酸敏感多肽在药物递送方面的作用机制及其应用
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摘要
作为一类新型的递送载体,多肽具有丰富的生物活性、较低的免疫原性及良好的生物相容性,近年来利用多肽递送药物或基因的研究得到广泛关注。其中,具有酸敏感性的多肽,在肿瘤微环境或溶酶体的弱酸性条件下可以产生二级结构的改变。因此,将酸敏感多肽作为递送载体,或将其修饰在其他载体上,负载药物后形成的纳米组装体可以在肿瘤组织中定点释放药物,促进药物的细胞内化,增强药物的治疗效果。目前发现酸敏感多肽种类较多,多肽的氨基酸侧链、极性氨基酸数量、氨基酸序列及肽链二级结构都可以影响其酸敏感性。本文列举了近年来文献中报道的酸敏感多肽类型,分析了多肽的结构与其酸敏感性之间的关系,并介绍了酸敏感多肽及其修饰载体在药物递送方面的作用机制和应用,为更好地开发和利用酸敏感多肽,实现药物的高效递送提供参考。
As a part of novel drug delivery carriers, peptides have diverse biological activities, low immu‐nogenicity and good biocompatibility. In recent years, studies on the delivery carriers modified by peptides have attracted much attention. Among them, the peptides with acid sensitivity can change their secondary structures under slightly acidic microenvironment of the tumor or in lysosome. Therefore, the carriers made or modified by acid-sensitive peptides can specifically release the loaded drug in the tumor tissue, enhance the cell internalization of drugs and improve its therapeutic effects. In accordance with acid-sensitive peptides studied, the side chains,number of polar residues, sequence and secondary structure of the peptides might be involved in the acid sensitivity. In this review, we summarize the acid-sensitive peptides from recent literatures, analyze the connection between the structure and the acid sensitivity, and focus on the mechanism and application of acid-sensitive peptides in drug delivery. This provides the basis for further development and utilization for acid-sensitive peptides for efficient drug delivery.
As a part of novel drug delivery carriers, peptides have diverse biological activities, low immu‐nogenicity and good biocompatibility. In recent years, studies on the delivery carriers modified by peptides have attracted much attention. Among them, the peptides with acid sensitivity can change their secondary structures under slightly acidic microenvironment of the tumor or in lysosome. Therefore, the carriers made or modified by acid-sensitive peptides can specifically release the loaded drug in the tumor tissue, enhance the cell internalization of drugs and improve its therapeutic effects. In accordance with acid-sensitive peptides studied, the side chains,number of polar residues, sequence and secondary structure of the peptides might be involved in the acid sensitivity. In this review, we summarize the acid-sensitive peptides from recent literatures, analyze the connection between the structure and the acid sensitivity, and focus on the mechanism and application of acid-sensitive peptides in drug delivery. This provides the basis for further development and utilization for acid-sensitive peptides for efficient drug delivery.
引文
[1]Aluri S,Janib SM,Mackay JA.Environmentally responsive peptides as anticancer drug carriers[J].Adv Drug Deliv Rev,2009,61:940-952.
[2]MacEwan SR,Callahan DJ,Chilkoti A.Stimulus-responsive macromolecules and nanoparticles for cancer drug delivery[J].Nanomedicine,2010,5:793-806.
[3]Vlieghe P,Lisowski V,Martinez J,et al.Synthetic therapeutic peptides:science and market[J].Drug Discov Today,2010,15:40-56.
[4]Craik DJ,Fairlie DP,Liras S,et al.The future of peptide-based drugs[J].Chem Biol Drug Des,2013,81:136-147.
[5]Lee S,Xie J,Chen XY.Peptide-based probes for targeted molecular imaging[J].Biochemistry,2010,49:1364-1376.
[6]Li ZJ,Cho CH.Development of peptides as potential drugs for cancer therapy[J].Curr Pharm Design,2010,16:1180-1189.
[7]Estroff LA,Hamilton AD.Water gelation by small organic molecules[J].Chem Rev,2004,104:1201-1218.
