Biodegradable amphiphilic PEG-PCL-PEI triblock copolymers designed for the self-assembly of multifunctional gene carriers

The great promise that gene therapy holds is the opportunity of directly introducing genetic material into cells for a causal therapy of yet incurable diseases. One promising way to achieve that goal is the usage of non-viral delivery vehicles, constructed from amphiphilic block copolymers. This...

Full description

Saved in:
Bibliographic Details
Main Author: Endres, Thomas
Contributors: Kissel, Thomas (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Published: Philipps-Universität Marburg 2012
Pharmazeutische Technologie und Biopharmazie
Online Access:PDF Full Text
Tags: Add Tag
No Tags, Be the first to tag this record!

1. K. V. Butsele, S. Cajot, S. V. Vlierberghe, P. Dubruel, C. Passirani, J.-P. Ben- oit, R. Jerome, C. Jerome, pH-Responsive Flower-Type Micelles Formed by a Biotinylated Poly(2-vinylpyridine)-block-poly(ethylene oxide)-block-poly(e- caprolactone) Triblock Copolymer, Adv. Funct. Mater. 19 (2009) 1416–1425.

2. Y. Lee, K. Miyata, M. Oba, T. Ishii, S. Fukushima, M. Han, H. Koyama, N. Nishiyama, K. Kataoka, Charge-Conversion Ternary Polyplex with Endo- some Disruption Moiety: A Technique for Efficient and Safe Gene Delivery, Angew. Chem., Int. Ed. 47 (28) (2008) 5163–5166.

3. R. Freeman, R. Gill, I. Shweky, M. Kotler, U. Banin, I. Willner, Biosensing and Probing of Intracellular Metabolic Pathways by NADH-Sensitive Quantum Dots, Angew. Chem., Int. Ed. 48 (2) (2009) 309–313.

4. Y. Lee, T. Ishii, H. Cabral, H. J. Kim, J.-H. Seo, N. Nishiyama, H. Oshima, K. Osada, K. Kataoka, Charge-Conversional Polyionic Complex Micelles- Efficient Nanocarriers for Protein Delivery into Cytoplasm, Angew. Chem., Int. Ed. 48 (29) (2009) 5309–5312.

5. P. R. Leroueil, S. Hong, A. Mecke, J. R. Baker, B. G. Orr, M. M. Holl, Nano- particle interaction with biological embranes: Does nanotechnology present a Janus Face?, Acc. Chem. Res. 40 (5) (2007) 335–342.

6. M. Breunig, U. Lungwitz, R. Liebl, C. Fontanari, J. Klar, A. Kurtz, T. Blunk, A. Goepferich, Gene delivery with low molecular weight linear polyethylen- imines, J. Gene Med. 7 (10) (2005) 1287–1298.

7. H. Ge, Y. Hu, X. Jiang, D. Cheng, Y. Yuan, H. Bi, C. Yang, Preparation, Characterization, and Drug Release Behaviors of Drug Nimodipine-Loaded Poly(e-caprolactone)-Poly(ethylene oxide)-Poly(e-caprolactone) Amphiphilic Triblock Copolymer Micelles, J. Pharm. Sci. 91 (6) (2002) 1463–1473.

8. J. Yu, T. J. Anchordoquy, Synergistic effects of surfactants and sugars on lipoplex stability during freeze-drying and rehydration, J. Pharm. Sci. 98 (9) (2009) 3319–3328.

9. L. D. Hahn, H. Kong, D. J. Mooney, Polycation structure mediates expression of lyophilized polycation/pDNA complexes, Macromol. Biosci. 10 (10) (2010) 1210–1215.

10. M. Benfer, R. Reul, T. Betz, T. Kissel, Folic acid-decorated nanocomposites prepared by a simple solvent displacement method, Macromol. Biosci. 12 (4) (2012) 438–445.

11. S.-W. Choi, I. W. Cheong, J.-H. Kim, Y. Xia, Preparation of uniform micro- spheres using a simple fluidic device and their crystallization into close-packed lattices, Small 5 (4) (2009) 454–459.

12. H. Kuramoto, Y.-S. Park, N. Kaji, M. Tokeshi, K. Kogure, Y. Shinohara, H. Harashima, Y. Baba, On-chip fabrication of mutifunctional envelope-type nanodevices for gene delivery, Anal. Bioanal. Chem. 391 (2008) 2729–2733.

13. C. Packhaeuser, K. Lahnstein, J. Sitterberg, T. Schmehl, T. Gessler, U. Bakowsky, W. Seeger, T. Kissel, Stabilization of aerosolizable nano-carriers by freeze-drying, Pharm. Res. 26 (2009) 129–138.

14. J. Nguyen, R. Reul, S. Roesler, E. Dayyoub, T. Schmehl, T. Gessler, W. See- ger, T. Kissel, Amine-Modified Poly(Vinyl Alcohol)s as Non-viral Vectors for siRNA Delivery: Effects of the Degree of Amine Substitution on Physicochem- ical Properties and Knockdown Efficiency, Pharm. Res. 27 (2010) 2670–2682.

15. J. Jeong, T. Park, S. Kim, Self-assembled and nanostructured siRNA delivery systems, Pharm. Res. 28 (2011) 2072–2085.

16. H. Cho, I. Cheong, J. Lee, J. Kim, Polymeric nanoparticles, micelles and polymersomes from amphiphilic block copolymer, Korean J. Chem. Eng. 27 (2010) 731–740.

17. L. Ilium, I. Hunneyball, S. Davis, The effect of hydrophilic coatings on the uptake of colloidal particles by the liver and by peritoneal macrophages, Int. J. Pharm. 29 (1) (1986) 53–65.

18. S. Sennato, F. Bordi, C. Cametti, M. Diociaiuti, P. Malaspina, Charge patch attraction and reentrant condensation in DNA-liposome complexes, Biochim. Biophys. Acta, Biomembr. 1714 (1) (2005) 11–24.

19. H. Tian, C. Deng, H. Lin, J. Sun, M. Deng, X. Chen, X. Jing, Biodegradable cationic PEG–PEI–PBLG hyperbranched block copolymer: synthesis and mi- celle characterization, Biomaterials 26 (2005) 4209–4217.

