujGhm
  48. Lee MS, Lee JE, Byun E, Kim NW, Lee K, et al. Target-specific delivery of siRNA by stabilized calcium phosphate nanoparticles using dopa-hyaluronic acid conjugate. J Control Release. 2014; 192: 122-130. Ref.: https://goo.gl/9BdWDp
  49. Jang YL, Ku SH, Jin S, Park JH, Kim WJ, et al. Hyaluronic acid-siRNA conjugate/reducible polyethylenimine complexes for targeted siRNA delivery. J Nanosci Nanotechnol. 2014; 14: 7388-7394. Ref.: https://goo.gl/yQ7KsP
  50. Mok H, Park JW, Park TG. Antisense oligodeoxynucleotide-conjugated hyaluronic acid/protamine nanocomplexes for intracellular gene inhibition. Bioconjug Chem. 2007; 18: 1483-1489. Ref.: https://goo.gl/AqgFzn
  51. Mizumoto S, Sugahara K. Glycosaminoglycans are functional ligands for receptor for advanced glycation end-products in tumors. FEBS J. 2013; 280: 2462-2470. Ref.: https://goo.gl/6WXTEh
  52. Henrotin Y, Mathy M, Sanchez C, Lambert C. Chondroitin sulfate in the treatment of osteoarthritis: from in vitro studies to clinical recommendations. Ther Adv Musculoskelet Dis. 2010; 2: 335-348. Ref.: https://goo.gl/bN4A1J
  53. Uchida S, Itaka K, Chen Q, Osada K, Miyata K, et al. T. Combination of chondroitin sulfate and polyplex micelles from Poly(ethylene glycol)-poly{N'-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} block copolymer for prolonged in vivo gene transfection with reduced toxicity. J Control Release. 2011; 155: 296-302.
  54. Hattori Y, Yamasaku H, Maitani Y. Anionic polymer-coated lipoplex for safe gene delivery into tumor by systemic injection. J Drug Target. 2013; 21: 639-647. Ref.: https://goo.gl/YnRp23
  55. Hattori Y, Arai S, Kikuchi T, Ozaki KI, Kawano K, et al. Therapeutic effect for liver-metastasized tumor by sequential intravenous injection of anionic polymer and cationic lipoplex of siRNA. J Drug Target. 2016; 24: 309-317. Ref.: https://goo.gl/HaoJZ1
  56. Lo YL, Sung KH, Chiu CC, Wang LF. Chemically conjugating polyethylenimine with chondroitin sulfate to promote CD44-mediated endocytosis for gene delivery. Mol Pharm. 2013; 10: 664-676. Ref.: https://goo.gl/hXHZmc
  57. Liang S, Duan Y, Xing Z, Han H, Zhang A, et al. Inhibition of cell proliferation and migration by chondroitin sulfate-g-polyethylenimine-mediated miR-34a delivery. Colloids Surf B Biointerfaces. 2015; 136: 577-584. Ref.: https://goo.gl/VcoikX
  58. Chen W, Liu Y, Liang X, Huang Y, Li Q. Chondroitin sulfate-functionalized polyamidoamine as a tumor-targeted carrier for miR-34a delivery. Acta biomater. 2017; 57: 238-250. Ref.: https://goo.gl/2VpD2E
  59. Kurosaki T, Kitahara T, Fumoto S, Nishida K, Yamamoto K, et al. Chondroitin sulfate capsule system for efficient and secure gene delivery. J Pharm Pharm Sci. 2010; 13: 351-361. Ref.: https://goo.gl/36Rj1T
  60. Hagiwara K, Nakata M, Koyama Y, Sato T. The effects of coating pDNA/chitosan complexes with chondroitin sulfate on physicochemical characteristics and cell transfection. Biomaterials. 2012; 33: 7251-7260. Ref.: https://goo.gl/PTwfKF
  61. Hagiwara K, Kishimoto S, Ishihara M, Koyama Y, Mazda O, et al. In vivo gene transfer using pDNA/chitosan/chondroitin sulfate ternary complexes: influence of chondroitin sulfate on the stability of freeze-dried complexes and transgene expression in vivo. J Gene Med. 2013; 15: 83-92. Ref.: https://goo.gl/Vbktx4
  62. Hamada K, Yoshihara C, Ito T, Tani K, Tagawa M, et al. Antitumor effect of chondroitin sulfate-coated ternary granulocyte macrophage-colony-stimulating factor plasmid complex for ovarian cancer. J Gene Med. 2012; 14: 120-127. Ref.: https://goo.gl/sc2j3a