[8]Zhang W,Song JJ,Zhang BZ,et al.Design of acid-activated cell penetrating peptide for delivery of active molecules into cancer cells[J].Bioconjugate Chem,2011,22:1410-1415.
[9]Shi KR,Li JP,Cao ZL,et al.A pH-responsive cell-penetrating peptide-modified liposomes with active recognizing of integrinανβ3for the treatment of melanoma[J].J Control Release,2015,217:138-150.
[10]Sun YX,Zhang XZ.Cholesteryl pH-responsive cell-penetrating peptide for co-delivery of drug and gene[J].J Control Release,2017,259:E185-E185.
[11]Guo XD,Zhang LJ,Chen Y,et al.Core/shell pH-sensitive micelles self-assembled from cholesterol conjugated oligopep‐tides for anticancer drug delivery[J].Aiche J,2010,56:1922-1931.
[12]Jiang TY,Zhang ZH,Zhang YL,et al.Dual-functional liposomes based on pH-responsive cell-penetrating peptide and hyaluronic acid for tumor-targeted anticancer drug delivery[J].Biomate‐rials,2012,33:9246-9258.
[13]Liang J,Wu WL,Xu XD,et al.pH responsive micelle selfassembled from a new amphiphilic peptide as anti-tumor drug carrier[J].Colloid Surf B,2014,114:398-403.
[14]Schneider JP,Pochan DJ,Ozbas B,et al.Responsive hydrogels from the intramolecular folding and self-assembly of a designed peptide[J].J Am Chem Soc,2002,124:15030-15037.
[15]Chang C,Liang PQ,Chen LL,et al.pH-responsive nanoparticle assembly from peptide amphiphiles for tumor targeting drug delivery[J].J Biomater Sci Polym Ed,2017,28:1338-1350.
[16]Kang YJ,Zhou XR,Luo SZ.Synthesis and characterization of a pH-responsive amphiphilic peptide hydrogel composed of pal-RLRRLRARARA[J].China Sciencepaper(中国科技论文),2012,7:437-441.
[17]Fei LK,Yap LP,Conti PS,et al.Tumor targeting of a cell pene‐trating peptide by fusing with a pH-sensitive histidine-glutamate co-oligopeptide[J].Biomaterials,2014,35:4082-4087.
[18]Haas DH,Murphy RM.Design of a pH-sensitive pore-forming peptide with improved performance[J].J Pept Res,2004,63:9-16.
[19]Wei YS,Liao RF,Mahmood AA,et al.pH-responsive pHLIP(pH low insertion peptide)nanoclusters of superparamagnetic iron oxide nanoparticles as a tumor-selective MRI contrast agent[J].Acta Biomater,2017,55:194-203.
[20]Wyatt LC,Moshnikova A,Crawford T,et al.Peptides of pHLIPfamily for targeted intracellular and extracellular delivery of cargo molecules to tumors[J].Proc Natl Acad Sci U S A,2018,115:E2811-E2818.
[21]Xu XD,Chu YF,Chen CS,et al.Facile construction of nanofibers as a functional template for surface boron coordina‐tion reaction[J].Small,2011,7:2201-2209.
[22]Tian L,Bae YH.Cancer nanomedicines targeting tumor extra‐cellular pH[J].Colloid Surf B,2012,99:116-126.
[23]Toriyabe N,Hayashi Y,Harashima H.The transfection activity of R8-modified nanoparticles and siRNA condensation using pH sensitive stearylated-octahistidine[J].Biomaterials,2013,34:1337-1343.
[24]Wu H,Zhu L,Torchilin VP.pH-sensitive poly(histidine)-PEG/DSPE-PEG co-polymer micelles for cytosolic drug delivery[J].Biomaterials,2013,34:1213-1222.
[25]Midoux P,Pichon C,Yaouanc JJ,et al.Chemical vectors for gene delivery:a current review on polymers,peptides and lipids containing histidine or imidazole as nucleic acids carriers[J].Br J Pharmacol,2009,157:166-178.
