用于肿瘤治疗的酶/pH敏感的支化聚合物–阿霉素偶联物（英文）
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摘要
本文设计了一种可生物降解的、肿瘤环境敏感的药物释放系统,以达到安全、高效治疗癌症的目的.我们利用单体N-(1,3-二羟基-2-丙基)甲基丙烯酰胺,通过可逆加成-断裂链转移聚合方法制备了含有对肿瘤细胞内组织蛋白酶B敏感的GFLG肽段的支化聚合物–药物偶联物.阿霉素通过pH敏感的腙键偶联到支化聚合物骨架上.支化聚合物药物偶联物可自组装形成纳米粒,平均粒径约为103 nm.连接到聚合物载体的阿霉素可在酸性环境中释放.较高分子量(M_W, 220 kDa)的含有GFLG连接的支化聚合物—阿霉素偶联物可在组织蛋白酶B的作用下降解为低分子量聚合物片段(<40 kDa).支化偶联物通过内吞途径进入细胞,然后释放抗癌药物,进而对肿瘤细胞引起明显的细胞毒性。偶联物的血液循环时间显著延长,使得阿霉素在肿瘤部位大量蓄积. 4T1荷瘤小鼠体内抗肿瘤实验表明,支化偶联物的抗肿瘤效果优于游离阿霉素.此外,体重测量和组织形态学检查的结果表明支化偶联物对正常组织的毒性很低.因此,这种对细胞内的酶和肿瘤组织或细胞内的酸性pH具有响应性的支化聚合物给药系统在肿瘤靶向治疗中具有一定的前景.
It is in a great demand to design a biodegradable, tumor microenvironment-sensitive drug delivery system to achieve safe and highly efficacious treatment of cancer.Herein, a novel pH/enzyme sensitive dendritic pdi HPMADOX conjugate was designed. di HPMA dendritic copolymer with GFLG segments in the branches which are sensitive to the intracellular enzyme of the tumor was prepared through RAFT polymerization. DOX was attached to dendritic di HPMA polymer through a pH-sensitive hydrazone bond. The dendritic pdi HPMA-DOX conjugate self-assembled into nanoparticles with an ideal spherical shape at a mean size of 103 nm. The DOX attached to the polymeric carrier was released in an acidic environment, and the GFLG linker for synthesizing the dendritic vehicle with a high molecular weight(M_W, 220 kDa) was cleaved to release low MWsegments(<40 kDa) in the presence of cathepsin B. The dendritic polymeric conjugate was internalized via an endocytic pathway, and then released the anticancer drug, which led to significant cytotoxicity for tumors. The blood circulation time was profoundly prolonged, resulting in high accumulation of DOX into tumors. In vivo anti-tumor experiments with 4 T1 tumor bearing mice demonstrated that the conjugate had a better antitumor efficacy in comparison with free DOX. Additionally, body weight measurements and histological examinations indicated that the conjugate showed low toxicities to normal tissues. This dendritic polymeric drug carrier in a response to intracellular enzyme and acidic pH of tumor tissue or cells holds great promise in tumor-targeted therapy.
It is in a great demand to design a biodegradable, tumor microenvironment-sensitive drug delivery system to achieve safe and highly efficacious treatment of cancer.Herein, a novel pH/enzyme sensitive dendritic pdi HPMADOX conjugate was designed. di HPMA dendritic copolymer with GFLG segments in the branches which are sensitive to the intracellular enzyme of the tumor was prepared through RAFT polymerization. DOX was attached to dendritic di HPMA polymer through a pH-sensitive hydrazone bond. The dendritic pdi HPMA-DOX conjugate self-assembled into nanoparticles with an ideal spherical shape at a mean size of 103 nm. The DOX attached to the polymeric carrier was released in an acidic environment, and the GFLG linker for synthesizing the dendritic vehicle with a high molecular weight(M_W, 220 kDa) was cleaved to release low MWsegments(<40 kDa) in the presence of cathepsin B. The dendritic polymeric conjugate was internalized via an endocytic pathway, and then released the anticancer drug, which led to significant cytotoxicity for tumors. The blood circulation time was profoundly prolonged, resulting in high accumulation of DOX into tumors. In vivo anti-tumor experiments with 4 T1 tumor bearing mice demonstrated that the conjugate had a better antitumor efficacy in comparison with free DOX. Additionally, body weight measurements and histological examinations indicated that the conjugate showed low toxicities to normal tissues. This dendritic polymeric drug carrier in a response to intracellular enzyme and acidic pH of tumor tissue or cells holds great promise in tumor-targeted therapy.
