Toward the design of LPEI containing block copolymers: Improved synthesis protocol, selective hydrolysis, and detailed characterization

The synthesis of poly(2-ethyl-2-oxazoline)-b-linear poly(ethylenimine) (PEtOx-b-LPEI) copolymers by selective basic hydrolysis of PEtOx-b-poly(2-H-2-oxazoline) (PEtOx-b-PHOx) is described. For this purpose, an easy method for the preparation of the 2-H-2-oxazoline (HOx) monomer was developed. Based on the microwave-assisted polymerization kinetics for this monomer, PEtOx-b-PHOx copolymers were prepared. Subsequently, the block copolymers were selectively hydrolyzed to PEtOx-b-LPEI under basic conditions. The success of the polymerizations and subsequent post-polymerization reactions was demonstrated by 1H NMR spectroscopy and MALDI-TOF-MS investigations of the obtained polymers. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

[1]  U. Schubert,et al.  Poly(2-ethyl-2-oxazoline) as alternative for the stealth polymer poly(ethylene glycol): comparison of in vitro cytotoxicity and hemocompatibility. , 2012, Macromolecular bioscience.

[2]  U. Schubert,et al.  Branched and linear poly(ethylene imine)-based conjugates: synthetic modification, characterization, and application. , 2012, Chemical Society reviews.

[3]  U. Schubert,et al.  Characterization of poly(2-oxazoline) homo- and copolymers by liquid chromatography at critical conditions. , 2011, Journal of chromatography. A.

[4]  U. Schubert,et al.  Linear Polyethyleneimine: Optimized Synthesis and Characterization - On the Way to ''Pharmagrade'' Batches , 2011 .

[5]  R. Luxenhofer,et al.  Structure-property relationship in cytotoxicity and cell uptake of poly(2-oxazoline) amphiphiles. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[6]  Z. Kroneková,et al.  In vitro bio-immunological and cytotoxicity studies of poly(2-oxazolines) , 2011, Journal of materials science. Materials in medicine.

[7]  F. Veronese,et al.  Polyoxazoline: chemistry, properties, and applications in drug delivery. , 2011, Bioconjugate chemistry.

[8]  U. Schubert,et al.  Selective partial hydrolysis of amphiphilic copoly(2-oxazoline)s as basis for temperature and ph responsive micelles , 2011 .

[9]  U. Schubert,et al.  Characterization of different poly(2‐oxazoline) block copolymers by MALDI‐TOF MS/MS and ESI‐Q‐TOF MS/MS , 2010 .

[10]  U. Schubert,et al.  Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. , 2010, Angewandte Chemie.

[11]  R. Luxenhofer,et al.  Doubly amphiphilic poly(2-oxazoline)s as high-capacity delivery systems for hydrophobic drugs. , 2010, Biomaterials.

[12]  U. Schubert,et al.  Linear Poly(ethylene imine)s by Acidic Hydrolysis of Poly(2-oxazoline)s: Kinetic Screening, Thermal Properties, and Temperature-Induced Solubility Transitions , 2010 .

[13]  R. Breslow,et al.  Synthesis and catalytic properties of diverse chiral polyamines. , 2008, Tetrahedron letters.

[14]  Xuesi Chen,et al.  Linear poly(ethylenimine)-graft-poly(ethylene glycol) copolymers: their micellization and secondary assembly. , 2008, Journal of colloid and interface science.

[15]  F. Veronese,et al.  Synthesis and characterization of poly(2-ethyl 2-oxazoline)-conjugates with proteins and drugs: suitable alternatives to PEG-conjugates? , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[16]  M. Textor,et al.  Poly-2-methyl-2-oxazoline: a peptide-like polymer for protein-repellent surfaces. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[17]  U. Schubert,et al.  Poly(2-oxazolines) in biological and biomedical application contexts. , 2007, Advanced drug delivery reviews.

[18]  G. Hsiue,et al.  Nonviral gene carriers based on diblock copolymers of poly(2-ethyl-2-oxazoline) and linear polyethylenimine. , 2006, Bioconjugate chemistry.