[26]Zhao BX,Zhao Y,Huang Y,et al.The efficiency of tumorspecific pH-responsive peptide-modified polymeric micelles containing paclitaxel[J].Biomaterials,2012,33:2508-2520.
[27]Zhang QY,Tang J,Fu L,et al.A pH-responsive alpha-helical cell penetrating peptide-mediated liposomal delivery system[J].Biomaterials,2013,34:7980-7993.
[28]Singh RS,Goncalves C,Sandrin P,et al.On the gene delivery efficacies of pH-sensitive cationic lipids via endosomal proton‐ation:a chemical biology investigation[J].Chem Biol,2004,11:713-723.
[29]Moreira C,Oliveira H,Pires LR,et al.Improving chitosan-medi‐ated gene transfer by the introduction of intracellular buffering moieties into the chitosan backbone[J].Acta Biomater,2009,5:2995-3006.
[30]Ma YY,Li L,Huang HF,et al.Advances of tumor targeting peptides drug delivery system with pH-sensitive activities[J].Acta Pharm Sin(药学学报),2016,51:717-724.
[31]Dehsorkhi A,Castelletto V,Hamley IW,et al.The effect of pHon the self-assembly of a collagen derived peptide amphiphile[J].Soft Matter,2013,9:6033-6036.
[32]Wan YM,Liu LB,Yuan SS,et al.pH-responsive peptide supra‐molecular hydrogels with antibacterial activity[J].Langmuir,2017,33:3234-3240.
[33]Huang HH,Li JY,Liao LH,et al.Poly(L-glutamic acid)-based star-block copolymers as pH-responsive nanocarriers for cationic drugs[J].Eur Polym J,2012,48:696-704.
[34]Ding JX,He CL,Xiao CS,et al.pH-responsive drug delivery systems based on clickable poly(L-glutamic acid)-grafted comb copolymers[J].Macromol Res,2012,20:292-301.
[35]Liu LH,Li ZY,Rong L,et al.Self-assembly of hybridized peptide nucleic acid amphiphiles[J].ACS Macro Lett,2014,3:467-471.
[36]Itoh T,Tamamitsu T,Shimomoto H,et al.Surface structure and composition of narrowly-distributed functional polystyrene parti‐cles prepared by dispersion polymerization with poly(L-glutamic acid)macromonomer as stabilizer[J].Polymer,2015,70:183-193.
[37]Andreev OA,Karabadzhak AG,Weerakkody D,et al.pH(low)insertion peptide(pHLIP)inserts across a lipid bilayer as a helix and exits by a different path[J].Proc Natl Acad Sci U S A,2010,107:4081-4086.
[38]Reshetnyak YK,Andreev OA,Segala M,et al.Energetics of peptide(pHLIP)binding to and folding across a lipid bilayer membrane[J].Proc Natl Acad Sci U S A,2008,105:15340-15345.
[39]Deacon JC,Engelman DM,Barrera FN.Targeting acidity in diseased tissues:mechanism and applications of the membraneinserting peptide,pHLIP[J].Arch Biochem Biophys,2015,565:40-48.
[40]Musial-Siwek M,Karabadzhak A,Andreev OA,et al.Tuning the insertion properties of pHLIP[J].Biochim Biophys Acta,2010,1798:1041-1046.
[41]Burns KE,McClérey TP,Thevenin D.pH-selective cytotoxicity of pHLIP-antimicrobial peptide conjugates[J].Sci Rep,2016,6:28465.
[42]Zaro JL,Fei LK,Shen WC.Recombinant peptide constructs for targeted cell penetrating peptide-mediated delivery[J].J Control Release,2012,158:357-361.
[43]Sun CM,Shen WC,Tu JS,et al.Interaction between cell-pene‐trating peptides and acid-sensitive anionic oligopeptides as a model for the design of targeted drug carriers[J].Mol Pharm,2014,11:1583-1590.
