Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy
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摘要
Hyaluronic acid(HA) is a natural ligand of tumor-targeted drug delivery systems(DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors(HARE and LYVE-1) are also overexpressing in the reticuloendothelial system(RES). Therefore,polyethylene glycol(PEG) modification of HA-based DDS is necessary to reduce RES capture.Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement,significantly compromising the in vivo antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform(Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage.The in vitro and in vivo investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and in vivo nonspecific biodistribution.
Hyaluronic acid(HA) is a natural ligand of tumor-targeted drug delivery systems(DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors(HARE and LYVE-1) are also overexpressing in the reticuloendothelial system(RES). Therefore,polyethylene glycol(PEG) modification of HA-based DDS is necessary to reduce RES capture.Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement,significantly compromising the in vivo antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform(Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage.The in vitro and in vivo investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and in vivo nonspecific biodistribution.
Hyaluronic acid(HA) is a natural ligand of tumor-targeted drug delivery systems(DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors(HARE and LYVE-1) are also overexpressing in the reticuloendothelial system(RES). Therefore,polyethylene glycol(PEG) modification of HA-based DDS is necessary to reduce RES capture.Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement,significantly compromising the in vivo antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform(Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage.The in vitro and in vivo investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and in vivo nonspecific biodistribution.
引文
1.Dosio F,Arpicco S,Stella B,Fattal E.Hyaluronic acid for anticancer drug and nucleic acid delivery.Adv Drug Deliv Rev 2016;97:204-36.
2.Jiang BP,Zhang L,Guo XL,Shen XC,Wang Y,Zhu Y,et al.Poly(N-phenylglycine)-based nanoparticles as highly effective and targeted near-infrared photothermal therapy/photodynamic therapeutic agents for malignant melanoma.Small 2017;13:1602496.
3.Zhou Y,Quan G,Wu Q,Zhang X,Niu B,Wu B,et al.Mesoporous silica nanoparticles for drug and gene delivery.Acta Pharm Sin B2018;8:165-77.
4.Platt VM,Szoka Jr.FC.Anticancer therapeutics:targeting macromolecules and nanocarriers to hyaluronan or CD44,a hyaluronan receptor.Mol Pharm 2008;5:474-86.
5.Choi KY,Chung H,Min KH,Yoon HY,Kim K,Park JH,et al.Selfassembled hyaluronic acid nanoparticles for active tumor targeting.Biomaterials 2010;31:106-14.
6.Wang M,Li J,Li X,Mu H,Zhang X,Shi Y,et al.Magnetically and p Hdual responsive dendrosomes for tumor accumulation enhanced folatetargeted hybrid drug delivery.J Control Release 2016;232:161-74.
7.Battogtokh G,Ko YT.Graphene oxide-incorporated pH-responsive folate-albumin-photosensitizer nanocomplex as image-guided dual therapeutics.J Control Release 2016;234:10-20.
8.Leamon CP,Low PS.Folate-mediated targeting:from diagnostics to drug and gene delivery.Drug Discov Today 2001;6:44-51.
9.Daniels TR,Bernabeu E,Rodríguez JA,Patel S,Kozman M,Chiappetta DA,et al.The transferrin receptor and the targeted delivery of therapeutic agents against cancer.BBA-Gen Subj 2012;1820:291-317.
10.Han X,Li Z,Sun J,Luo C,Li L,Liu Y,et al.Stealth CD44-targeted hyaluronic acid supramolecular nanoassemblies for doxorubicin delivery:probing the effect of uncovalent pegylation degree on cellular uptake and blood long circulation.J Control Release 2015;197:29-40.
11.Chi Y,Yin X,Sun K,Feng S,Liu J,Chen D,et al.Redox-sensitive and hyaluronic acid functionalized liposomes for cytoplasmic drug delivery to osteosarcoma in animal models.J Control Release 2017;261:113-25.
