Go to the content. | Move to the navigation | Go to the site search | Go to the menu | Contacts | Accessibility

| Create Account

Bersani, Sara (2008) Studio di sistemi supramolecolari per il delivery di proteine terapeutiche. [Ph.D. thesis]

Full text disponibile come:

Documento PDF

Abstract (english)

Novel strategies for site-specific protein modification have been investigated by using low molecular weight linkers.
In the first part of the study, glycoside-derivatives have been obtained by conjugation of alkyl chains and then activated with a maleimido function for selective derivatization of cysteines. The linkers were used to modify the free cysteins (Cys) of serum albumin (HSA) and recombinant human granulocyte colony-stimulating factor (rh-G-CSF). Hydrazide polyethylenglycole (PEG-Hz) was conjugated to the aldehydes groups generated by selective oxidation of the glycosides with periodate. This PEGylation strategy yielded "flag-type" bioconjugates as several PEG chains are attached to the glycosidic residues of the semi-synthetic neo-glycoprotein. The PEG-Hz conjugation to the oxidized glycosides yields pH-dependent cleavable hydrazone bonds which allow for PEG release. Therefore, un-PEGylated active protein can be released over time under physiological conditions.
In the second part of the work preliminary studies of polyethylene methacrylate (PEGMA) radical polymerization from protein surface were conducted in aqueous solution using the Atom Transfer Radical Polymerization (ATRP) technique.
Two different alkyl halide derivatives were synthesized: 2-bromo-isobutyryl-ethoxyethyl-maleimide and 2-bromo-isobutyryl-cadaverine. The linkers were used to modify selectively aminoacids of protein models: HSA, rh-G-CSF and recombinant human growth hormone (rh-GH) and to yield macro-initiators. The synthesized 2-bromo-isobutyryl- derivatives have been characterized by chromatographic and spectrometric techniques. However, preliminary studies of radical polymerization using ATRP from the protein surfaces did not give reasonable results. Therefore more detailed investigation will be worked up in order to set up a convenient polymerization protocol.

Statistiche Download - Aggiungi a RefWorks
EPrint type:Ph.D. thesis
Tutor:Caliceti, Paolo
Supervisor:Salmaso, Stefano
Ph.D. course:Ciclo 20 > Scuole per il 20simo ciclo > SCIENZE MOLECOLARI > SCIENZE FARMACEUTICHE
Data di deposito della tesi:31 January 2008
Anno di Pubblicazione:31 January 2008
Key Words:Protein bioconjugation, PEG, selective PEGylation, protein glycation, glycosylic linkers, ATRP, PEGMA
Settori scientifico-disciplinari MIUR:Area 03 - Scienze chimiche > CHIM/09 Farmaceutico tecnologico applicativo
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Farmaceutiche
Codice ID:598
Depositato il:14 Nov 2008
Simple Metadata
Full Metadata
EndNote Format


I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

1. Borgia JA, Fields GB. Chemical synthesis of proteins. Trends Biotechnol. 2000; 18, 243-251. Cerca con Google

2. Molowa DT, Mazanet R. The state of biopharmaceutical manufacturing. Biotechnol. Annu. Rev. 2003; 9: 285-302. Cerca con Google

3. Langer R. Drug delivery and targeting. Nature. 1998; 392: 5-10. Cerca con Google

4. Cleland JL, Daugherty A, Mrsny R. Emerging protein delivery methods. Curr Opinion Biotechnol. 2001; 12, 212-219. Cerca con Google

5. Orive G, Hernández RM, Gascón RA, Domínguez-Gil A, Pedraz LJ. Drug delivery in biotechnology: present and future. Curr. Opinion Biotechnol. 2003; 14, 659-664. Cerca con Google

6. McNall EJ. Protein Formulation and Delivery. Marcel Dekker, McNall EJ Eds., New York, 2000. Cerca con Google

7. Salmaso S, Bersani S, Semenzato A, Caliceti P. Nanotechnologies in protein delivery. J Nanosci Nanotechnol. 2006; 6: 2736-2753. Cerca con Google

8. Sinha VR, Trehan A. Biodegradable microspheres for protein delivery. J Control Release. 2003; 90: 261-280. Cerca con Google

9. Almeida AJ, Souto E. Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Adv Drug Del Rev. 2007; 6: 478-490. Cerca con Google

10. Yang L, Alexandridis P. Physicochemical aspects of drug. delivery and release from polymer-based colloids. Curr Opin Coll Interf Sci. 2000; 5, 132-143. Cerca con Google