引文
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8 Li Y.Realize molecular surgical knife in tumor therapy by nanotechnology.Sci China Mater,2015,58:851-851
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19 Luo Q,Xiao X,Dai X,et al.Cross-linked and biodegradable polymeric system as a safe magnetic resonance imaging contrast agent.ACS Appl Mater Interfaces,2018,10:1575-1588
20 Yang J,Kope?ek J.Design of smart HPMA copolymer-based nanomedicines.J Control Release,2016,240:9-23
21 Noguchi Y,Wu J,Duncan R,et al.Early phase tumor accumulation of macromolecules:a great difference in clearance rate between tumor and normal tissues.Jpnese J Cancer Res,1998,89:307-314
22 Duan Z,Zhang Y,Zhu H,et al.Stimuli-sensitive biodegradable and amphiphilic block copolymer-gemcitabine conjugates self-assemble into a nanoscale vehicle for cancer therapy.ACS Appl Mater Interfaces,2017,9:3474-3486
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28 She W,Pan D,Luo K,et al.PEGylated dendrimer-doxorubicin cojugates as p H-sensitive drug delivery systems:synthesis and in vitro characterization.J Biomed nanotechnol,2015,11:964-978
29 Wei X,Luo Q,Sun L,et al.Enzyme-and p H-sensitive branched polymer-doxorubicin conjugate-based nanoscale drug delivery system for cancer therapy.ACS Appl Mater Interfaces,2016,8:11765-11778
30 Zhang C,Pan D,Luo K,et al.Dendrimer-doxorubicin conjugate as enzyme-sensitive and polymeric nanoscale drug delivery vehicle for ovarian cancer therapy.Polym Chem,2014,5:5227-5235
31 Huang X,Du F,Ju R,et al.Novel acid-labile,thermoresponsive poly(methacrylamide)s with pendentortho ester moieties.Macromol Rapid Commun,2007,28:597-603
32 Song XR,Wang X,Yu SX,et al.Co9Se8nanoplates as a new theranostic platform for photoacoustic/magnetic resonance dualmodal-imaging-guided chemo-photothermal combination therapy.Adv Mater,2015,27:3285-3291
33 Shi K,Li J,Cao Z,et al.A p H-responsive cell-penetrating peptidemodified liposomes with active recognizing of integrinαvβ3for the treatment of melanoma.J Control Release,2015,217:138-150
34 Tang M,Zhou M,Huang Y,et al.Dual-sensitive and biodegradable core-crosslinked HPMA copolymer-doxorubicin conjugate-based nanoparticles for cancer therapy.Polym Chem,2017,8:2370-2380
35 Hickey JW,Santos JL,Williford JM,et al.Control of polymeric nanoparticle size to improve therapeutic delivery.J Control Release,2011,219:536-547
36 He C,Hu Y,Yin L,et al.Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles.Biomaterials,2010,31:3657-3666
37 Felber AE,Dufresne MH,Leroux JC.p H-sensitive vesicles,polymeric micelles,and nanospheres prepared with polycarboxylates.Adv Drug Deliver Rev,2012,64:979-992
38 Yuan YY,Mao CQ,Du XJ,et al.Surface charge switchable nanoparticles based on zwitterionic polymer for enhanced drug delivery to tumor.Adv Mater,2012,24:5476-5480
39 Karimi M,Ghasemi A,Sahandi Zangabad P,et al.Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems.Chem Soc Rev,2016,45:1457-1501
40 Ben-Nun Y,Fichman G,Adler-Abramovich L,et al.Cathepsin nanofiber substrates as potential agents for targeted drug delivery.JControl Release,2016,257:60-67
41 Sahay G,Alakhova DY,Kabanov AV.Endocytosis of nanomedicines.J Control Release,2010,145:182-195
42 Chen K,Li X,Zhu H,et al.Endocytosis of nanoscale systems for cancer treatments.Curr Med Chem,2017,24:1-1