20. H. Sun, L. Mei, C. Song, X. Cui, P. Wang, The in vivo degradation, absorption and excretion of PCL-based implant, Biomaterials 27 (9) (2006) 1735–1740.

21. T.-M. Sun, J.-Z. Du, L.-F. Yan, H.-Q. Maod, J. Wang, Self-assembled biode- gradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery, Biomaterials 29 (2008) 4348–4355.

22. M. Ou, R. Xu, S. H. Kim, D. A. Bull, S. W. Kim, A family of bioreducible poly(disulfide amine)s for gene delivery, Biomaterials 30 (2009) 5804–5814.

23. C. Zhu, S. Jung, S. Luo, F. Meng, X. Zhu, T. G. Park, Z. Zhong, Co-delivery of siRNA and paclitaxel into cancer cells by biodegradable cationic micelles based on PDMAEMA-PCL-PDMAEMA triblock copolymers, Biomaterials 31 (8) (2010) 2408–2416.

24. C.-Q. Mao, J.-Z. Du, T.-M. Sun, Y.-D. Yao, P.-Z. Zhang, E.-W. Song, J. Wang, A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy, Biomaterials 32 (11) (2011) 3124–3133.

25. T. K. Endres, M. Beck-Broichsitter, O. Samsonova, T. Renette, T. H. Kissel, Self-assembled biodegradable amphiphilic PEG-PCL-lPEI triblock copolymers at the borderline between micelles and nanoparticles designed for drug and gene delivery, Biomaterials 32 (2011) 7721–7731.

26. J.-M. Li, M.-X. Zhao, H. Su, Y.-Y. Wang, C.-P. Tan, L.-N. Ji, Z.-W. Mao, Multifunctional quantum-dot-based siRNA delivery for HPV18 E6 gene silence and intracellular imaging, Biomaterials 32 (31) (2011) 7978–7987.

27. J.-M. Li, Y.-Y. Wang, M.-X. Zhao, C.-P. Tan, Y.-Q. Li, X.-Y. Le, L.-N. Ji, Z.-W. Mao, Multifunctional QD-based co-delivery of siRNA and doxorubi- cin to HeLa cells for reversal of multidrug resistance and real-time tracking, Biomaterials 33 (9) (2012) 2780–2790.

28. C. Liu, P. Zhang, X. Zhai, F. Tian, W. Li, J. Yang, Y. Liu, H. Wang, W. Wang, W. Liu, Nano-carrier for gene delivery and bioimaging based on carbon dots References with PEI-passivation enhanced fluorescence, Biomaterials 33 (13) (2012) 3604– 3613.

29. M. Zheng, D. Librizzi, A. Kilic, Y. Liu, H. Renz, O. M. Merkel, T. Kissel, Enhancing in vivo circulation and siRNA delivery with biodegradable polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol) copoly- mers, Biomaterials 33 (27) (2012) 6551–6558.

30. J. C. Kasper, D. Schaffert, M. Ogris, E. Wagner, W. Friess, The establish- ment of an up-scaled micro-mixer method allows the standardized and repro- ducible preparation of well-defined plasmid/LPEI polyplexes, Eur. J. Pharm. Biopharm. 77 (1) (2011) 182–185.

31. M. Beck-Broichsitter, E. Rytting, T. Lebhardt, X. Wang, T. Kissel, Prepara- tion of nanoparticles by solvent displacement for drug delivery: A shift in the "ouzo region" upon drug loading, Eur. J. Pharm. Sci. 41 (2) (2010) 244–253.

32. G. Vandermeulen, L. Rouxhet, A. Arien, M. Brewster, V. Préat, Encap- sulation of amphotericin B in poly(ethylene glycol)-block-poly([var epsilon]- caprolactone-co-trimethylenecarbonate) polymeric micelles, Int. J. Pharm. 309 (1-2) (2006) 234–240.

33. A. Richter, C. Olbrich, M. Krause, T. Kissel, Solubilization of Sagopilone, a poorly water-soluble anticancer drug, using polymeric micelles for parenteral delivery, Int. J. Pharm. 389 (1-2) (2010) 244–253.

34. M. Chen, X. Liu, A. Fahr, Skin penetration and deposition of carboxyfluores- cein and temoporfin from different lipid vesicular systems: In vitro study with finite and infinite dosage application, Int. J. Pharm. 408 (1-2) (2011) 223–234.

35. N. Zhao, S. Roesler, T. Kissel, Synthesis of a new potential biodegradable di- sulfide containing poly(ethylene imine)-poly(ethylene glycol) copolymer cross- linked with click cluster for gene delivery, Int. J. Pharm. 411 (1-2) (2011) 197–205.

36. A. K. Kundu, P. K. Chandra, S. Hazari, G. Ledet, Y. V. Pramar, S. Dash, T. K. Mandal, Stability of lyophilized siRNA nanosome formulations, Int. J. Pharm. 432 (2) (2011) 525–534.

37. T. Endres, M. Zheng, M. Beck-Broichsitter, T. Kissel, Lyophilised ready-to-use formulations of PEG-PCL-PEI nano-carriers for siRNA delivery, International Journal of Pharmaceutics 428 (1-2) (2012) 121–124.

38. J. S. Kim, K. J. Cho, T. H. Tran, M. Nurunnabi, T. H. Moon, S. M. Hong, Y. kyu Lee, In vivo NIR imaging with CdTe/CdSe quantum dots entrapped in PLGA nanospheres, J. Colloid Interface Sci. 353 (2) (2011) 363–371.

39. M. Reinisalo, A. Urtti, P. Honkakoski, Freeze-drying of cationic polymer DNA complexes enables their long-term storage and reverse transfection of post- mitotic cells, J. Controlled Release 110 (2) (2006) 437–443.

40. Y.-P. Ho, H. H. Chen, K. W. Leong, T.-H. Wang, Evaluating the intracellular stability and unpacking of DNA nanocomplexes by quantum dots-FRET, J. Controlled Release 116 (1) (2006) 83–89.

41. O. M. Merkel, M. Zheng, M. A. Mintzer, G. M. Pavan, D. Librizzi, M. Maly, H. Höffken, A. Danani, E. E. Simanek, T. Kissel, Molecular modeling and in vivo imaging can identify successful flexible triazine dendrimer-based siRNA delivery systems, J. Controlled Release 153 (1) (2011) 23–33.