11. Spangler RS. Insulin administration via liposomes. Diabetes Care. 1990; 13: 911-922. Cerca con Google

12. Soula O, Meyrueix R, Chan YP, Grangeon C, Kravtzoff R, Soula G. Sustained release of IL-2 from MEDUSA comb-like hydrophobically modified polyglutammate. Contr Rel Soc.30th Annual Meeting, 2003; 688. Cerca con Google

13. Meyrueix R, Lacomte JP, Soula O, Pouliquen G, Chan YP, Nicolas F, Kravtzoff P, Soula G, Sustained release of interferon alpha 2b from MEDUSA nanoparticles of comb-like hydrophobically modified polyglutammate. Contr Rel Soc. 30th Annual Meeting, 2003; 690. Cerca con Google

14. Salmaso S, Schrepfer R, Cavallaro G, Bersani S, Caboi F, Giammona G, Tonon G, Caliceti P. Supramolecular association of recombinant human growth hormone with hydrophobized polyhydroxyethylaspartamides. Eur J Pharm Biopharm. 2007; in press. Cerca con Google

15. Duncan R, Spreafico F. Polymer conjugates: pharmacokinetic considerations for design and development. Clin. Pharmacokinet. 1994; 27: 290-306. Cerca con Google

16. Thordarson P, Le Droumaguet B, Velonia K. Well-defined protein’polymer conjugates-synthesis and potential applications. Appl Microbiol Biotechnol. 2006; 73: 243-254. Cerca con Google

17. Ginger LG. Streptokinase chemically bonded to carbohydrate matrix. US. Patent 3639213, 1972. Cerca con Google

18. Poznansky MJ, Mao GD. Superoxide dismutase-catalase conjugates. Biomat Art Cells & Art Org. 1989; 17: 229-244. Cerca con Google

19. Maeda H. SMANCS and polymer conjugated macromolecular drugs: advantages in cancer chemotherapy, Adv Drug Delivery Rev. 2001; 46: 169-185. Cerca con Google

20. Abuchowski A, Kazo GM, Verhoest CR, Van Es T, Kafkewitz D, Nucci ML, Viau AT, Davis FF. Cancer therapy with chemically modified enzymes. I. Antitumor properties of polyethylene glycol-asparaginase conjugates. Cancer Biochem Biopys. 1984; 7: 175-186. Cerca con Google

21. Caliceti P, Veronese FM. Pharmacokinetics and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev. 2003; 55: 1261-1277. Cerca con Google

22. Bailey Jr FE, Koleske JV. Poly(ethylene-oxide). Academic Press, New York. 1976. Cerca con Google

23. Powell GM. Polyethylene glycol. Handbook of water soluble gums and resins. Davidson RL. Eds., McGraw-Hill, New York. 1980; 18: 1-31. Cerca con Google

24. Mutter M, Bayer E. The peptides. Academic Press, New York. 1979; 285-332. Cerca con Google

25. Dreborg S, Akerblom EB. Immunotherapy with monomethoxypolyethylene glycol modified allergens. Crit Rev Ther Drug Carrier Syst. 1990; 6: 315-365. Cerca con Google

26. Yamaoka T, Tabata Y, Ikada Y. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm Sci. 1994; 83: 601-606. Cerca con Google

27. Bhadra D, Bhadra S, Jain P. PEG: a review of PEGylated systems. Pharmazie. 2002; 57: 5-29. Cerca con Google

28. Roberts MJ, Bentley MD, Harris JM. Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev. 2002; 54: 459-476. Cerca con Google

29. Fee CJ, Van Alstine JM. PEG-proteins: Reaction engineering and separation issues. Chem Eng Sci. 2006; 61: 924-939. Cerca con Google

30. Pasut G, Veronese FM. Polymer-drug conjugation, recent achievements and general strategies. Progr Polym Sci. 2007; 32: 933-961. Cerca con Google

31. Youn YS, Lee KC. Site-Specific PEGylation for High-Yield Preparation of Lys21-Amine PEGylated Growth Hormone-Releasing Factor (GRF) (1-29) using a GRF(1-29) Derivative FMOC-Protected at Tyr1 and Lys12. Bioconjugate Chem. 2007, 18: 500-506. Cerca con Google

32. Hinds K, Koh JJ, Joss L, Liu F, Baudys M, Kim SW. Synthesis and Characterization of Poly(ethylene glycol)-Insulin Conjugates. Bioconjugate Chem. 2000; 11: 195-201. Cerca con Google

33. Kinstler O, Molineux G, Treuheit M, Ladd D, Gegg C. Mono-N-terminal poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev. 2002; 54: 477-485. Cerca con Google

