Abstract��Poly(2-oxazoline)s (POx) have the same repeated C-C heteroatomic chains, which is very similar to polyethylene glycol (PEG), so POx have the similar properties to PEG, such as hydrophilicity and flexibility and low immunogenicity, etc. However, POx also possesses pH-sensitivity, thermo-responsibility, and does not interfere with the cellular uptake of nanocarriers, which highlights the potential of POx as an ideal alternative to PEG for constructing and modifying liposomes, micelles, polymer-drug conjugates and other nanocarriers. Among the POx, the chemical nature of poly(2-ethyl-2-oxazoline) (PEOZ) is the most active, which is the most widely used. In this paper, the synthesis of POx serial derivatives and their application in drug delivery systems were reviewed, mainly focused on PEOZ.
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YUE Hong-xin, WANG Xiao-chan, XU Huan. Synthesis and Application of 2-Oxazoline Polymer in Drug Delivery Systems: A Review. Chinese Pharmaceutical Journal, 2017, 52(9): 713-720.
TANG F, CAI C G, JIA D M. Application of oxazoline in polymer modification[J]. New Chem Mater (�������Ͳ���), 2004, 32(7):43-45.
[2]
LUXENHOFER R, HAN Y C, SCHULZ A, et al. Poly(2-oxazoline)s as polymer therapeutics [J]. Macromol Rapid Commun, 2012, 33(19):1613-1631.
[3]
SEDLACEK O, MONNERY B D, FILIPPOV S K, et al. Poly(2-oxazoline)s��are they more advantageous for biomedical applications than other polymers?[J]. Macromol Rapid Commun, 2012, 33(19):1648-1662.
[4]
WEBER C, HOOGENBOOM R, SCHUBERT U S. Temperature responsive biocompatible polymers based on poly(ethylene oxide) and poly(2-oxazoline)s[J]. Prog Polym Sci, 2012, 37(5):686-714.
[5]
WANG C H, HSIUE G H. Synthesis and characterization of temperature-and pH-sensitive hydrogels based on poly(2-ethyl-2-oxazoline) and poly(D,L-lactide)[J]. J Polym Sci Part A, 2002, 40(11):1112-1121.
[6]
KIBRIA G, HATAKEYAMA H, OHGA N, et al. Dual-ligand modification of PEGylated liposomes shows better cell selectivity and efficient gene delivery[J]. J Controlled Release, 2011, 153(2):141-148.
[7]
WEI M Y, XU Y H, ZOU Q, et al. Hepatocellular carcinoma targeting effect of PEGylated liposomes modified with lactoferrin[J]. Eur J Pharm Sci, 2012, 46(3):131-141.
[8]
JANG J S, DING Z S, LU G Y. Research progress on polyethylene glycol prodrugs[J]. Chin Pharm J(�й�ҩѧ��־), 2007, 42(12):881-885.
[9]
HATAKEYAMA H, AKITA H, HARASHIMA H. A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect:a strategy for overcoming the PEG dilemma[J]. Adv Drug Delivery Rev, 2011, 63(3):152-160.
[10]
ZHANG D, XU H, HU M N, et al. Recent advances in the study of ��PEG dilemma�� for liposomes and its solving approachs[J]. Acta Pharm Sin (ҩѧѧ��), 2015, 50(3):252-260.
[11]
VIEGAS T X, BENTLEY M D, HARRIS J M, et al. Polyoxazoline:chemistry, properties, and applications in drug delivery[J]. Bioconjugate Chem, 2011, 22(5):976-986.
[12]
ZHAO Y, ZHOU Y X, WANG D S, et al. pH-Responsive polymeric micelles based on poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) for tumor-targeting and controlled delivery of doxorubicin and P-glycoprotein inhibitor[J]. Acta Biomater, 2015, 17(1):182-192.
[13]
XIA G M, AN Z J, WANG Y, et al. Synthesis of a novel polymeric material folate-poly(2-ethyl-2-oxazoline)-distearoyl phosphatidyl ethanolamine tri-block polymer for dual receptor and pH-sensitive targeting liposome[J]. Chem Pharm Bull, 2013, 61(4):390-398.