[44]Ouahab A,Cheraga N,Onoja V,et al.Novel pH-sensitive chargereversal cell penetrating peptide conjugated PEG-PLA micelles for docetaxel delivery:in vitro study[J].Int J Pharm,2014,466:233-245.
[45]Li W,Nicol F,Szoka FC Jr.GALA:a designed synthetic pH-responsive amphipathic peptide with applications in drug and gene delivery[J].Adv Drug Deliv Rev,2004,56:967-985.
[46]Kakudo T,Chaki S,Futaki S,et al.Transferrin-modified liposomes equipped with a pH-sensitive fusogenic peptide:an artificial viral-like delivery system[J].Biochemistry,2004,43:5618-5628.
[47]Schach DK,Rock W,Franz J,et al.Reversible activation of a cell-penetrating peptide in a membrane environment[J].J Am Chem Soc,2015,137:12199-12202.
[48]Parente RA,Nir S,Szoka FC Jr.Mechanism of leakage of phospholipid vesicle contents induced by the peptide GALA[J].Biochemistry,1990,29:8720-8728.
[49]Nouri FS,Wang X,Dorrani M,et al.A recombinant biopoly‐meric platform for reliable evaluation of the activity of pH-responsive amphiphile fusogenic peptides[J].Biomacromole‐cules,2013,14:2033-2040.
[50]Yu PH,Liang J,Zhao HL,et al.Advances in peptide-modified pH-sensitive liposomes[J].Chin Pharm J(中国药学杂志),2018,53:849-853.
[2]MacEwan SR,Callahan DJ,Chilkoti A.Stimulus-responsive macromolecules and nanoparticles for cancer drug delivery[J].Nanomedicine,2010,5:793-806.
[3]Vlieghe P,Lisowski V,Martinez J,et al.Synthetic therapeutic peptides:science and market[J].Drug Discov Today,2010,15:40-56.
[4]Craik DJ,Fairlie DP,Liras S,et al.The future of peptide-based drugs[J].Chem Biol Drug Des,2013,81:136-147.
[5]Lee S,Xie J,Chen XY.Peptide-based probes for targeted molecular imaging[J].Biochemistry,2010,49:1364-1376.
[6]Li ZJ,Cho CH.Development of peptides as potential drugs for cancer therapy[J].Curr Pharm Design,2010,16:1180-1189.
[7]Estroff LA,Hamilton AD.Water gelation by small organic molecules[J].Chem Rev,2004,104:1201-1218.
[8]Zhang W,Song JJ,Zhang BZ,et al.Design of acid-activated cell penetrating peptide for delivery of active molecules into cancer cells[J].Bioconjugate Chem,2011,22:1410-1415.
[9]Shi KR,Li JP,Cao ZL,et al.A pH-responsive cell-penetrating peptide-modified liposomes with active recognizing of integrinανβ3for the treatment of melanoma[J].J Control Release,2015,217:138-150.
[10]Sun YX,Zhang XZ.Cholesteryl pH-responsive cell-penetrating peptide for co-delivery of drug and gene[J].J Control Release,2017,259:E185-E185.
[11]Guo XD,Zhang LJ,Chen Y,et al.Core/shell pH-sensitive micelles self-assembled from cholesterol conjugated oligopep‐tides for anticancer drug delivery[J].Aiche J,2010,56:1922-1931.
[12]Jiang TY,Zhang ZH,Zhang YL,et al.Dual-functional liposomes based on pH-responsive cell-penetrating peptide and hyaluronic acid for tumor-targeted anticancer drug delivery[J].Biomate‐rials,2012,33:9246-9258.
[13]Liang J,Wu WL,Xu XD,et al.pH responsive micelle selfassembled from a new amphiphilic peptide as anti-tumor drug carrier[J].Colloid Surf B,2014,114:398-403.
[14]Schneider JP,Pochan DJ,Ozbas B,et al.Responsive hydrogels from the intramolecular folding and self-assembly of a designed peptide[J].J Am Chem Soc,2002,124:15030-15037.