  63. Iwanaga M, Kodama Y, Muro T, Nakagawa H, Kurosaki T, et al. Biocompatible complex coated with glycosaminoglycan for gene delivery. J Drug Target. 2017; 25: 370-378. Ref.: https://goo.gl/23rjZJ
  64. Imamura M, Kodama Y, Higuchi N, Kanda K, Nakagawa H, et al. Ternary complex of plasmid DNA electrostatically assembled with polyamidoamine dendrimer and chondroitin sulfate for effective and secure gene delivery. Biol Pharm Bull. 2014; 37: 552-559. Ref.: https://goo.gl/mrgDuM
  65. Kurosaki T, Uematsu M, Shimoda K, Suzuma K, Nakai M, et al. Ocular gene delivery systems using ternary complexes of plasmid DNA, polyethylenimine, and anionic polymers. Biol Pharm Bull. 2013; 36: 96-101. Ref.: https://goo.gl/asDxcu
  66. Liao ZX, Peng SF, Ho YC, Mi FL, Maiti B, et al. Mechanistic study of transfection of chitosan/DNA complexes coated by anionic poly(gamma-glutamic acid). Biomaterials. 2012; 33: 3306-3315. Ref.: https://goo.gl/4zW749
  67. Peng SF, Tseng MT, Ho YC, Wei MC, Liao ZX, et al. Mechanisms of cellular uptake and intracellular trafficking with chitosan/DNA/poly(gamma-glutamic acid) complexes as a gene delivery vector. Biomaterials. 2011; 32: 239-248. Ref.: https://goo.gl/amcfS3
  68. Hanigan MH, Ricketts WA. Extracellular glutathione is a source of cysteine for cells that express gamma-glutamyl transpeptidase. Biochemistry. 1993; 32: 6302-6306. Ref.: https://goo.gl/cvbf71
  69. Pompella A, De Tata V, Paolicchi A, Zunino F. Expression of gamma-glutamyltransferase in cancer cells and its significance in drug resistance. Biochem Pharmacol. 2006; 71: 231-238. Ref.: https://goo.gl/PXag69
  70. Schafer C, Fels C, Brucke M, Holzhausen HJ, Bahn H, et al. Gamma-glutamyl transferase expression in higher-grade astrocytic glioma. Acta Oncol. 2001; 40: 529-535. Ref.: https://goo.gl/YneGs5
  71. Yao D, Jiang D, Huang Z, Lu J, Tao Q, et al. Abnormal expression of hepatoma specific gamma-glutamyl transferase and alteration of gamma-glutamyl transferase gene methylation status in patients with hepatocellular carcinoma. Cancer. 2000; 88: 761-769. Ref.: https://goo.gl/9AhhC2
  72. Hanigan MH, Frierson HF Jr, Brown JE, Lovell MA, Taylor PT. Human ovarian tumors express gamma-glutamyl transpeptidase. Cancer Res. 1994; 54: 286-290. Ref.: https://goo.gl/PWbnX5
  73. Liao ZX, Ho YC, Chen HL, Peng SF, Hsiao CW, et al. Enhancement of efficiencies of the cellular uptake and gene silencing of chitosan/siRNA complexes via the inclusion of a negatively charged poly(gamma-glutamic acid). Biomaterials. 2010; 31: 8780-8788. Ref.: https://goo.gl/K4fK1H
  74. Kodama Y, Kuramoto H, Mieda Y, Muro T, Nakagawa H, et al. Application of biodegradable dendrigraft poly-l-lysine to a small interfering RNA delivery system. J Drug Target. 2017; 25: 49-57. Ref.: https://goo.gl/M7pyVt
  75. Kanda K, Kodama Y, Kurosaki T, Imamura M, Nakagawa H, et al. Ternary complex of plasmid DNA with protamine and gamma-polyglutamic acid for biocompatible gene delivery system. Biol Pharm Bull. 2013; 36: 1794-1799. Ref.: https://goo.gl/bBRTNr
  76. Kodama Y, Shiokawa Y, Nakamura T, Kurosaki T, Aki K, et al. Novel siRNA delivery system using a ternary polymer complex with strong silencing effect and no cytotoxicity. Biol Pharm Bull. 2014; 37: 1274-1281. Ref.: https://goo.gl/L61STv