42. Y. Liu, O. Samsonova, B. Sproat, O. Merkel, T. Kissel, Biophysical charac- terization of hyper-branched polyethylenimine-graft-polycaprolactone-block- mono-methoxyl-poly(ethylene glycol) copolymers (hy-PEI-PCL-mPEG) for siRNA delivery, J. Controlled Release 153 (2011) 262–268.

43. M. Beck-Broichsitter, O. M. Merkel, T. Kissel, Controlled pulmonary drug and gene delivery using polymeric nano-carriers, J. Controlled Release 161 (2) (2012) 214–224.

44. T. Endres, M. Zheng, M. Beck-Broichsitter, O. Samsonova, H. Debus, T. Kissel, Optimising the self-assembly of siRNA loaded PEG-PCL-lPEI nano- carriers employing different preparation techniques, J. Controlled Release 160 (3) (2012) 583–591.

45. Y. Liu, J. Nguyen, T. Steele, O. Merkel, T. Kissel, A new synthesis method and degradation of hyper-branched polyethylenimine grafted polycaprolactone block mono-methoxyl poly (ethylene glycol) copolymers (hy-PEI-g-PCL-b- mPEG) as potential DNA delivery vectors, Polymer 50 (16) (2009) 3895–3904.

46. A. Beyerle, O. Merkel, T. Stoeger, T. Kissel, PEGylation affects cytotoxicity and cell-compatibility of poly(ethylene imine) for lung application: Structure- function relationships, Toxicol. Appl. Pharmacol. 242 (2) (2010) 146–154.

47. O. Harush-Frenkel, M. Bivas-Benita, T. Nassar, C. Springer, Y. Sherman, A. Avital, Y. Altschuler, J. Borlak, S. Benita, A safety and tolerability study of differently-charged nanoparticles for local pulmonary drug delivery, Toxicol. Appl. Pharmacol. 246 (1-2) (2010) 83–90.

48. C. Rudolph, U. Schillinger, C. Plank, A. Gessner, P. Nicklaus, R. H. Müller, J. Rosenecker, Nonviral gene delivery to the lung with copolymer- protected and transferrin-modified polyethylenimine, Biochim. Biophys. Acta 1573 (2002) 75–83.

49. Y. Ding, X. Bian, W. Yao, R. Li, D. Ding, Y. Hu, X. Jiang, Y. Hu, Surface- potential-regulated transmembrane and cytotoxicity of chitosan/gold hybrid nanospheres, ACS Appl. Mater. Interfaces 2 (5) (2010) 1456–1465.

50. J. Zhu, A. Tang, L. P. Law, M. Feng, K. M. Ho, D. K. L. Lee, F. W. Harris, P. Li, Amphiphilic coreshell nanoparticles with poly(ethylenimine) shells as potential gene delivery carriers, Bioconjugate Chem. 16 (1) (2004) 139–146.

51. B. Brissault, C. Leborgne, C. Guis, O. Danos, H. Cheradame, A. Kichler, Linear topology confers in vivo gene transfer activity to polyethylenimines, Bioconjugate Chem. 17 (2006) 759–765.

52. O. M. Merkel, M. Zheng, H. Debus, T. Kissel, Pulmonary Gene Delivery Using Polymeric Nonviral Vectors, Bioconjugate Chem. 23 (1) (2012) 3–20.

53. L. Liu, M. Zheng, T. Renette, T. Kissel, Modular Synthesis of Folate Con- jugated Ternary Copolymers: Polyethylenimine-graft-Polycaprolactone-block- Poly(ethylene glycol)-Folate for Targeted Gene Delivery, Bioconjugate Chem. 23 (6) (2012) 1211–1220.

54. J. Akimoto, M. Nakayama, K. Sakai, T. Okano, Temperature-Induced Intra- cellular Uptake of Thermoresponsive Polymeric Micelles, Biomacromolecules 10 (6) (2009) 1331–1336.

55. F. Bordi, C. Cametti, M. Diociaiuti, D. Gaudino, T. Gili, S. Sennato, Com- plexation of anionic polyelectrolytes with cationic liposomes: Evidence of reentrant condensation and lipoplex formation, Langmuir 20 (13) (2004) 5214– 5222.

56. V. Milkova, K. Kamburova, I. Petkanchin, T. Radeva, Complexation of ferric oxide particles with pectins of different charge density, Langmuir 24 (17) (2008) 9495–9499.

57. J. Zhu, W. Jiang, Self-Assembly of ABC Triblock Copolymer into Giant Seg- mented Wormlike Micelles in Dilute Solution, Macromolecules (Washington, DC, United States) 38 (22) (2005) 9315–9323.

58. Y. Wang, K. Kimura, P. L. Dubin, W. Jaeger, Polyelectrolyte-Micelle Coacer- vation: Effects of micelle surface charge density, polymer molecular weight, and polymer/surfactant ratio, Macromolecules (Washington, DC, United States) 33 (9) (2000) 3324–3331.

59. O. M. Merkel, M. A. Mintzer, D. Librizzi, O. Samsonova, T. Dicke, B. Sproat, H. Garn, P. J. Barth, E. E. Simanek, T. Kissel, Triazine dendrimers as nonviral vectors for in vitro and in vivo RNAi: The effects of peripheral groups and core structure on biological activity, Mol. Pharmaceutics 7 (4) (2010) 969–983.

60. Y. Wu, Y.-P. Ho, Y. Mao, X. Wang, B. Yu, K. W. Leong, L. J. Lee, Up- take and Intracellular Fate of Multifunctional Nanoparticles: A Comparison between Lipoplexes and Polyplexes via Quantum Dot Mediated Förster Res- onance Energy Transfer, Mol. Pharmaceutics 8 (5) (2011) 1662–1668.

61. A. Besheer, J. Vogel, D. Glanz, J. Kressler, T. Groth, K. Mäder, Character- ization of PLGA Nanospheres Stabilized with Amphiphilic Polymers: Hydro- phobically Modified Hydroxyethyl Starch vs Pluronics, Mol. Pharmaceutics 6 (2) (2009) 407–415.