[15]Chang C,Liang PQ,Chen LL,et al.pH-responsive nanoparticle assembly from peptide amphiphiles for tumor targeting drug delivery[J].J Biomater Sci Polym Ed,2017,28:1338-1350.
[16]Kang YJ,Zhou XR,Luo SZ.Synthesis and characterization of a pH-responsive amphiphilic peptide hydrogel composed of pal-RLRRLRARARA[J].China Sciencepaper(中国科技论文),2012,7:437-441.
[17]Fei LK,Yap LP,Conti PS,et al.Tumor targeting of a cell pene‐trating peptide by fusing with a pH-sensitive histidine-glutamate co-oligopeptide[J].Biomaterials,2014,35:4082-4087.
[18]Haas DH,Murphy RM.Design of a pH-sensitive pore-forming peptide with improved performance[J].J Pept Res,2004,63:9-16.
[19]Wei YS,Liao RF,Mahmood AA,et al.pH-responsive pHLIP(pH low insertion peptide)nanoclusters of superparamagnetic iron oxide nanoparticles as a tumor-selective MRI contrast agent[J].Acta Biomater,2017,55:194-203.
[20]Wyatt LC,Moshnikova A,Crawford T,et al.Peptides of pHLIPfamily for targeted intracellular and extracellular delivery of cargo molecules to tumors[J].Proc Natl Acad Sci U S A,2018,115:E2811-E2818.
[21]Xu XD,Chu YF,Chen CS,et al.Facile construction of nanofibers as a functional template for surface boron coordina‐tion reaction[J].Small,2011,7:2201-2209.
[22]Tian L,Bae YH.Cancer nanomedicines targeting tumor extra‐cellular pH[J].Colloid Surf B,2012,99:116-126.
[23]Toriyabe N,Hayashi Y,Harashima H.The transfection activity of R8-modified nanoparticles and siRNA condensation using pH sensitive stearylated-octahistidine[J].Biomaterials,2013,34:1337-1343.
[24]Wu H,Zhu L,Torchilin VP.pH-sensitive poly(histidine)-PEG/DSPE-PEG co-polymer micelles for cytosolic drug delivery[J].Biomaterials,2013,34:1213-1222.
[25]Midoux P,Pichon C,Yaouanc JJ,et al.Chemical vectors for gene delivery:a current review on polymers,peptides and lipids containing histidine or imidazole as nucleic acids carriers[J].Br J Pharmacol,2009,157:166-178.
[26]Zhao BX,Zhao Y,Huang Y,et al.The efficiency of tumorspecific pH-responsive peptide-modified polymeric micelles containing paclitaxel[J].Biomaterials,2012,33:2508-2520.
[27]Zhang QY,Tang J,Fu L,et al.A pH-responsive alpha-helical cell penetrating peptide-mediated liposomal delivery system[J].Biomaterials,2013,34:7980-7993.
[28]Singh RS,Goncalves C,Sandrin P,et al.On the gene delivery efficacies of pH-sensitive cationic lipids via endosomal proton‐ation:a chemical biology investigation[J].Chem Biol,2004,11:713-723.
[29]Moreira C,Oliveira H,Pires LR,et al.Improving chitosan-medi‐ated gene transfer by the introduction of intracellular buffering moieties into the chitosan backbone[J].Acta Biomater,2009,5:2995-3006.
[30]Ma YY,Li L,Huang HF,et al.Advances of tumor targeting peptides drug delivery system with pH-sensitive activities[J].Acta Pharm Sin(药学学报),2016,51:717-724.
[31]Dehsorkhi A,Castelletto V,Hamley IW,et al.The effect of pHon the self-assembly of a collagen derived peptide amphiphile[J].Soft Matter,2013,9:6033-6036.
[32]Wan YM,Liu LB,Yuan SS,et al.pH-responsive peptide supra‐molecular hydrogels with antibacterial activity[J].Langmuir,2017,33:3234-3240.