43 Liu J,Bauer H,Callahan J,et al.Endocytic uptake of a large array of HPMA copolymers:Elucidation into the dependence on the physicochemical characteristics.J Control Release,2010,143:71-79
44 Li N,Cai H,Jiang L,et al.Enzyme-sensitive and amphiphilic PEGylated dendrimer-paclitaxel prodrug-based nanoparticles for enhanced stability and anticancer efficacy.ACS Appl Mater Interfaces,2017,9:6865-6877
45 Jin W,Wang Q,Wu M,et al.Lanthanide-integrated supramolecular polymeric nanoassembly with multiple regulation characteristics for multidrug-resistant cancer therapy.Biomaterials,2017,129:83-97
46 Zhang Z,Wang J,Nie X,et al.Near infrared laser-induced targeted cancer therapy using thermoresponsive polymer encapsulated gold nanorods.J Am Chem Soc,2014,136:7317-7326
47 Malugin A,KopeckováP,Kopecek J.Liberation of doxorubicin from HPMA copolymer conjugate is essential for the induction of cell cycle arrest and nuclear fragmentation in ovarian carcinoma cells.J Control Release,2007,124:6-10
48 Etrych T,Ková?L,Strohalm J,et al.Biodegradable star HPMApolymer-drug conjugates:Biodegradability,distribution and antitumor efficacy.J Control Release,2011,154:241-248
49 KostkováH,Etrych T,RíhováB,et al.HPMA copolymer conjugates of DOX and mitomycin C for combination therapy:physicochemical characterization,cytotoxic effects,combination index analysis,and anti-tumor efficacy.Macromol Biosci,2013,13:1648-1660
50 Chytil P,KoziolováE,Janou?kováO,et al.Synthesis and properties of star HPMA copolymer nanocarriers synthesised by RAFTpolymerisation designed for selective anticancer drug delivery and imaging.Macromol Biosci,2015,15:839-850
51 Su J,Sun H,Meng Q,et al.Long circulation red-blood-cell-mimetic nanoparticles with peptide-enhanced tumor penetration for simultaneously inhibiting growth and lung metastasis of breast cancer.Adv Funct Mater,2016,26:1243-1252
2 Treml BE,Mc Kenzie RN,Buskohl P,et al.Soft robotics:autonomous motility of polymer films.Adv Mater,2018,30:1870046
3 Wang F,Xiao J,Chen S,et al.Polymer vesicles:modular platforms for cancer theranostics.Adv Mater,2018,28:1705674
4 Liu Y,Li M,Yang F,et al.Magnetic drug delivery systems.Sci China Mater,2017,60:471-486
5 Jia Q,Chen M,Liu Q,et al.Ethylene glycol-mediated synthetic route for production of luminescent silicon nanorod as photodynamic therapy agent.Sci China Mater,2017,60:881-891
6 Webber MJ,Langer R.Drug delivery by supramolecular design.Chem Soc Rev,2017,46:6600-6620
7 Cai H,Wang X,Zhang H,et al.Enzyme-sensitive biodegradable and multifunctional polymeric conjugate as theranostic nanomedicine.Appl Mater Today,2018,11:207-218
8 Li Y.Realize molecular surgical knife in tumor therapy by nanotechnology.Sci China Mater,2015,58:851-851
9 Blanco E,Shen H,Ferrari M.Principles of nanoparticle design for overcoming biological barriers to drug delivery.Nat Biotechnol,2015,33:941-951
10 Torchilin VP.Multifunctional,stimuli-sensitive nanoparticulate systems for drug delivery.Nat Rev Drug Discov,2014,13:813-827
11 Zhang X,Xia LY,Chen X,et al.Hydrogel-based phototherapy for fighting cancer and bacterial infection.Sci China Mater,2017,60:487-503
12 Anselmo AC,Mitragotri S.An overview of clinical and commercial impact of drug delivery systems.J Control Release,2014,190:15-28