62. V. Bagalkot, L. Zhang, E. Levy-Nissenbaum, S. Jon, P. W. Kantoff, R. Langer, O. C. Farokhzad, Quantum DotAptamer Conjugates for Synchronous Cancer Imaging, Therapy, and Sensing of Drug Delivery Based on Bi-Fluorescence Resonance Energy Transfer, Nano Lett. 7 (10) (2007) 3065–3070.

63. T.-M. Sun, J.-Z. Du, Y.-D. Yao, C.-Q. Mao, S. Dou, S.-Y. Huang, P.-Z. Zhang, K. W. Leong, E.-W. Song, J. Wang, Simultaneous Delivery of siRNA and Pac- litaxel via a "Two-in-One " Micelleplex Promotes Synergistic Tumor Suppres- sion, ACS Nano 5 (2) (2011) 1483–1494.

64. B. J. Nehilla, P. G. Allen, T. A. Desai, Surfactant-Free, Drug-Quantum-Dot Coloaded Poly(lactide-co-glycolide) Nanoparticles: Towards Multifunctional Nanoparticles, ACS Nano 2 (3) (2008) 538–544.

65. N. Bhattarai, S. R. Bhattarai, H. K. Yi, J. C. Lee, M. S. Khil, P. H. Hwang, H. Y. Kim, Novel Polymeric Micelles of Amphiphilic Triblock Copolymer Poly (p-Dioxanone-co-L-Lactide)-block-Poly (ethylene glycol), Pharm. Res. 20 (2003) 2021–2027.

66. H. H. Chen, Y.-P. Ho, X. Jiang, H.-Q. Mao, T.-H. Wang, K. W. Leong, Quantitative Comparison of Intracellular Unpacking Kinetics of Polyplexes by a Model Constructed From Quantum Dot-FRET, Mol. Ther. 16 (2) (2008) 324–332.

67. V. Incani, A. Lavasanifar, H. Uludag, Lipid and hydrophobic modification of cationic carriers on route to superior gene vectors, Soft Matter. 6 (2010) 2124–2138.

68. J. Kim, I. Hwang, D. Britain, T. D. Chung, Y. Sun, D.-H. Kim, Microfluidic approaches for gene delivery and gene therapy, Lab Chip 11 (2011) 3941–3948.

69. S. Hou, N. Ziebacz, S. A. Wieczorek, E. Kalwarczyk, V. Sashuk, T. Kal- warczyk, T. S. Kaminski, R. Holyst, Formation and structure of PEI/DNA complexes: quantitative analysis, Soft Matter. 7 (2011) 6967–6972.

70. W. G. Eversole, P. H. Lahr, Evidence for a Rigid Multilayer at a Solid-Liquid Interface, J. Chem. Phys. 9 (7) (1941) 530–534.

71. D. Truzzolillo, F. Bordi, F. Sciortino, S. Sennato, Interaction between like- charged polyelectrolyte-colloid complexes in electrolyte solutions: A Monte Carlo simulation study in the Debye-Hückel approximation, J. Chem. Phys. 133 (2) (2010) 024901.

72. S. W. Poxon, J. A. Hughes, The effect of lyophilization on plasmid DNA activity, Pharm. Dev. Technol. 5 (1) (2000) 115–122.

73. H. Cabral, K. Kataoka, Multifunctional nanoassemblies of block copolymers for future cancer therapy, Sci. Technol. Adv. Mater. 11 (1) (2010) 014109.

74. R. Bertolotti, Editorial: Transient or long-term transgene expression and gene repair/ inactivation, Gene Ther. Regul. 1 (1) (2000) 1–8.

75. A. D. S. Delgado, M. Leonard, E. Dellacherie, Surface modification of poly- styrene nanoparticles using dextrans and dextran-POE copolymers: Polymer adsorption and colloidal characterization, J. Biomater. Sci. 11 (12) (2000) 1395–1410.

76. J. B. Delehanty, K. Boeneman, C. E. Bradburne, K. Robertson, I. L. Med- intz, Quantum dots: a powerful tool for understanding the intricacies of nanoparticle-mediated drug delivery, Expert Opin. Drug Delivery 6 (10) (2009) 1091–1112.

77. R. Rastogi, S. Anand, V. Koul, Polymerosomes of PCL and PEG Demonstrate Enhanced Therapeutic Efficacy of Insulin, Curr. Nanosci. 5 (2009) 409–416.

78. References [107] K. Shimada, A. Miyagishima, Y. Sadzuka, Y. Nozawa, Y. Mochizuki, H. Ohshima, S. Hirota, Determination of the Thickness of the Fixed Aqueous Layer Around Polyethyleneglycol-coated Liposomes, J. Drug Targeting 3 (4) (1995) 283–289.

79. V. C. F. Mosqueira, P. Legrand, R. Gref, B. Heurtault, M. Appel, G. Barratt, Interactions between a Macrophage Cell Line (J774A1) and Surface-modified Poly(D,L-lactide) Nanocapsules Bearing Poly(ethylene glycol), J. Drug Tar- geting 7 (1) (1999) 65–78.

80. S. Oh, S. Kang, J. Lee, Degradation behavior of hydrophilized PLGA scaffolds prepared by melt-molding particulate-leaching method: Comparison with con- trol hydrophobic one, J. Mater. Sci.: Mater. Med. 17 (2006) 131–137.

81. M. S. Shim, Y. J. Kwon, Acid-Responsive Linear Polyethylenimine for Effi- cient, Specific, and Biocompatible siRNA Delivery, Bioconjugate Chem. 20 (2009) 488–499.

82. M. L. Adams, A. Lavasanifar, G. S. Kwon, Amphiphilic Block Copolymers for Drug Delivery, J. Pharm. Sci. 92 (7) (2003) 1343–1355.

83. Y. Matsumura, H. Maeda, A New Concept for Macromolecular Therapeutics in Cancer Chemotherapy: Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs, Cancer Res. 46 (1986) 6387–6392.

84. R. Tong, J. Cheng, Anticancer Polymeric Nanomedicines, Polym. Rev. (Phil- adelphia, PA, U. S.) 47 (3) (2007) 345–381.

85. W. T. Godbey, K. W. Kenneth, G. M. Antonios, PEI and its role in gene delivery, J. Controlled Release 60 (1999) 149–160.