[19]  J. Feijen,et al.  Low molecular weight linear polyethylenimine-b-poly(ethylene glycol)-b-polyethylenimine triblock copolymers: synthesis, characterization, and in vitro gene transfer properties. , 2005, Biomacromolecules.

[20]  D. Fischer,et al.  Recent advances in rational gene transfer vector design based on poly(ethylene imine) and its derivatives , 2005, The journal of gene medicine.

[21]  Haeshin Lee,et al.  DNA transfection using linear poly(ethylenimine) prepared by controlled acid hydrolysis of poly(2-ethyl-2-oxazoline). , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[22]  Jae Chol Lee,et al.  Total Synthesis of (−)-Colchicine by an Oxyallyl [4+3] Cycloaddition , 2000 .

[23]  Atsushi Harada,et al.  Synthesis of Poly(ethylene glycol)-block-poly(ethylenimine) Possessing an Acetal Group at the PEG End , 2000 .

[24]  T. Molinski,et al.  First Total Synthesis of Bengazole A. , 1999, The Journal of organic chemistry.

[25]  Kunio Ito,et al.  Retro-ene reactions in heterocyclic synthesis, III. A new route to 4,5-dihydrooxazoles and 5,6-dihydro-4H-1,3-oxazines , 1997 .

[26]  T. Allen,et al.  Evaluation of blood clearance rates and biodistribution of poly(2-oxazoline)-grafted liposomes. , 1996, Journal of pharmaceutical sciences.

[27]  Jaewoong Lee,et al.  A Facile and Practical N-formylation of Aminoalcohol: For the Synthesis of 2-substituted 2-Oxazolines and 5,6-Dihydro-4H-1,3-Oxazines , 1993 .

[28]  M. Litt,et al.  Selective hydrolysis of oxazoline block copolymers , 1992 .

[29]  F. Smith,et al.  Condensation of homophthalic anhydrides with heterocyclic imines and DMAD under mild conditions , 1991 .

[30]  C. Overberger,et al.  Nucleic acid base grafted polyethylenimine. Cytosyl pendant groups: Elucidation of structure with solution spectroscopy , 1985 .

[31]  S. Saitō,et al.  High molecular weight linear polyethylenimine and poly(N-methylethylenimine) , 1983 .

[32]  J. Bartulin,et al.  Synthese und charakterisierung von linearem poly(iminoethylen) , 1982 .

[33]  J. Muchowski,et al.  A convenient laboratory synthesis of 2‐oxazoline , 1980 .

[34]  T. Saegusa.  Polymerization and copolymerization of cyclic imino-ethers , 1974 .

[35]  T. Saegusa,et al.  Synthetic Reactions by Complex Catalysts XXXV. A Facile Synthetic Method of Cyclic Imino Ethers and Imino Thioethers , 1974 .

[36]  T. Saegusa,et al.  Synthetic reactions by complex catalysts. XXXI. Novel and versatile method of heterocycle synthesis , 1973 .

[37]  T. Saegusa,et al.  Isomerization Polymerization of 2-Oxazoline. V. Kinetic Studies on the Polymerization of 2-Oxazoline , 1973 .

[38]  T. Saegusa,et al.  Isomerization Polymerization of 2-Oxazoline. III. Reactivities of Unsisbstituted and 2-Substittited 2-Oxazoline Monomers , 1973 .

[39]  T. Saegusa,et al.  Isomerization Polymerization of 2-Oxazoline. II. Propagating Species and Mechanism of Unsubstituted 2-Oxazoline Polymerization , 1972 .

[40]  T. Saegusa,et al.  Isomerization Polymerization of 2-Oxazoline. I. Preparation of Unsubstituted 2-Oxazoline Polymer , 1972 .

[41]  H. Bredereck,et al.  Säureamid‐Reaktionen, XLI. Synthese des Oxazols , 1964 .

[42]  J. Cornforth,et al.  24. A new synthesis of oxazoles and iminazoles including its application to the preparation of oxazole , 1947 .

[43]  H. Wenker.  Syntheses from Ethanolamine. V. Synthesis of Δ2-Oxazoline and of 2,2'-Δ2-Dioxazoline , 1938 .