13 Dai Y,Cai H,Duan Z,et al.Effect of polymer side chains on drug delivery properties for cancer therapy.J Biomed Nanotechnol,2017,13:1369-1385
14 Pan D,She W,Guo C,et al.PEGylated dendritic diaminocyclohexyl-platinum(II)conjugates as p H-responsive drug delivery vehicles with enhanced tumor accumulation and antitumor efficacy.Biomaterials,2014,35:10080-10092
15 She W,Luo K,Zhang C,et al.The potential of self-assembled,p H-responsive nanoparticles of m PEGylated peptide dendron-doxorubicin conjugates for cancer therapy.Biomaterials,2013,34:1613-1623
16 Duncan R.Development of HPMA copolymer-anticancer conjugates:Clinical experience and lessons learnt.Adv Drug Deliver Rev,2009,61:1131-1148
17 Zhang R,Luo K,Yang J,et al.Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel.J Control Release,2013,166:66-74
18 Zhang R,Yang J,Sima M,et al.Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates.Proc Natl Acad Sci USA,2014,111:12181-12186
19 Luo Q,Xiao X,Dai X,et al.Cross-linked and biodegradable polymeric system as a safe magnetic resonance imaging contrast agent.ACS Appl Mater Interfaces,2018,10:1575-1588
20 Yang J,Kope?ek J.Design of smart HPMA copolymer-based nanomedicines.J Control Release,2016,240:9-23
21 Noguchi Y,Wu J,Duncan R,et al.Early phase tumor accumulation of macromolecules:a great difference in clearance rate between tumor and normal tissues.Jpnese J Cancer Res,1998,89:307-314
22 Duan Z,Zhang Y,Zhu H,et al.Stimuli-sensitive biodegradable and amphiphilic block copolymer-gemcitabine conjugates self-assemble into a nanoscale vehicle for cancer therapy.ACS Appl Mater Interfaces,2017,9:3474-3486
23 Li X,Sun L,Wei X,et al.Stimuli-responsive biodegradable and gadolinium-based poly[N-(2-hydroxypropyl)methacrylamide]copolymers:their potential as targeting and safe magnetic resonance imaging probes.J Mater Chem B,2017,5:2763-2774
24 Xu W,Ledin PA,Shevchenko VV,et al.Architecture,assembly,and emerging applications of branched functional polyelectrolytes and poly(ionic liquid)s.ACS Appl Mater Interfaces,2015,7:12570-12596
25 Venkataraman S,Hedrick JL,Ong ZY,et al.The effects of polymeric nanostructure shape on drug delivery.Adv Drug Deliver Rev,2011,63:1228-1246
26 Kalyanaraman B,Joseph J,Kalivendi S,et al.Doxorubicin-induced apoptosis:Implications in cardiotoxicity.Mol Cellular Biochem,2002,234/235:119-124
27 Chai Z,Hu X,Lu W.Cell membrane-coated nanoparticles for tumor-targeted drug delivery.Sci China Mater,2017,60:504-510
28 She W,Pan D,Luo K,et al.PEGylated dendrimer-doxorubicin cojugates as p H-sensitive drug delivery systems:synthesis and in vitro characterization.J Biomed nanotechnol,2015,11:964-978
29 Wei X,Luo Q,Sun L,et al.Enzyme-and p H-sensitive branched polymer-doxorubicin conjugate-based nanoscale drug delivery system for cancer therapy.ACS Appl Mater Interfaces,2016,8:11765-11778
30 Zhang C,Pan D,Luo K,et al.Dendrimer-doxorubicin conjugate as enzyme-sensitive and polymeric nanoscale drug delivery vehicle for ovarian cancer therapy.Polym Chem,2014,5:5227-5235
31 Huang X,Du F,Ju R,et al.Novel acid-labile,thermoresponsive poly(methacrylamide)s with pendentortho ester moieties.Macromol Rapid Commun,2007,28:597-603
32 Song XR,Wang X,Yu SX,et al.Co9Se8nanoplates as a new theranostic platform for photoacoustic/magnetic resonance dualmodal-imaging-guided chemo-photothermal combination therapy.Adv Mater,2015,27:3285-3291