86. K. Letchford, H. Burt, A review of the formation and classification of am- phiphilic block copolymer nanoparticulate structures: micelles, nanospheres, nanocapsules and polymersomes, Eur. J. Pharm. Biopharm. 65 (3) (2007) 259–269.

87. C. Xu, B. Xing, J. Rao, A self-assembled quantum dot probe for detecting beta-lactamase activity, Biochem. Biophys. Res. Commun. 344 (3) (2006) 931– 935.

88. E. Blanco, E. A. Bey, Y. Dong, B. D. Weinberg, D. M. Sutton, D. A. Booth- man, J. Gao, beta-Lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells, J. Controlled Re- lease 122 (3) (2007) 365–374.

89. L. Liu, K.-T. Yong, I. Roy, W.-C. Law, L. Ye, J. Liu, J. Liu, R. Kumar, X. Zhang, P. N. Prasad, Bioconjugated Pluronic Triblock-Copolymer Micelle- Encapsulated Quan-tum Dots for Targeted Imaging of Cancer: In Vitro and In Vivo Studies, Theranostics 2 (7) (2012) 705–713.

90. S. Zhou, X. Deng, H. Yang, Biodegradable poly(epsilon-caprolactone)- poly(ethylene glycol) block copolymers: characterization and their use as drug carriers for a controlled delivery system, Biomaterials 24 (20) (2003) 3563– 3570.

91. H. S. Yoo, T. G. Park, Biodegradable polymeric micelles composed of doxoru- bicin conjugated PLGA-PEG block copolymer, J. Controlled Release 70 (1-2) (2001) 63–70.

92. G. Gaucher, M.-H. Dufresne, V. P. Sant, N. Kang, D. Maysinger, J.-C. Leroux, Block copolymer micelles: preparation, characterization and application in drug delivery, J. Controlled Release 109 (1-3) (2005) 169–188.

93. C. Lee, H. S. Choi, T. Ooya, N. Yui, Block-Selective Polypseudorotaxane Formation in PEI-b-PEG-b-PEI Copolymers via pH Variation, Macromolec- ules (Washington, DC, United States) 37 (2004) 7464.

94. Y. Wang, S. Gao, W.-H. Ye, H. S. Yoon, Y.-Y. Yang, Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegrad- able copolymer, Nat. Mater. 5 (10) (2006) 791–796.

95. T. Riley, T. Govender, S. Stolnik, C. D. Xiong, M. C. Garnett, L. Illum, S. S. Davis, Colloidal stability and drug incorporation aspects of micellar-like PLA-PEG nanoparticles, Colloids Surf., B 16 (1-4) (1999) 147–159.

96. J.-F. Gohy, N. Willet, S. Varshney, J.-X. Zhang, R. Jerome, Core-Shell-Corona Micelles with a Responsive Shell, Angew. Chem., Int. Ed. 40 (17) (2001) 3214– 3216.

97. Herrn Prof. Culmsee bin ich für die Übernahme des Vorsitzes der Prüfungskommis- sion und seine Funktion als Nebenfachprüfer zu Dank verpflichtet.

98. Y. Liu, T. Steele, T. Kissel, Degradation of Hyper-Branched Poly(ethylenimine)-graft-poly(caprolactone)- block-monomethoxyl- poly(ethylene glycol) as a Potential Gene Delivery Vector, Macromol.

99. References [130] C. G. Koh, X. Zhang, S. Liu, S. Golan, B. Yu, X. Yang, J. Guan, Y. Jin, Y. Talmon, N. Muthusamy, K. K. Chan, J. C. Byrd, R. J. Lee, G. Mar- cucci, L. J. Lee, Delivery of antisense oligodeoxyribonucleotide lipopolyplex nanoparticles assembled by microfluidic hydrodynamic focusing, J. Controlled Release 141 (1) (2010) 62–69.

100. M. Ã. Andersen, K. A. Howard, S. R. Paludan, F. Besenbacher, J. Kjems, Delivery of siRNA from lyophilized polymeric surfaces, Biomaterials 29 (4) (2008) 506–512.

101. D. W. Pack, A. S. Hoffman, S. Pun, P. S. Stayton, Design and development of polymers for gene delivery, Nat. Rev. Drug Discovery 4 (7) (2005) 581–593. References [26] Z.-Y. Zhang, B. D. Smith, High-Generation Polycationic Dendrimers Are Un- usually Effective at Disrupting Anionic Vesicles: Membrane Bending Model, Bioconjugate Chem. 11 (2000) 805–814.

102. L. Wightman, R. Kircheis, V. Rösser, S. Carotta, R. Ruzicka, M. Kursa, E. Wagner, Different behavior of branched and linear polyethylenimine for gene delivery in vitro and in vivo, J. Gene Med. 3 (4) (2001) 362–372.

103. K. Avgoustakis, A. Beletsi, Z. Panagi, P. Klepetsanis, E. Livaniou, G. Evan- gelatos, D. Ithakissios, Effect of copolymer composition on the physicochemical characteristics, in vitro stability, and biodistribution of PLGA-mPEG nano- particles, Int. J. Pharm. 259 (2003) 115–127.

104. P. Yadava, M. Gibbs, C. Castro, J. Hughes, Effect of lyophilization and freeze- thawing on the stability of siRNA-liposome complexes, AAPS PharmSciTech 9 (2008) 335–341.

105. M. Vittaz, D. Bazile, G. Spenlehauer, T. Verrecchia, M. Veillard, F. Puisieux, D. Labarre, Effect of PEO surface density on long-circulating PLA-PEO nan- oparticles which are very low complement activators, Biomaterials 17 (16) (1996) 1575–1581.

106. J. H. Choi, J. S. Choi, H. Suh, J. S. Park, Effect of Poly(ethylene glycol) Grafting on Polyethylenimine as a Gene Transfer Vector in vitro, Bull. Korean Chem. Soc. 22 (1) (2001) 46–52.

107. Y. Sadzuka, A. Nakade, R. Hirama, A. Miyagishima, Y. Nozawa, S. Hirota, T. Sonobe, Effects of mixed polyethyleneglycol modification on fixed aqueous layer thickness and antitumor activity of doxorubicin containing liposome, Int. J. Pharm. 238 (1-2) (2002) 171–180.

