GROWTH FACTOR LOADED FUNCTIONALIZED GOLD NANOPARTICLES AS POTENTIAL TARGETED TREATMENT FOR ACUTE RENAL FAILURE
Objective: Gold nanoparticles (GNPs) have been synthesized and functionalized with chitosan alkanethiol polyethylene glycol as a renal targeting ligand (CS-PEG-AlkSH-GNPs) and finally loaded with insulin-like growth factor-I (IGF-I) for selectively and effectively treating acute renal failure.
Methods: In this study, GNPs were prepared and characterized using transmission electron microscopy, photon correlation spectroscopy and inductively coupled plasma (ICP-OES). The surface of the GNPs was further decorated using synthesized CS-PEG-Alk-SH and IGF-I. IGF-I loaded CS-PEG-ALK-SH-GNP were characterized for their growth factor loading capacity, particle size, zeta potential and dispersion stability. In vitro release profile and bioactivity of IGF-I from IGF-I loaded CS-PEG-AlkSH-GNPs were assessed using cell culture technique. Biological distribution, pharmacokinetic investigation and toxicity study of IGF-I loaded CS-PEG-AlkSH-GNPs were carried out using experimental animals.
Results: The size of GNPs was less than 50 nm with a surface charge of about-45 mV. Coating GNPs with CS-PEG-Alk-SH acquired the particles high in vitro stability in 5 M NaCl and bovine serum albumin (BSA). The assemblyâ€™s bioactivity was tested on cell culture and the released IGF-I was found to maintain bioactivity equivalent to its released percentage. When tested on mice, IGF-I loaded CS-PEG-ALK-SH-GNP reached a concentration of 60% in 6 h time in the kidneys with an elimination half-life higher than that of the control GNPs indicating efficient renal residence and targeting processes. The system was proved nontoxic.
Conclusion: CS-PEG-AlkSH-GNPs could represent an efficient tool for the targeted delivery of growth factors and other biomolecules to the kidneys.
2. Liano F, Pascual P. Outcomes in acute renal failure. Semin Nephrol 1998;18:541-50.
3. Mahon P, Shorten G. Perioperative acute renal failure. Curr Opin Anaesthesiol 2006;19:332-8.
4. Lazarus JM, Denker BM, Owen WF. Hemodialysis. In: Brenner BM. editor. The Kidney. Philadelphia: Saunders; 1996. p. 2424-506.
5. Jayaraman R, Van der Voort J. Principles of management of chronic kidney disease. Pediatrics Child Health 2010;20:291-6.
6. Molitoris BA, Weinberg JM, Venkatachalam MA, Zager RA, Nath KA, Goligorsky MS. Acute renal failure. II. Experimental models of acute renal failure: imperfect but indispensable. Am J Physiol Renal Physiol 2000;278:F1-F12.
7. Standiford TJ, Huffnagle GB. Cytokines in host defenses against pneumonia. J Investig Med 1997;45:335-45.
8. Toback FG. Regeneration after acute tubular necrosis. Kidney Int 1992;41:226-46.
9. Wagener OE, Lieske JC, Toback FG. Molecular and cell biology of acute renal failure: new therapeutic strategies. New Horizons 1995;3:634-49.
10. Heldin CH. Dimerization of cell surface receptors in signal transduction. Cell 1995;80:213-23.
11. Nigam SK, Lieberthal W. Acute renal failure III. The role of growth factors in the process of renal regeneration and repair. Am J Physiol Renal Physiol 2000;279:F3-F11.
12. Hammerman MR, Miller SB. Therapeutic use of growth factors in renal failure. J Am Soc Nephrol 1994;5:1-11.
13. Fervenza FC, Tsao T, Rabkin R. Response of the intrarenal insulin-like growth factor axis I to acute ischemic injury and treatment with growth hormone and epidermal factor. Kidney Int 1996;49:344-54.
14. Hammerman MR. Growth factors in renal development. Semin Nephrol 1995;15:291-9.
15. Bier DM. Growth hormone and insulin-like growth factor I: nutritional pathophysiology and therapeutic potential. Acta Paediatr Scand Suppl 1991;374:119â€“28.
16. Jacob R, Barrett E, Plewe G, Fagin KD, Sherwin RS. J Clin Invest 1989;83:1717-23.
17. Hammerman HM. The growth hormone-insulin-like growth factor axis in the kidney. Am J Physiol 1989;257:F503-F514.
18. Kumar P, Roy I. Applications of gold nanoparticles in clinical medicine. Int J Pharm Pharm Sci 2015;8:9-16.
19. Averitt RD, Westcott SL, Halas NJ. Linear optical properties of gold nanoshells. J Opt Soc Am B 1999;16:1824-32.
20. Huang X, Jain PK, El-Sayed IH, El-Sayed MA. Plasmonic photothermal therapy (PPTT) using gold nanoparticles. Laser Med Sci 2008;23:217-28.