[33]Huang HH,Li JY,Liao LH,et al.Poly(L-glutamic acid)-based star-block copolymers as pH-responsive nanocarriers for cationic drugs[J].Eur Polym J,2012,48:696-704.
[34]Ding JX,He CL,Xiao CS,et al.pH-responsive drug delivery systems based on clickable poly(L-glutamic acid)-grafted comb copolymers[J].Macromol Res,2012,20:292-301.
[35]Liu LH,Li ZY,Rong L,et al.Self-assembly of hybridized peptide nucleic acid amphiphiles[J].ACS Macro Lett,2014,3:467-471.
[36]Itoh T,Tamamitsu T,Shimomoto H,et al.Surface structure and composition of narrowly-distributed functional polystyrene parti‐cles prepared by dispersion polymerization with poly(L-glutamic acid)macromonomer as stabilizer[J].Polymer,2015,70:183-193.
[37]Andreev OA,Karabadzhak AG,Weerakkody D,et al.pH(low)insertion peptide(pHLIP)inserts across a lipid bilayer as a helix and exits by a different path[J].Proc Natl Acad Sci U S A,2010,107:4081-4086.
[38]Reshetnyak YK,Andreev OA,Segala M,et al.Energetics of peptide(pHLIP)binding to and folding across a lipid bilayer membrane[J].Proc Natl Acad Sci U S A,2008,105:15340-15345.
[39]Deacon JC,Engelman DM,Barrera FN.Targeting acidity in diseased tissues:mechanism and applications of the membraneinserting peptide,pHLIP[J].Arch Biochem Biophys,2015,565:40-48.
[40]Musial-Siwek M,Karabadzhak A,Andreev OA,et al.Tuning the insertion properties of pHLIP[J].Biochim Biophys Acta,2010,1798:1041-1046.
[41]Burns KE,McClérey TP,Thevenin D.pH-selective cytotoxicity of pHLIP-antimicrobial peptide conjugates[J].Sci Rep,2016,6:28465.
[42]Zaro JL,Fei LK,Shen WC.Recombinant peptide constructs for targeted cell penetrating peptide-mediated delivery[J].J Control Release,2012,158:357-361.
[43]Sun CM,Shen WC,Tu JS,et al.Interaction between cell-pene‐trating peptides and acid-sensitive anionic oligopeptides as a model for the design of targeted drug carriers[J].Mol Pharm,2014,11:1583-1590.
[44]Ouahab A,Cheraga N,Onoja V,et al.Novel pH-sensitive chargereversal cell penetrating peptide conjugated PEG-PLA micelles for docetaxel delivery:in vitro study[J].Int J Pharm,2014,466:233-245.
[45]Li W,Nicol F,Szoka FC Jr.GALA:a designed synthetic pH-responsive amphipathic peptide with applications in drug and gene delivery[J].Adv Drug Deliv Rev,2004,56:967-985.
[46]Kakudo T,Chaki S,Futaki S,et al.Transferrin-modified liposomes equipped with a pH-sensitive fusogenic peptide:an artificial viral-like delivery system[J].Biochemistry,2004,43:5618-5628.
[47]Schach DK,Rock W,Franz J,et al.Reversible activation of a cell-penetrating peptide in a membrane environment[J].J Am Chem Soc,2015,137:12199-12202.
[48]Parente RA,Nir S,Szoka FC Jr.Mechanism of leakage of phospholipid vesicle contents induced by the peptide GALA[J].Biochemistry,1990,29:8720-8728.
[49]Nouri FS,Wang X,Dorrani M,et al.A recombinant biopoly‐meric platform for reliable evaluation of the activity of pH-responsive amphiphile fusogenic peptides[J].Biomacromole‐cules,2013,14:2033-2040.
[50]Yu PH,Liang J,Zhao HL,et al.Advances in peptide-modified pH-sensitive liposomes[J].Chin Pharm J(中国药学杂志),2018,53:849-853.