[14]
ZHANG D, LI J Y, WANG X C, et al. Preparation and evaluation of doxorubicin hydrochloride liposomes modified by poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate[J]. Acta Pharm Sin (ҩѧѧ��), 2015, 50(9):1174-1179.
[15]
WANG C H, WANG C H, HSIUE G H. Polymeric micelles with a pH-responsive structure as intracellular drug carriers[J]. J Controlled Release, 2005, 108(1):140-149.
[16]
WANG C H, HSIUE G H. New amphiphilic poly(2-ethyl-2-oxazoline)/poly(L-lactide) triblock copolymers[J]. Biomacromolecules, 2003, 4(6):1487-1490.
[17]
CHRISTOVA D, VELICHKOVA R, LOOS W, et al. New thermo-responsive polymer materials based on poly(2-ethyl-2-oxazoline) segments[J]. Polymer, 2003, 44(8):2255-2261.
[18]
PARK J S, AKIYAMA Y, WINNIK F M, et al. Versatile synthesis of end-functionalized thermosensitive poly(2-isopropyl-2-oxazolines)[J]. Macromoleules, 2004, 37(18):6786-6792.
[19]
XU H, HU M N, YU X, et al. Design and evaluation of pH sensitive liposomes constructed by poly(2-ethyl-2-oxazoline)-cholesterol hemisuccinate for doxorubicin delivery[J]. Eur J Pharm Biopharm, 2015, 91(1):66-74.
[20]
QIU L Y, YAN L, ZHANG L, et al. Folate-modified poly(2-ethyl-2-oxazoline) as hydrophilic corona in polymeric micelles for enhanced intracellular doxorubicin delivery[J]. Int J Pharm, 2013, 456(2):315-324.
[21]
GAO Y J, ZHOU Y X, ZHAO L, et al. Enhanced antitumor efficacy by cyclic RGDyK-conjugated and paclitaxel-loaded pH-responsive polymeric micelles[J]. Acta Biomater, 2015, 23:127-135.
[22]
GASPAR V M, BARIL P, COSTA E C, et al. Bioreducible poly(2-ethyl-2-oxazoline)-PLA-PEI-SS triblock copolymer micelles for co-delivery of DNA minicircles and doxorubicin[J]. J Controlled Release, 2015, 213(1):175-191.
[23]
LI J W, ZHOU Y X, LI C W, et al. Poly(2-ethyl-2-oxazoline)-doxorubicin conjugate-based dual endosomal pH-sensitive micelles with enhanced antitumor efficacy[J]. Bioconjug Chem, 2015, 26(1):110-119.
[24]
GLASSNER M, D��HOOGE D R, PARK J Y, et al. Systematic investigation of alkyl sulfonate initiators for the cationic ring-opening polymerization of 2-oxazolines revealing optimal combinations of monomers and initiators[J]. Eur Polym J, 2015, 65(1):298-304.
[25]
DINTAMAN J M, SILVERMAN J A. Inhibition of P-glycoprotein by D-��-tocopheryl polyethylene glycol 1000 succinate (TPGS)[J]. Pharm Res, 1999, 16(10):1550-1556.
[26]
CHEN Y, CAO W B, ZHOU J L, et al. Poly(L-lysine)-graft-folic acid-coupled poly(2-methyl-2-oxazoline) (PLL-g-PMOXA-c-FA):a novel bioactive copolymer for specific targeting to folate receptor-positive cancer cells[J]. ACS Appl Mater Inter, 2015, 7(4):2919-2930.
[27]
WOODLE M C, ENGBERS C M, ZALIPSKY S. New amphipatic polymer-lipid conjugates forming long-circulating reticuloendothelial system-evading liposomes[J]. Bioconjug Chem, 1994, 5(6):493-496.
[28]
ZALIPSKY S, HANSEN C B, OAKS J M, et al. Evaluation of blood clearance rates and biodistribution of poly(2-oxazoline)-grafted liposomes[J]. J Pharm Sci, 1996, 85(2):133-137.