21. Tong L, Wei Q, Wei A, Cheng JX. Gold nanorods as contrast agents for biological imaging: optical properties, surface conjugation and photothermal effects. Photo Chem Photo Biol 2009;85:21-32.
22. Shimida A, Kawamura N, Okajima M, Kaewamatawong T, Inoue H, Morita T. Translocation pathway of the intratracheally instilled ultrafine particles from the lung into blood circulation in the mouse. Toxicol Pathol 2006;34:949-57.
23. DeJong WH, Hagens WI, Krystek P, Burger MC, Sips A, Geertsma RE. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 2008;29:1912-9.
24. Jain TK, Reddy MK, Morales MA, Leslie-Pelecky DL, Labhasetwar V. Biodistribution, clearance and biocompatibility of iron oxide magnetic nanoparticles in rats. Mol Pharm 2008;5:306-27.
25. Bhadra D, Bhadra S, Jain S, Jain NK. A PEGylated dendritic nanoparticulate carrier of fluorouracil. Int J Pharm 2003;257:111-24.
26. Wang M, Thanou M. Targeting nanoparticles to cancer: review. Pharmacol Res 2010;62:90-9.
27. Paciotti GF, Kingston DGI, Tamarkin L. Colloidal gold nanoparticles: a novel nanoparticle platform for developing multifunctional tumor-targeted drug delivery vectors. Drug Dev Res 2006;67:47-54.
28. Kommareddy S, Amiji M. Poly (ethyleneglycol)-modified thiolated gelatin nanoparticles for glutathione-responsive intracellular DNA delivery. Nanomedicine 2007;3:32-42.
29. Hualin FU, Zhirong Z, Tao G. Influence of the deacetylation degree on the in vivo distribution of chitosan in mice. Latt Am J Pharm 2013;32:1178-83.
30. Zhi-Xiang Y, Jing-Jing L, Di Zhu L, Xun S, Tao G, Zhi-rong Z. Enhanced accumulation of low-molecular-weight chitosan in kidneys: a study on the influence of N-acetylation of chitosan on the renal targeting. J Drug Targeting 2011;19:540-51.
31. Peng Z, Xun S, Zhirong Z. Kidney-targeted drug delivery systems. Acta Pharm Sinica B 2014;4:37-42.
32. Shan G, San H, Frederik DH, Kathrin W, Chuanxu Y, Rikke N, et al. Megalin-mediated specific uptake of chitosan/sirna nanoparticles in mouse kidney proximal tubule epithelial cells enables aqp1 gene silencing. Theranostics 2014;4:1039-51.
33. Xia Kai H, Zhi Xiang Y, Xiao Juan W, Chao Qun X, Wan Yu L. Low molecular weight hydroxyethyl chitosan-prednisolone conjugate for renal targeting therapy: synthesis, characterization and in vivo studies. Theranostics 2012;2:1054-63.
34. Zayed GMS, Tessmar JKV. Heterobifunctional poly(ethylene glycol) derivatives for the surface modification of gold nanoparticles toward bone mineral targeting. Macromol Biosci 2012;12:1124-36.
35. Gadogbe M, Ansar SM, He G, Collier WE, Rodriguez J, Liu D, et al. Determination of colloidal gold nanoparticle surface areas, concentrations, and sizes through quantitative ligand adsorption. Anal Bioanal Chem 2013;405:413-22.
36. Yoo S, Lee J, Young S, Kim Y, Chang P, Gyu H. Effects of selective oxidation of chitosan on physical and biological properties. Int J Biol Macromol 2005;35:27-31.
37. Charhouf I, Bennamara A, Abourriche A, Chenite A, Zhu J, Berrada M. Characterization of dialdehyde chitosan generated by periodate oxidation. Int J Sci Basic Appl Res 2014;4531:336-48.
38. Bordenave N. Advances on selective C-6 oxidation of chitosan by TEMPO. Biomacromolecules 2008;244:2377-82.
39. Zhu C, Zheng Q, Wang L, Xu HF, Tong J, Zhang Q. Synthesis of novel galactose functionalized gold nanoparticles and its radiosensitizing mechanism. J Nanobiotechnol 2015;13:67-77.
40. Piella J, Bastus NG, Puntes V. Size-controlled synthesis of sub-10 nm citrate-stabilized gold nanoparticles and related optical properties. Chem Mater 2016;28:1066-75.
41. Khaled AK, Amin MA, Abdelhafez WA, Zayed G, Shaykhon M, Mohamed MS. Synthesis and characterization of gold nanoparticles loaded with 5-fluorouracil. Int J Pharm Pharm Res 2016;6:411-22.
42. Tawfeek HM. Novel gold nanoparticles coated with somatostatin as a potential delivery system for targeting somatostatin receptors. Drug Dev Ind Pharm 2016;42:1782-91.
43. Mahou R, Wandrey C. Versatile route to synthesize heterobifunctional poly (ethylene glycol) of variable functionality for subsequent pegylation. Polymers (Basel) 2012;4:561-89.