33 Shi K,Li J,Cao Z,et al.A p H-responsive cell-penetrating peptidemodified liposomes with active recognizing of integrinαvβ3for the treatment of melanoma.J Control Release,2015,217:138-150
34 Tang M,Zhou M,Huang Y,et al.Dual-sensitive and biodegradable core-crosslinked HPMA copolymer-doxorubicin conjugate-based nanoparticles for cancer therapy.Polym Chem,2017,8:2370-2380
35 Hickey JW,Santos JL,Williford JM,et al.Control of polymeric nanoparticle size to improve therapeutic delivery.J Control Release,2011,219:536-547
36 He C,Hu Y,Yin L,et al.Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles.Biomaterials,2010,31:3657-3666
37 Felber AE,Dufresne MH,Leroux JC.p H-sensitive vesicles,polymeric micelles,and nanospheres prepared with polycarboxylates.Adv Drug Deliver Rev,2012,64:979-992
38 Yuan YY,Mao CQ,Du XJ,et al.Surface charge switchable nanoparticles based on zwitterionic polymer for enhanced drug delivery to tumor.Adv Mater,2012,24:5476-5480
39 Karimi M,Ghasemi A,Sahandi Zangabad P,et al.Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems.Chem Soc Rev,2016,45:1457-1501
40 Ben-Nun Y,Fichman G,Adler-Abramovich L,et al.Cathepsin nanofiber substrates as potential agents for targeted drug delivery.JControl Release,2016,257:60-67
41 Sahay G,Alakhova DY,Kabanov AV.Endocytosis of nanomedicines.J Control Release,2010,145:182-195
42 Chen K,Li X,Zhu H,et al.Endocytosis of nanoscale systems for cancer treatments.Curr Med Chem,2017,24:1-1
43 Liu J,Bauer H,Callahan J,et al.Endocytic uptake of a large array of HPMA copolymers:Elucidation into the dependence on the physicochemical characteristics.J Control Release,2010,143:71-79
44 Li N,Cai H,Jiang L,et al.Enzyme-sensitive and amphiphilic PEGylated dendrimer-paclitaxel prodrug-based nanoparticles for enhanced stability and anticancer efficacy.ACS Appl Mater Interfaces,2017,9:6865-6877
45 Jin W,Wang Q,Wu M,et al.Lanthanide-integrated supramolecular polymeric nanoassembly with multiple regulation characteristics for multidrug-resistant cancer therapy.Biomaterials,2017,129:83-97
46 Zhang Z,Wang J,Nie X,et al.Near infrared laser-induced targeted cancer therapy using thermoresponsive polymer encapsulated gold nanorods.J Am Chem Soc,2014,136:7317-7326
47 Malugin A,KopeckováP,Kopecek J.Liberation of doxorubicin from HPMA copolymer conjugate is essential for the induction of cell cycle arrest and nuclear fragmentation in ovarian carcinoma cells.J Control Release,2007,124:6-10
48 Etrych T,Ková?L,Strohalm J,et al.Biodegradable star HPMApolymer-drug conjugates:Biodegradability,distribution and antitumor efficacy.J Control Release,2011,154:241-248
49 KostkováH,Etrych T,RíhováB,et al.HPMA copolymer conjugates of DOX and mitomycin C for combination therapy:physicochemical characterization,cytotoxic effects,combination index analysis,and anti-tumor efficacy.Macromol Biosci,2013,13:1648-1660
50 Chytil P,KoziolováE,Janou?kováO,et al.Synthesis and properties of star HPMA copolymer nanocarriers synthesised by RAFTpolymerisation designed for selective anticancer drug delivery and imaging.Macromol Biosci,2015,15:839-850
51 Su J,Sun H,Meng Q,et al.Long circulation red-blood-cell-mimetic nanoparticles with peptide-enhanced tumor penetration for simultaneously inhibiting growth and lung metastasis of breast cancer.Adv Funct Mater,2016,26:1243-1252