[29]
XU H, ZHANG W, LI Y, et al. The bifunctional liposomes constructed by poly(2-ethyl-oxazoline)-cholesteryl methyl carbonate:an effectual approach to enhance liposomal circulation time,pH-sensitivity and endosomal escape[J]. Pharm Res, 2014, 31(11):3038-3050.
[30]
JIANG X H, HUANG X, HUANG X, et al. Advance in study of polymer micelle drug carrier systems[J]. Chin J Exp Tradit Med Form (�й�ʵ�鷽��ѧ��־), 2010, 16(10):220-223.
[31]
HUANG R B, TANG G T. Progress in the study of acid-sensitive micelles for the targeting drug delivery system[J]. Acta Pharm Sin (ҩѧѧ��), 2012, 47(4):440-445.
[32]
HSIUE G H, WANG C H, LO C L, et al. Environmental-sensitive micelles based on poly(2-ethyl-2-oxazoline)-b-poly(L-lactide) diblock copolymer for application in drug delivery[J]. Int J Pharm, 2006, 317(1):69-75.
[33]
LEE S C, KIM C, KWON I C, et al. Polymeric micelles of poly(2-ethyl-2-oxazoline)-block-poly(��-caprolactone) copolymer as a carrier for paclitaxel[J]. J Controlled Release, 2003, 89(3):437-446.
[34]
LUXENHOFER R, SCHULZ A, ROQUES C, et al. Doubly amphiphilic poly(2-oxazoline)s as high-capacity delivery systems for hydrophobic drugs[J]. Biomaterials, 2010, 31(18):4972-4979.
[35]
HAN Y C, HE Z J, SCHULZ A, et al. Synergistic combinations of multiple chemotherapeutic agents in high capacity poly(2-oxazoline) micelles[J]. Mol Pharm, 2012, 9(8):2302-2313.
[36]
GASPAR V M, GONCALVES C, DE MELO-DIOGO D, et al. Poly(2-ethyl-2-oxazoline)-PLA-g-PEI amphiphilic triblock micelles for co-delivery of minicircle DNA and chemotherapeutics[J]. J Controlled Release, 2014, 189(36):90-104.
[37]
NISHIYAMA N, BAE Y, MIYATA K, et al. Smart polymeric micelles for gene and drug delivery[J]. Drug Discov Today:Technol, 2005, 2(1):21-26.
[38]
NATALYA R. Physical stimuli-responsive polymeric micelles for anti-cancer drug delivery[J]. Prog Polym Sci, 2007, 32(8-9):962-990.
[39]
THOMTON P D, MCCONNELL G, ULIJN R V. Enzyme responsive polymer hydrogel beads[J]. Chem Commun, 2005, 47(47):5913-5915.
[40]
JIA L, QIAO M X, HU H Y, et al. The characterisitics of temperature/pH sensitive block copolymer micelles in vitro[J]. Acta Pharm Sin (ҩѧѧ��), 2011, 46(7):839-844.
[41]
GANTA S, DEVALAPALLY H, SHAHIWALA A, et al. A review of stimuli-responsive nanocarriers for drug and gene delivery[J]. J Controlled Release, 2008, 126(3):187-204.
[42]
STUBBS M, MCSHEEHY P M, GRIFFITHS J R, et al. Causes and consequences of tumour acidity and implications for treatment[J]. Mol Med Today, 2000, 6(1):15-19.
[43]
ENGIN K, LEEPER D B, CATER J R, et al. Extracellular pH distribution in human tumours[J]. Int J Hyperther, 1995, 11(2):211-216.
[44]
GERWECK L E, SEETHARAMAN K. Cellular pH gradient in tumor versus normal tissue:potential exploitation for the treatment of cancer[J]. Cancer Res, 1996, 56(6):1194-1198.
[45]
DALEKE D L, HONG K, PAPAHADJOPOULOS D. Endocytosis of liposomes by macrophages:binding, acidification and leakage of liposomes monitored by a new fluorescence assay[J]. BBA-Biomembranes, 1990, 1024(2):352-366.
[46]
STRAUBINGER R M, DUZGUNES N, PAPAHADJOPOULOS D. pH-Sensitive liposomes mediate cytoplasmic delivery of encapsulated macromolecules[J]. FEBS Lett, 1985, 179(1):148-154.