44. Madhusudhan A, Reddy GB, Venkatesham M. Efficient pH dependent drug delivery to target cancer cells by gold nanoparticles capped with carboxymethyl chitosan. Int J Mol Sci 2014;15:8216-34.
45. Bhumkar DR, Joshi HM, Sastry M, Pokharkar VB. Chitosan reduced gold nanoparticles as novel carriers for transmucosal delivery of insulin. Pharm Res 2007;24:1415-26.
46. Elasser M, Abdel-Aziz M, El-Kassas R. Antioxidant, antimicrobial, antiviral and antitumor activities of pyranone derivative obtained from Aspergillus candidus. J Microbiol Biotech Res 2011;1:5-17.
47. Jo M, Bae S, Go M, Kim H, Hwang Y, Choi S. Toxicity and biokinetics of colloidal gold nanoparticles. Nanomaterials 2015;5:835-50.
48. Mohamed AI, Hussain AK, Zayed GM, Shaykoon M, Mahmoud RA. Preparation and characterization of cytotoxic drug-loaded gold nanoparticles. Int J Pharm Pharm Res 2016;6:640-52.
49. Kumar D, Meenan BJ, Mutreja I, D'SA R, Dixon D. Controlling the size and size distribution of gold nanoparticles: a design of experiment study. Int J Nanosci 2012;11:1-7.
50. Sebak AA. Particle size enlargement has been observed on comparison of PEGylated and non-PEGylated nanocarriers. Int J Appl Pharm 2018;10:6-12.
51. Shalkevich N, Shalkevich A, Si-ahmed L, Bu T. Reversible formation of gold nanoparticle-surfactant composite assemblies for the preparation of concentrated colloidal solutions. Phys Chem Chem Phys 2009;11:10175-9.
52. Mukohara T, Shimada H, Ogasawara N, Wanikawa R, Shimomura M, Nakatsura T, et al. Sensitivity of breast cancer cell lines to the novel insulin-like growth factor-1 receptor (IGF-1R) inhibitor NVP-AEW541 is dependentâ€¨on the level of IRS-1 expression. Cancer Lett 2009;282:14-24.
53. De Blaquiere GE, May FE, Westley BR. Increased expression of both insulin receptor substrates 1 and 2 confers increased sensitivity to IGF-1 stimulated cell migration. Endocr Relat Cancer 2009;16:635-47.
54. Faure AC, Dufort S, Josserand V, Perriat P, Coll JL, Roux S, Tillement O. Control of the in vivo biodistribution of hybrid nanoparticles with different poly(ethylene glycol) coatings. Small 2009;5:2565-75.
55. Alric C, Miladi I, Kryza D, Taleb J, Lux F, Bazzi R, et al. The biodistribution of gold nanoparticles designed for renal clearance. Nanoscale 2013;5:5930-9.
56. Varna M, Ratajczak P, Ferreira I, Leboeuf C, Bousquet G, Janin A. In vivo distribution of inorganic nanoparticles in preclinical models. J Biomater Nanobiotechnol 2012;3:269-79.
57. Alalaiwe A, Roberts G, Carpinone P, Munson J. Influence of PEG coating on the oral bioavailability of gold nanoparticles in rats Influence of PEG coating on the oral bioavailability of gold nanoparticles in rats. Drug Delivery 2017;24:591-8.
58. He X, Yuan Z, Wu X, Xu C, Li W. Low molecular weight hydroxyethyl chitosan-prednisolone conjugate for renal targeting therapy: synthesis, characterization and in vivo studies. Theranostics 2012;2:1054-63.
59. Lipka J, Semmler Behnke M, Sperling RA, Wenk A, Takenaka S, Schleh C, et al. Biodistribution of PEG-modified gold nanoparticles following intratracheal instillation and intravenous injection. Biomaterials 2010;31:6574-81.
60. Cho WS, Cho M, Jeong J, Choi M, Han BS, Shin HS, et al. Size-dependent tissue kinetics of PEG-coated gold nanoparticles. Toxicol Appl Pharmacol 2010;245:116-23.
61. Guerrero S, Herance JR, Rojas S, Mena JF, Gispert JD, Acosta GA, et al. Synthesis and in vivo evaluation of the biodistribution of a 18 F-labeled conjugate gold-nanoparticle-peptide with potential biomedical application. Bioconjugate Chem 2012;23:399-408.
62. Wang J, Bai R, Yang R, Liu J, Tang J, Liu Y, et al. Size-and surface chemistry-dependent pharmacokinetics and tumor accumulation of engineered gold nanoparticles after intravenous administration. Metallomics 2015;7:516-24.
63. Choi CHJ, Zuckerman JE, Webster P, Davis ME. Targeting kidney mesangium by nanoparticles of defined size. Proc Natl Acad Sci 2011;108:6656â€“61.
64. El-Sayed MA, Yassin NA, Shabaka AA, El-Shbrawy OA, Mahmoud SS, El-Shenawy SM, et al. Toxicological and pharmacological assessment of gold nanorods in normal rats. Int J Pharm Pharm Sci 2015;7:41-50.