34. Wang YS, Youngster S, Grace M, Bausch J, Bordens R, Wyss DF. Structural and biological characterization of pegylated recombinant interferon alpha-2b and its therapeutic implications. Adv Drug Deliv Rev. 2002; 54: 547-570. Cerca con Google

35. Geoghegan KF, Stroh JG. Site-directed conjugation of nanopeptide groups to peptides and proteins via periodate oxidation of a 2-amino alcohol. Application modification at N-terminal serine. Bioconjugate Chem. 1992; 3: 138-146. Cerca con Google

36. Youn YS, Na DH, Yoo SD, Song SC, Lee KC. Carbohydrate-specifically polyethylene glycol-modified ricin A-chain with improved therapeutic potential. Int J Biochem Cell Biol. 2005; 37: 1525-1533. Cerca con Google

37. Kochendoerfer GG. Site-specific polymer modification of therapeutic proteins. Curr Opin Chem Biol. 2005; 9:555-560. Cerca con Google

38. Zappe H, Snell ME, Bossard MJ. PEGylation of cyanovirin-N (CV-N), an entry inhibitor of HIV. Adv Drug Del Rev. 2008; 60: 79-87. Cerca con Google

39. Leong SR, DeForge L, Presta L, Gonzalez T, Fan A, Reichert M, Chuntharapai A, Kim KJ, Tumas DB, Lee WP, Gribling P, Snedecor B, Chen H, Hsei V, Schoenhoff M, Hale V, Deveney J, Koumenis I, Shahrokh Z, McKay P, Galan W, Wagner B, Narindray D, Hebert C, Zapata G. Adapting pharmacokinetic properties of a humanized anti-interleukin-8 antibody for therapeutic applications using site-specific pegylation. Cytokine. 2001; 16: 106-119. Cerca con Google

40. Balan S, Choi J, Godwin A, Teo I, Laborde CM, Heidelberger S, Zloh M, Shaunak S, Brocchini S. Site-Specific PEGylation of Protein Disulfide Bonds Using a Three-Carbon Bridge. Bioconjugate Chem. 2007; 18: 61-76. Cerca con Google

41. Hinds KD, Kim SW. Effects of PEG conjugation on insulin properties. Adv Drug Del Rev. 2002; 54: 505-530. Cerca con Google

42. Esposito P, Barbero L, Caccia P, Caliceti P, D’Antonio M, Piquet G, Veronese FM. PEGylation of growth hormone-releasing hormone (GRF) analogues. Adv Drug Del Rev. 2003; 55: 1279-1291. Cerca con Google

43. Sato H. Enzymatic procedure for site-specific pegylation of proteins. Adv. Drug Deliv. Rev. 2002; 54: 487-504. Cerca con Google

44. Peschke B, Zundel M, Bak S, Clausen TR, Blume N, Pedersen A, Zaragoza F, Madsen K. C-Terminally PEGylated hGH-derivatives. Bioorg Med Chem Lett. 2007; 15: 4382-4395. Cerca con Google

45. DeFrees S, Wang ZG, Xing R, Scott AE, Wang J, Zopf D, Gouty DL, Sjoberg ER, Panneerselvam K, Brinkman-Van der Linden EC, Bayer RJ, Tarp MA, Clausen H. GlycoPEGylation of recombinant therapeutic proteins produced in Escherichia coli. Glycobiology. 2006; 16: 833-843. Cerca con Google

46. Webster OW, Hertler WR, Sogah DY, Farnham, WB, RajanBabu TV. Group-transfer polymerization. 1. A new concept for addition polymerization with organosilicon initiators. J Am Chem Soc. 1983; 105, 5706-5708. Cerca con Google

47. Matyjaszewski K, Xia J. Atom transfer radical polymerization. Chem Rev. 2001; 101, 291-299. Cerca con Google

48. Hawker CJ, Bosman AW, Harth E. New polymer synthesis by nitroxide mediated living radical polymerizations. Chem Rev. 2001; 101: 3661-3688. Cerca con Google

49. Chiefari J, Chong YK, Ercole F, Krstina J, Jeffery J, Le TPT, Mayadunne RTA, Meijs GF, Rizzardo E, Tang SH. Living Free-Radical Polymerization by Reversible Addition-Fragmentation Chain Transfer: The RAFT Process. Macromolecules. 1998; 31: 5559-5562. Cerca con Google

50. Wang JS, Matyjaszewski K. Controlled/"living" radical polymerization. atom transfer radical polymerization in the presence of transition-metal complexes. J Am Chem Soc. 1995; 117: 5614-5615. Cerca con Google