[47]
XU Y L, JIANG H Y, QIAN X Z, et al. Perparation and properties of pH-sensitive doxorubicin nanoliposomes[J]. J East China Univ Sci Technol:Nat Sci Edit (��������ѧѧ��:��Ȼ��ѧ��), 2008, 34(3):364-368.
[48]
TURK M J, REDDY J A, CHMIELEWSKI J A, et al. Characterization of a novel pH-sensitive peptide that enhances drug release from folate-targeted liposomes at endosomal pHs[J]. Biochim Biophys Acta, 2002, 1559(1):56-68.
[49]
CHEN D W, YAN L, QIAO M X, et al. Preparation of docetaxel-loaded pH-sensitive block copolymer micelles[J]. Acta Pharm Sin (ҩѧѧ��), 2008, 43(10):1066-1070.
[50]
YAN L. Targeed micelles based on folate conjugated poly(2-ethy-2-oxazoline)-b-poly(��-caprolactone)polymer:preparation and application in tumor therapy[D]. Zhejiang:Zhejiang University, 2014.
[51]
TYRRELL Z L, SHEN Y Q, RADOSE M. Fabrication of micellar nanoparticles for drug delivery through the self-assembly of block copolymers[J]. Prog Polym Sci, 2010, 35(9):1128-1143.
[52]
RIJCKEN C J, SNEL C J, SCHIFFELERS R M, et al. Hydrolysable core-crosslinked thermosensitive polymeric micelles:synthesis, characterisation and in vivo studies[J]. Biomaterials, 2007, 28(36):5581-5593.
[53]
ZHAO B X, ZHAO Y, HUANG Y, et al. The efficiency of tumor-specific pH-responsive peptide-modified polymeric micelles containing paclitaxel[J]. Biomaterials, 2012, 33(8):2508-2520.
[54]
GAO Y J, ZHANG C, ZHOU Y X, et al. Endosomal pH-responsive polymer-based dual-ligand-modified micellar nanoparticles for tumor targeted delivery and facilitated intracellular release of paclitaxel[J]. Pharm Res, 2015, 32(8):2649-2662.
[55]
DRUMMOND D C, ZIGNANI M, LEROUX J C. Current status of pH-sensitive liposomes in drug delivery[J]. Prog Lipid Res, 2000, 39(5):409-460.
[56]
YUBA E, HARADA A, SAKANISHI Y, et al. Carboxylated hyperbranched poly(glycidol)s for preparation of pH-sensitive liposomes[J]. J Controlled Release, 2011, 149(1):72-80.
[57]
MERO A, PASUT G, VIA L D, et al. Synthesis and characterization of poly(2-ethyl -2-oxazoline)-conjugates with proteins and drugs:suitable alternatives to PEG-conjugates?[J]. J Controlled Release, 2008, 125(2):87-95.
[58]
MERO A, FANG Z H, PASUT G, et al. Selective conjugation of poly(2-ethyl-2-oxazoline) to granulocyte colony stimulating factor[J]. J Controlled Release, 2012, 159(3):353-361.
[59]
TONG J, LUXENHOFER R, YI X, et al. Protein modification with amphiphilic block copoly(2-oxazoline)s as a new platform for enhanced cellular delivery[J]. Mol Pharm, 2010, 7(4):984-992.
[60]
DE LA ROSA V R. Poly(2-oxazoline)s as materials for biomedical applications[J]. J Mater Sci:Mater Med, 2014, 25(5):1211-1225.
[61]
HOFFMAN A S. ��Intelligent��polymers in medicine and biotechnology[J]. Macromol Symp, 1995, 98(1):645-664.
[62]
OKANO T, BAE Y H, JACOBS H, et al. Thermally on-off switching polymers for drug permeation and release[J]. J Controlled Release, 1990, 11(1-3):255-265.
[63]
KYLUIK-PRICE D L, LI L, SCOTT M D. Comparative efficacy of blood cell immunocamouflage by membrane grafting of methoxypoly(ethylene glycol) and polyethyloxazoline[J]. Biomaterials, 2014, 35(1):412-422.