108. Y.-K. Lee, S. M. Hong, J. S. Kim, Encapsulation of CdSe/ZnS Quantum Dots in Poly(ethylene glycol)-Poly(D,L-lactide) Micelle for Biomedical Imaging and Detection, Macromol. Res. 15 (4) (2007) 330–336.

109. M. Ferrari, Experimental therapies: Vectoring siRNA therapeutics into the clinic, Nat. Rev. Clin. Oncol. 7 (9) (2010) 485–486.

110. W. Abdelwahed, G. Degobert, S. Stainmesse, H. Fessi, Freeze-drying of nano- particles: Formulation, process and storage considerations, Adv. Drug Deliv- ery Rev. 58 (15) (2006) 1688–1713.

111. I. Worbel, D. Collins, Fusion of cationic liposomes with mammalian cells occurs after endocytosis, Biochim. Biophys. Acta 1235 (1994) 296–304.

112. S. Y. Kim, Y. M. Lee, H. J. Shin, J. S. Kang, Indomethacin-loaded methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) diblock copolymeric nano- sphere: pharmacokinetic characteristics of indomethacin in the normal Sprague-Dawley rats, Biomaterials 22 (14) (2001) 2049 – 2056.

113. U. Griesenbach, C. Kitson, S. Garcia, R. Farley, C. Singh, L. Somerton, H. Painter, R. Smith, D. Gill, S. Hyde, Y.-H. Chow, J. Hu, M. Gray, M. Ed- brooke, V. Ogilvie, G. MacGregor, R. Scheule, S. Cheng, N. Caplen, E. Alton, Inefficient cationic lipid-mediated siRNA and antisense oligonucleotide trans- fer to airway epithelial cells in vivo, Respiratory Research 7 (1) (2006) 26.

114. Investigated factors and levels of the central composite design . . 86 IV.1

115. D. Fischer, Y. Li, B. Ahlemeyer, J. Krieglstein, T. Kissel, In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis, Biomaterials 24 (2003) 1121–1131.

116. R. Weissleder, C.-H. Tung, U. Mahmood, A. Bogdanov, In vivo imaging of tumors with protease-activated near-infrared fluorescent probes, Nat. Biotech- nol. 17 (4) (1999) 375–378.

117. C. Bremer, C.-H. Tung, R. Weissleder, In vivo molecular target assessment of matrix metalloproteinase inhibition, Nat. Med. 7 (6) (2001) 743–748.

118. S. Stolnik, L. Illum, S. S. Davis, Long circulating microparticulate drug carri- ers, Adv. Drug Delivery Rev. 16 (2-3) (1995) 195–214.

119. Z. Zhong, J. Feijen, M. C. Lok, W. E. Hennink, L. V. Christensen, J. W. Yock- man, Y.-H. Kim, S. W. Kim, Low Molecular Weight Linear Polyethylenimine- b-poly(ethylene glycol)-b-polyethylenimine Triblock Copolymers: Synthesis, References Characterization, and in Vitro Gene Transfer Properties, Biomacromolecules 6 (6) (2005) 3440–3448.

120. M. Breunig, U. Lungwitz, R. Liebl, J. Klar, B. Obermayer, T. Blunk, A. Goepferich, Mechanistic insights into linear polyethylenimine-mediated gene, Biochim. Biophys. Acta, Gen. Subj. 1770 (2007) 196–205.

121. I. G. Shin, S. Y. Kim, Y. M. Lee, C. S. Cho, Y. K. Sung, Methoxy poly(ethylene glycol)/epsilon-caprolactone amphiphilic block copolymeric micelle contain- ing indomethacin.: I. Preparation and characterization, J. Controlled Release 51 (1) (1998) 1–11.

122. L. Zhang, A. Eisenberg, Multiple Morphologies of "Crew-Cut" Aggregates of Polystyrene-b-poly(acrylic acid) Block Copolymers, Science 268 (5218) (1995) 1728–1731.

123. X. Shuai, T. Merdan, F. Unger, M. Wittmar, T. Kissel, Novel biodegradable ternary copolymers hy-PEI-g-PCL-b-PEG, Macromolecules (Washington, DC, United States) 36 (2003) 5751–5759.

124. J. Clement, K. Kiefer, A. Kimpfler, P. Garidel, R. Peschka-Süss, Large-scale production of lipoplexes with long shelf-life, Eur. J. Pharm. Biopharm. 59 (1) (2005) 35–43.

125. Philipps-Universität Marburg Studium der Chemie Schwerpunkt: Polymerchemie Diplom Sep 1993 -Jun 2002

126. D. S. W. Benoit, S. M. Henry, A. D. Shubin, A. S. Hoffman, P. S. Stayton, pH- Responsive Polymeric siRNA Carriers Sensitize Multidrug Resistant Ovarian Cancer Cells to Doxorubicin via Knockdown of Polo-like Kinase 1, Mol. Phar- maceutics 7 (2) (2010) 442–455.

127. A. Wieber, T. Selzer, J. Kreuter, Physico-chemical characterisation of cationic DOTAP liposomes as drug delivery system for a hydrophilic decapeptide be- fore and after freeze-drying, Eur. J. Pharm. Biopharm. 80 (2) (2011) 358–367.

128. T. Riley, S. Stolnik, C. R. Heald, C. D. Xiong, M. C. Garnett, L. Illum, S. S. Davis, S. C. Purkiss, R. J. Barlow, P. R. Gellert, Physicochemical Evalu- ation of Nanoparticles Assembled from Poly(lactic acid)Poly(ethylene glycol) (PLAPEG) Block Copolymers as Drug Delivery Vehicles, Langmuir 17 (11) (2001) 3168–3174.

129. J. M. Chan, L. Zhang, K. P. Yuet, G. Liao, J.-W. Rhee, R. Langer, O. C. Farokhzad, PLGA-lecithin-PEG core-shell nanoparticles for controlled drug delivery, Biomaterials 30 (8) (2009) 1627–1634.

130. C. Allen, Y. Yu, D. Maysinger, A. Eisenberg, Polycaprolactone-b- poly(ethylene Oxide) Block Copolymer Micelles as a Novel Drug Delivery Vehicle for Neurotrophic Agents FK506 and L-685,818, Bioconjugate Chem. 9 (5) (1998) 564–572.