51. Kato M, Kamigaito M, Sawamoto M, Higashimura T. Polymerization of Methyl Methacrylate with the Carbon Tetrachloride/Dichlorotris-(triphenylphosphine)ruthenium(II)/Methylaluminum Bis(2,6-di-tert-butylphenoxide) Initiating System: Possibility of Living Radical Polymerization. Macromolecules. 1995; 28: 1721-1723. Cerca con Google

52. Nicolas J, Mantovani G, Haddleton DM. Living Radical Polymerization as a Tool for the Synthesis of Polymer-Protein/Peptide Bioconjugates. Macromol Rapid Commun. 2007, 28: 1083-1111. Cerca con Google

53. Brauneker WA, Matyjaszewski K. Controlled/living radical polymerization: Features, developments, and perspectives. Progr Polym Sci. 2007; 32:93-146. Cerca con Google

54. Jakubowski W, Min K, Matyjaszewski K. Activators Regenerated by Electron Transfer for Atom Transfer Radical Polymerization of Styrene. Macromolecules. 2006; 39:39-45. Cerca con Google

55. Lecolley F, Tao L, Mantovani G, Durkin I, Lautru S, Haddleton DM. A new approach to bioconjugates for proteins and peptides ("pegylation") utilising living radical polymerisation. Chem Commun (Camb). 2004; 21: 2026-2027. Cerca con Google

56. Mantovani G, Lecolley F, Tao L, Haddleton DM, Clerx J, Cornelissen JJ, Velonia K. Design and synthesis of N-maleimido-functionalized hydrophilic polymers via copper-mediated living radical polymerization: a suitable alternative to PEGylation chemistry. J Am Chem Soc. 2005; 127: 2966-2973. Cerca con Google

57. Tao L, Mantovani G, Lecolley F, Haddleton DM. Alpha-aldehyde terminally functional methacrylic polymers from living radical polymerization: application in protein conjugation "pegylation". J Am Chem Soc. 2004; 126: 13220-13221. Cerca con Google

58. Heredia KL, Maynard HD. Synthesis of Protein-Polymer Conjugates. Org Biomol Chem. 2007; 5: 45-53. Cerca con Google

59. Lele BS, Murata H, Matyiaszewski K, Russel AJ. Synthesis of Uniform Protein-Polymer Conjugates, Biomacromolecules. 2005; 6: 3380-3387. Cerca con Google

60. Heredia KL, Bontempo D, Ly T, Byers JT, Halstenberg S, Maynard HD. In Situ Preparation of Protein-“Smart” Polymer Conjugates with Retention of Bioactivity, J. Am. Chem. Soc. 2005; 127: 16955-16960. Cerca con Google

61. Nicolas J, San Miguel V, Mantovani G, Haddleton DM. Fluorescently Tagged Polymer Bioconjugates from Protein derived Macroinitiators, Chem. Comm. 2006; 45: 4697-4699. Cerca con Google

62. Gill, S.G., von Hippel, P.H., Calculation of protein extinction coefficients from amino acid sequence data. Anal. Biochem. 1989; 182, 319-326. Cerca con Google

63. Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985; 150:76-85. Cerca con Google

64. Habeeb AFSA. Reaction of protein sulfhydryl group with Ellman’s reagent. Methods in Enzymology. 1972; 25: 457-464. Cerca con Google

65. Snyder SL, Sobocinsky PZ. An improved 2,4,6-trinitroben-nesulphonic acid method for the determination of amines. Anal. Biochem. 1975; 64: 284-288. Cerca con Google

66. Sims GE, Snape TJ. A method for the estimation of polyethylene glycol in plasma protein fractions. Anal Biochem. 1980; 107: 60-63. Cerca con Google

67. Jain S, Hreczuk-Hirst DH, McCormack B, Mital M, Epenetos A, Laing P, Gregoriadis G. Polysialylated insulin: synthesis, characterization and biological activity in vivo. Biochim. Biophys. Acta. 2003; 1622: 42-49. Cerca con Google

68. Laemmli UK. Cleavage of structural proteins during the assembly of bacteriophage T4. Nature. 1970; 227:680-685. Cerca con Google

69. Kobayashi, K., Sumitomo, H., Ina, Y., Synthesis and Function of Polystyrene Derivates Having Pedant Oligosaccharides. Polymer J. 1985; 17: 567-575. Cerca con Google

70. Hansen CB, Kao GY, Moase EH, Zalipsky S, Allen TM. Attachment of antibodies to sterically stabilized liposomes: evaluation, comparison and optimization of coupling procedures. Biochim Biophys Acta. 1995; 1239: 133-144. Cerca con Google