  77. Hattori Y, Nakamura A, Arai S, Nishigaki M, Ohkura H, et al. In vivo siRNA delivery system for targeting to the liver by poly-l-glutamic acid-coated lipoplex, Results Pharma Sci. 2014; 4: 1-7. Ref.: https://goo.gl/96eSUj
  78. Schlegel A, Largeau C, Bigey P, Bessodes M, Lebozec K, et al. Anionic polymers for decreased toxicity and enhanced in vivo delivery of siRNA complexed with cationic liposomes. J Control Release. 2011; 152: 393-401. Ref.: https://goo.gl/uQDVxW
  79. Schlegel A, Bigey P, Dhotel H, Scherman D, Escriou V. Reduced in vitro and in vivo toxicity of siRNA-lipoplexes with addition of polyglutamate. J Control Release. 2013; 165: 1-8. Ref.: https://goo.gl/tZHkSo
  80. Kodama Y, Nakamura T, Kurosaki T, Egashira K, Mine T, et al. Biodegradable nanoparticles composed of dendrigraft poly-L-lysine for gene delivery. Eur J Pharm Biopharm. 2014; 87: 472-479. Ref.: https://goo.gl/7ghqB4
  81. Kurosaki T, Kitahara T, Fumoto S, Nishida K, Nakamura J, et al. Ternary complexes of pDNA, polyethylenimine, and gamma-polyglutamic acid for gene delivery systems. Biomaterials. 2009; 30: 2846-2853. Ref.: https://goo.gl/CEjceW
  82. Kurosaki T, Kodama Y, Muro T, Higuchi N, Nakamura T, et al. Secure splenic delivery of plasmid DNA and its application to DNA vaccine. Biol Pharm Bull. 2013; 36: 1800-1806. Ref.: https://goo.gl/sPQjwY
  83. Tripathi SK, Goyal R, Ansari KM, Ravi Ram K, Shukla Y, et al. Polyglutamic acid-based nanocomposites as efficient non-viral gene carriers in vitro and in vivo. Eur J Pharm Biopharm. 2011; 79: 473-484. Ref.: https://goo.gl/9m2ySs
  84. Boyle WS, Senger K, Tolar J, Reineke TM. Heparin Enhances Transfection in Concert with a Trehalose-Based Polycation with Challenging Cell Types. Biomacromolecules. 2017; 18: 56-67. Ref.: https://goo.gl/6PyzkG
  85. Zhou X, Li X, Gou M, Qiu J, Li J,et al. Antitumoral efficacy by systemic delivery of heparin conjugated polyethylenimine-plasmid interleukin-15 complexes in murine models of lung metastasis. Cancer Sci. 2011; 102: 1403-1409. Ref.: https://goo.gl/hLQiCc
  86. Hattori Y, Arai S, Okamoto R, Hamada M, Kawano K, et al. Sequential intravenous injection of anionic polymer and cationic lipoplex of siRNA could effectively deliver siRNA to the liver. Int J Pharm. 2014; 476: 289-298. Ref.: https://goo.gl/ojVgE1
  87. Hattori Y, Arai S, Kikuchi T, Hamada M, Okamoto R, et al. Optimization of siRNA delivery method into the liver by sequential injection of polyglutamic acid and cationic lipoplex. Pharmacol & Pharma. 2015; 6: 302-310. Ref.: https://goo.gl/K6JkPs
  88. Hattori Y, Yoshiike Y, Kikuchi T, Yamamoto N, Ozaki K, et al. Evaluation of injection route of anionic polymer for siRNA delivery into the liver by sequential injection of anionic polymer and cationic lipoplex of siRNA. J. Drug Deliv. Sci. Tec. 2016; 35: 40-49. Ref.: https://goo.gl/VmbwSG
  89. Tan GK, Tabata Y. Chondroitin-6-sulfate attenuates inflammatory responses in murine macrophages via suppression of NF-kappaB nuclear translocation. Acta Biomater. 2014; 10: 2684-2692. Ref.: https://goo.gl/uj47Ym
  90. Stabler TV, Huang Z, Montell E, Vergés J, Kraus VB. Chondroitin sulphate inhibits NF-κB activity induced by interaction of pathogenic and damage associated molecules. Osteoarthritis Cartilage. 2017; 25: 166-174. Ref.: https://goo.gl/3GAnRV
  91. Hattori Y, Kikuchi T, Nakamura M, Ozaki K, Onishi H. Therapeutic effects of protein kinase N3 small interfering RNA and doxorubicin combination therapy on liver and lung metastases. Oncol Lett, in press.