12.Choi KY,Min KH,Yoon HY,Kim K,Park JH,Kwon IC,et al.PEGylation of hyaluronic acid nanoparticles improves tumor targetability in vivo.Biomaterials 2011;32:1880-9.
13.Ran R,Liu Y,Gao H,Kuang Q,Zhang Q,Tang J,et al.Enhanced gene delivery efficiency of cationic liposomes coated with PEGylated hyaluronic acid for anti P-glycoprotein siRNA:a potential candidate for overcoming multi-drug resistance.Int J Pharm 2014;477:590-600.
14.Yoon HY,Koo H,Choi KY,Lee SJ,Kim K,Kwon IC,et al.Tumortargeting hyaluronic acid nanoparticles for photodynamic imaging and therapy.Biomaterials 2012;33:3980-9.
15.Qhattal HS,Hye T,Alali A,Liu X.Hyaluronan polymer length,grafting density,and surface poly(ethylene glycol)coating influence in vivo circulation and tumor targeting of hyaluronan-grafted liposomes.ACS Nano 2014;8:5423-40.
16.Ju Y,Cui J,Sun H,Müllner M,Dai Y,Guo J,et al.Engineered metalphenolic capsules show tunable targeted delivery to cancer cells.Biomacromolecules 2016;17:2268-76.
17.Mishra P,Nayak B,Dey RK.PEGylation in anti-cancer therapy:an overview.Asian J Pharm Sci 2016;11:337-48.
18.Tu Y,Zhu L.Enhancing cancer targeting and anticancer activity by a stimulus-sensitive multifunctional polymer-drug conjugate.J Control Release 2015;212:94-102.
19.Wang T,Wang D,Liu J,Feng B,Zhou F,Zhang H,et al.Aciditytriggered ligand-presenting nanoparticles to overcome sequential drug delivery barriers to tumors.Nano Lett 2017;17:5429-36.
20.Lv Y,Xu C,Zhao X,Lin C,Yang X,Xin X,et al.Nanoplatform assembled from a CD44-targeted prodrug and smart liposomes for dual targeting of tumor microenvironment and cancer cells.ACS Nano2018;12:1519-36.
21.Liu Y,Wang W,Yang J,Zhou C,Sun J.pH-Sensitive polymeric micelles triggered drug release for extracellular and intracellular drug targeting delivery.Asian J Pharm Sci 2013;8:159-67.
22.Li R,He Y,Zhang S,Qin J,Wang J.Cell membrane-based nanoparticles:a new biomimetic platform for tumor diagnosis and treatment.Acta Pharm Sin B 2018;8:14-22.
23.Li HJ,Du JZ,Liu J,Du XJ,Shen S,Zhu YH,et al.Smart superstructures with ultrahigh pH-sensitivity for targeting acidic tumor microenvironment:instantaneous size switching and improved tumor penetration.ACS Nano 2016;10:6753-61.
24.Zhang M,Liu J,Kuang Y,Li Q,Chen H,Ye H,et al."Stealthy''chitosan/mesoporous silica nanoparticle based complex system for tumor-triggered intracellular drug release.J Mater Chem B2016;4:3387-97.
25.Zeng X,Liu G,Tao W,Ma Y,Zhang X,He F,et al.A drug-self-gated mesoporous antitumor nanoplatform based on p H-sensitive dynamic covalent bond.Adv Funct Mater 2017;27:1605985.
26.Zhao C,Deng H,Xu J,Li S,Zhong L,Shao L,et al."Sheddable"PEG-lipid to balance the contradiction of PEGylation between long circulation and poor uptake.Nanoscale 2016;8:10832-42.
27.Yang Y,Xu L,Zhu W,Feng L,Liu J,Chen Q,et al.One-pot synthesis of p H-responsive charge-switchable PEGylated nanoscale coordination polymers for improved cancer therapy.Biomaterials2018;156:121-33.
28.Chen X,Liu L,Jiang C.Charge-reversal nanoparticles:novel targeted drug delivery carriers.Acta Pharm Sin B 2016;6:261-7.