71. Price CC., Kroll H. The Kinetics of the Periodate Oxidation of 1,2-Glycols. II. Ethylene Glycol, Pinacol and cis- and trans-Cyclohexene Glycols. J Am Chem Soc. 1938; 60: 2726-2729. Cerca con Google

72. Sherman MR, Williams LD, Saifer MGP, French JA, Kwak LW, Oppenheim JJ. Conjugation of high molecular weight poly(ethylene glycol) to cytokines: Granulocyte-macrophage colony-stimulating factors as model substrates. Chemistry and Biological Applications of Poly(ethylene glycol). ACS Symposium Series 680, Am Chem Soc, Washington, DC. 1997; 155-169. Cerca con Google

73. Weber RW, Boutin RH, Nedelman MA, Lister-James J, Dean RT. Enhanced Kidney Clearance with an Ester-Linked 99mTc-Radiolabeled Antibody Fab'-Chelator Conjugate. Bioconjugate Chem.1990; 1:431-437. Cerca con Google

74. Lomant AJ, Fairbanks G. Chemical probes of extended biological structures: Synthesis and properties of the cleavable protein cross-linking reagent [35S]dithiobis(succinimidyl propionate). J Mol Biol. 1976; 104: 243-261. Cerca con Google

75. Staros J, Wright R, Swingle D. Enhancement by N-Hydroxysulfo-Succinimide of Water-Soluble Carbodiimide Mediated Coupling Reagents. Anal Chem. 1986; 156: 220-222. Cerca con Google

76. Tsubery H, Mironchik M, Fridkin M, Shechter Y. Prolonging the action of protein and peptide drugs by a novel approach of reversible polyethylene glycol modification. J Biol Chem. 2004; 279: 38118-38124. Cerca con Google

77. Stewart AJ, Blindauer CA, Berezenko S, Sleep D, Tooth D, Sadler PJ. Role of Tyr84 in controlling the reactivity of Cys34 of human albumin. FEBS J. 2005; 272: 353-362. Cerca con Google

78. Pedersen AO, Jacobsen J. Reactivity of the thiol group in human and bovine albumin at pH 3-9, as measured by exchange with 2,2'-dithiodipyridine. Eur J Biochem. 1980; 106, 291-295. Cerca con Google

79. Buechler KF, Banaszczyk MG, Noar JB. N-aryl-carbamic acid ester-derived and valeric acid ester-derived cross-linkers and conjugates, and methods for their synthesis and use. US. Patent 6967107, 2005. Cerca con Google

80. Bruneel D, Schatch E. Chemical modification of pullulan: 1. Periodate oxidation. Polymer. 1993; 34:2628-2632. Cerca con Google

81. Arakawa T, Prestrelski SJ, Narhi LO, Boone TC, Kenney WC. Cysteine 17 of recombinant human granulocyte-colony stimulating factor is partially solvent-exposed. J Prot Chem. 1993; 12: 525-531. Cerca con Google

82. Veronese FM, Mero A, Caboi F, Sergi M, Marongiu C, Pasut G. Site-Specific Pegylation of G-CSF by Reversible Denaturation. Bioconjug Chem. 2007; 18: 1824-1830. Cerca con Google

83. Rajan RS, Li T, Aras M, Sloey C, Sutherland W, Arai H, Briddell R, Kinstler O, Lueras AM, Zhang Y, Yeghnazar H, Treuheit M, Brems DN. Modulation of protein aggregation by polyethylene glycol conjugation: G-CSF as a case study. Protein Sci. 2006; 15: 1063-1075. Cerca con Google

84. Narhi LO, Kenney WC, Arakawa T. Conformational changes of recombinant human granulocyte-colony stimulating factor induced by pH and guanidine hydrochloride. J Protein Chem. 1991; 10: 359-367. Cerca con Google

85. Raso SW, Abel J, Barnes JM, Maloney KM, Pipes G, Treuheit MJ, King J, Brems DN. Aggregation of granulocyte-colony stimulating factor in vitro involves a conformationally altered monomeric state. Protein Sci. 2005; 14: 2246-2257. Cerca con Google

86. Yim Z, Zupon M, Chaudry I. Insoluble copper-alpha interferon complex. U.S. Patent 4871538, 1989. Cerca con Google

87. Dörwald F, Johansen N, Iversen L. Transglutaminase-mediated conjugation of growth hormone. Patent WO/134148, 2006. Cerca con Google

Download statistics

Solo per lo Staff dell Archivio: Modifica questo record