131. T. Ameller, V. Marsaud, P. Legrand, R. Gref, G. Barratt, J.-M. Renoir, Polyester-Poly(Ethylene Glycol) Nanoparticles Loaded with the Pure Anti- estrogen RU 58668: Physicochemical and Opsonization Properties, Pharm. Res. 20 (2003) 1063–1070.

132. R. Kircheis, L. Wightman, A. Schreiber, B. Robitza, V. Rössler, M. Kursa, E. Wagner, Polyethylenimine/DNA complexes shielded by transferrin target gene expression to tumors after systemic application, Gene Ther. 8 (2001) 28–40.

133. H. Petersen, P. Fechner, A. Martin, K. Kunath, S. Stolnik, C. Roberts, D. Fisc- her, M. Davies, T. Kissel, Polyethylenimine-graft-Poly(ethylene glycol) Co- polymers: Influence of Copolymer Block Structure on DNA Complexation and Biological Activities as Gene Delivery System, Bioconjugate Chem. 13 (4) (2002) 845–854.

134. D. J. Gary, N. Puri, Y.-Y. Won, Polymer-based siRNA delivery: Perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery, J. Controlled Release 121 (2007) 64–73.

135. A. Richter, C. Olbrich, M. Krause, J. Hoffmann, T. Kissel, Polymeric Micelles for parenteral delivery of Sagopilone: Physicochemical characterization, novel formulation approaches and their toxicity assessment in vitro as well as in vivo, Eur. J. Pharm. Biopharm. 75 (2) (2010) 80–89.

136. References [165] A. V. Ulasov, Y. V. Khramtsov, G. A. Trusov, A. A. Rosenkranz, E. D. Sverdlov, A. S. Sobolev, Properties of PEI-based Polyplex Nanoparticles That Correlate With Their Transfection Efficacy, Mol. Ther. 19 (1) (2011) 103–112.

137. T. Merdan, J. Kopecek, T. Kissel, Prospects for cationic polymers in gene and oligonocleotide therapy against cancer, Adv. Drug Delivery Rev. 54 (2002) 715–758.

138. J. I. Lee, K.-S. Ha, H. S. Yoo, Quantum-dot-assisted fluorescence resonance energy transfer approach for intracellular trafficking of chitosan/DNA com- plex, Acta Biomater. 4 (4) (2008) 791–798.

139. I. L. Medintz, H. Mattoussi, Quantum dot-based resonance energy transfer and its growing application in biology, Phys. Chem. Chem. Phys. 11 (2009) 17–45.

140. M. Neu, D. Fischer, T. Kissel, Recent advances in rational gene transfer vector design based on PEI and its derivates, J. Gene Med. 7 (2005) 992–1009.

141. K. Rihova, Receptor-mediated targeted drug or toxin delivery, Adv. Drug Delivery Rev. 29 (1998) 273–289.

142. I. L. Medintz, A. R. Clapp, H. Mattoussi, E. R. Goldman, B. Fisher, J. M. Mauro, Self-assembled nanoscale biosensors based on quantum dot FRET donors, Nat. Mater. 2 (9) (2003) 630–638.

143. L. Y. Qiu, Y. H. Bae, Self-assembled polyethylenimine-graft-poly(epsilon- caprolactone) micelles as potential dual carriers of genes and anticancer drugs, Biomaterials 28 (28) (2007) 4132–4142.

144. M. Wang, M. Zhang, J. Li, S. Kumar, G. C. Walker, G. D. Scholes, M. A. Winnik, Self-Assembly of Colloidal Quantum Dots on the Scaffold of Triblock Copolymer Micelles, ACS Appl. Mater. Interfaces 2 (11) (2010) 3160–3169. Appendices List of tables I.1

145. H. H. Chen, Y.-P. Ho, X. Jiang, H.-Q. Mao, T.-H. Wang, , K. W. Leong, Simultaneous Non-invasive Analysis of DNA Condensation and Stability by Two-step QD-FRET, Nano Today 4 (2) (2009) 135–134.

146. /s Pionierbataillon Volkach Marburg, 16.10.2012

147. C. Brus, E. Kleemann, A. Aigner, F. Czubayko, T. Kissel, Stabilization of oligonucleotide-polyethylenimine complexes by freeze-drying: physicochemical and biological characterization, J. Controlled Release 95 (1) (2004) 119–131.

148. O. Zelphati, C. Nguyen, M. Ferrari, J. Felgner, Y. Tsai, P. L. Felgner, Stable and monodisperse lipoplex formulations for gene delivery, Gene Ther. 5 (9) (1998) 1272–1282.

149. M. A. Kay, State-of-the-art gene-based therapies: the road ahead, Nat. Rev. Genet. 12 (5) (2011) 316–328.

150. B. Shi, C. Fang, M. X. You, Y. Zhang, S. Fu, Y. Pei, Stealth MePEG-PCL mi- celles: effects of polymer composition on micelle physicochemical characterist- ics, in vitro drug release, in vivo pharmacokinetics in rats and biodistribution in tumor bearing mice, Colloid Polym. Sci. 283 (9) (2005) 954–967.

151. F. Podo, A. Ray, G. Nemethy, Structure and hydration of nonionic detergent micelles. High resolution nuclear magnetic resonance study, J. Am. Chem. Soc. 95 (19) (1973) 6164–6171.

152. D. Singh, S. Heinhorst, G. C. Cannon, S. E. Morgan, Synthesis and charac- terization of amphiphilic block copolymers for polymerosomes., Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.) 51 (2) (2010) 561–562.

153. H. Petersen, P. Fechner, D. Fischer, T. Kissel, Synthesis, Characterization, and Biocompatibility of Polyethylenimine-graft-poly(ethylene glycol) Block Copolymers, Macromolecules (Washington, DC, United States) 35 (18) (2002) 6867–6874.

154. A. M. Derfus, A. A. Chen, D.-H. Min, E. Ruoslahti, S. N. Bhatia, Targeted Quantum Dot Conjugates for siRNA Delivery, Bioconjugate Chem. 18 (5) (2009) 1391–1396.

155. Institut für Pharm. Technologie und Biopharmazie Philipps-Universität Marburg Promotion Okt 2003 -Nov 2009

156. J. Y. Cherng, H. Talsama, R. Verrijk, D. J. A. Crommelin, W. E. Hennink, The effect of formulation parameters on the size of poly-((2-dimethylamino)ethyl methacrylate)-plasmid complexes, Eur. J. Pharm. Biopharm. 47 (1998) 215– 224.

157. F. J. Carrión, A. D. L. Maza, J. L. Parra, The Influence of Ionic Strength and Lipid Bilayer Charge on the Stability of Liposomes, J. Colloid Interface Sci. 164 (1) (1994) 78–87.

158. Y. Wang, C.-Y. Ke, C. W. Beh, S.-Q. Liu, S.-H. Goh, Y.-Y. Yang, The self- assembly of biodegradable cationic polymer micelles as vectors for gene trans- fection, Biomaterials 28 (35) (2007) 5358–5368.

159. M. Ogris, P. Steinlein, M. Kursa, K. Mechtler, R. Kircheis, E. Wagner, The size of DNA/transferrin-PEI complexes is an important factor for gene expression in cultured cells, Gene Ther. 5 (1998) 1425–1433.

160. C.-L. Tseng, W.-Y. Su, K.-C. Yen, K.-C. Yang, F.-H. Lin, The use of biotinylated-EGF-modified gelatin nanoparticle carrier to enhance cisplatin accumulation in cancerous lungs via inhalation, Biomaterials 30 (20) (2009) 3476–3485.

161. C. Plank, K. Mechtler, F. C. Szoka, E. Wagner, Activation of the Complement System by Synthetic DNA Complexes: A Potential Barrier for Intravenous Gene Delivery, Hum. Gene Ther. 7 (12) (2008) 1437–1446.

162. X. Zhang, S.-R. Pan, H.-M. Hu, G.-F. Wu, M. Feng, W. Zhang, X. Luo, Poly(ethylene glycol)-block-polyethylenimine copolymers as carriers for gene delivery: Effects of PEG molecular weight and PEGylation degree, J. Biomed. Mater. Res., Part A 84A (3) (2008) 795–804.

163. T. D. Perrine, W. R. Landis, Analysis of polyethylenimine by spectrophoto- metry of Its copper chelate, J. Polym. Sci., Part A-1: Polym. Chem. 5 (1967) 1993–2003.

164. Y. Zhang, S. Guo, C. Lu, L. Liu, Z. Li, J. Gu, Poly(e-caprolactone)-b- Poly(ethylene glycol)-b-Poly (e-caprolactone) Triblock Copolymers: Synthesis and Self-Assembly in Aqueous Solutions, J. Polym. Sci., Part A: Polym. Chem. 45 (2007) 605–613.

165. C. G. Koh, X. Kang, Y. Xie, Z. Fei, J. Guan, B. Yu, X. Zhang, L. J. Lee, Deliv- ery of polyethylenimine/DNA complexes assembled in a microfluidics device, Mol. Pharmaceutics 6 (5) (2009) 1333–1342.

166. Y.-P. Ho, C. L. Grigsby, F. Zhao, K. W. Leong, Tuning physical properties of nanocomplexes through microfluidics-assisted confinement, Nano Lett. 11 (5) (2011) 2178–2182.

167. C.-H. Yang, K.-S. Huang, Y.-S. Lin, K. Lu, C.-C. Tzeng, E.-C. Wang, C.- H. Lin, W.-Y. Hsu, J.-Y. Chang, Microfluidic assisted synthesis of multi- functional polycaprolactone microcapsules: incorporation of CdTe quantum dots, Fe3O4 superparamagnetic nanoparticles and tamoxifen anticancer drugs, Lab Chip 9 (2009) 961–965.

168. F. Bordi, C. Cametti, S. Sennato, M. Diociaiuti, Direct evidence of multicom- partment aggregates in polyelectrolyte-charged liposome complexes, Biophys. J. 91 (4) (2006) 1513–1520.

169. Y.-C. Chang, I.-M. Chu, Methoxy poly(ethylene glycol)-b-poly(valerolactone) diblock polymeric micelles for enhanced encapsulation and protection of camp- tothecin, Eur. Polym. J. 44 (12) (2008) 3922–3930.

170. N. Cao, D. Cheng, S. Zou, H. Ai, J. Gao, X. Shuai, The synergistic effect of hierarchical assemblies of siRNA and chemotherapeutic drugs co-delivered into hepatic cancer cells, Biomaterials 32 (8) (2011) 2222–2232.

171. F. Ahmed, D. E. Discher, Self-porating polymersomes of PEG-PLA and PEG- PCL: hydrolysis-triggered controlled release vesicles, J. Controlled Release 96 (1) (2004) 37–53.

172. K. Sarlo, K. L. Blackburn, E. D. Clark, J. Grothaus, J. Chaney, S. Neu, J. Flood, D. Abbott, C. Bohne, K. Casey, C. Fryer, M. Kuhn, Tissue distribu- tion of 20 nm, 100 nm and 1000 nm fluorescent polystyrene latex nanospheres following acute systemic or acute and repeat airway exposure in the rat, Tox- icology 263 (2-3) (2009) 117–126.

173. T. Chandran, U. Katragadda, Q. Teng, C. Tan, Design and evaluation of micellar nanocarriers for 17-allyamino-17-demethoxygeldanamycin (17-AAG), Int. J. Pharm. 392 (1-2) (2010) 170–177.

174. M. Zheng, Y. Liu, O. Samsonova, T. Endres, O. Merkel, T. Kissel, Amphiphilic and biodegradable hy-PEI-g-PCL-b-PEG copolymers efficiently mediate trans- gene expression depending on their graft density, Int. J. Pharm. 427 (1) (2011) 80–87.

175. M. Bivas-Benita, S. Romeijn, H. E. Junginger, G. Borchard, PLGA-PEI nano- particles for gene delivery to pulmonary epithelium, Eur. J. Pharm. Biopharm. 58 (1) (2004) 1–6.

176. S. Stolnik, C. R. Heald, J. Neal, M. C. Garnett, S. S. Davis, L. Illum, S. C. Purkis, R. J. Barlow, P. R. Gellert, Polylactide-poly(ethylene Glycol) Micellar- like Particles as Potential Drug Carriers: Production, Colloidal Properties and Biological Performance, J. Drug Targeting 9 (5) (2001) 361–378.