29.Zhang W,Cheng Q,Guo S,Lin D,Huang P,Liu J,et al.Gene transfection efficacy and biocompatibility of polycation/DNA complexes coated with enzyme degradable PEGylated hyaluronic acid.Biomaterials 2013;34:6495-503.
30.Shin JM,Oh SJ,Kwon S,Deepagan VG,Lee M,Song SH,et al.APEGylated hyaluronic acid conjugate for targeted cancer immunotherapy.J Control Release 2017;267:181-90.
31.Li D,Ma Y,Du J,Tao W,Du X,Yang X,et al.Tumor acidity/NIRcontrolled interaction of transformable nanoparticle with biological systems for cancer therapy.Nano Lett 2017;17:2871-8.
32.Zhu L,Wang T,Perche F,Taigind A,Torchilin VP.Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety.Proc Natl Acad Sci U S A 2013;110:17047-52.
33.Romberg B,Hennink WE,Storm G.Sheddable coatings for longcirculating nanoparticles.Pharm Res 2008;25:55-71.
34.Fay F,Hansen L,Hectors SJ,Sanchez-Gaytan BL,Zhao Y,Tang J,et al.Investigating the cellular specificity in tumors of a surfaceconverting nanoparticle by multimodal imaging.Bioconjug Chem2017;28:1413-21.
35.Yang XZ,Du JZ,Dou S,Mao CQ,Long HY,Wang J.Sheddable ternary nanoparticles for tumor acidity-targeted siRNA delivery.ACSNano 2012;6:771-81.
36.Fan Y,Li C,Li F,Chen D.p H-activated size reduction of large compound nanoparticles for in vivo nucleus-targeted drug delivery.Biomaterials 2016;85:30-9.
37.Zhao J,Liu J,Xu S,Zhou J,Han S,Deng L,et al.Graft copolymer nanoparticles with pH and reduction dual-induced disassemblable property for enhanced intracellular curcumin release.ACS Appl Mater Interfaces 2013;5:13216-26.
38.Guan X,Guo Z,Wang T,Lin L,Chen J,Tian H,et al.A pH-responsive detachable PEG shielding strategy for gene delivery system in cancer therapy.Biomacromolecules 2017;18:1342-9.
39.Vander Heiden MG,Cantley LC,Thompson CB.Understanding the Warburg effect:the metabolic requirements of cell proliferation.Science 2009;324:1029-33.
40.Lyssiotis CA,Kimmelman AC.Metabolic interactions in the tumor microenvironment.Trends Cell Biol 2017;27:863-75.
41.Yamagata M,Hasuda K,Stamato T,Tannock IF.The contribution of lactic acid to acidification of tumours:studies of variant cells lacking lactate dehydrogenase.Br J Cancer 1998;77:1726-31.
42.Qiu L,Zhu M,Gong K,Peng H,Ge L,Zhao L,et al.p H-Triggered degradable polymeric micelles for targeted anti-tumor drug delivery.Mat Sci Eng C:Mater Biol Appl 2017;78:912-22.
43.Guo X,Wang L,Duval K,Fan J,Zhou S,Chen Z.Dimeric drug polymeric micelles with acid-active tumor targeting and FRET-traceable drug release.Adv Mater 2018;30 Available from:?https://doi.org/10.1002/adma.201705436?.
44.Wei J,Shuai X,Wang R,He X,Li Y,Ding M,et al.Clickable and imageable multiblock polymer micelles with magnetically guided and PEG-switched targeting and release property for precise tumor theranosis.Biomaterials 2017;145:138-53.
45.Zhang J,Zheng Y,Xie X,Wang L,Su Z,Wang Y,et al.Cleavable multifunctional targeting mixed micelles with sequential pH-triggered TAT peptide activation for improved antihepatocellular carcinoma efficacy.Mol Pharm 2017;14:3644-59.
46.Gu J,Cheng WP,Liu J,Lo SY,Smith D,Qu X,et al.pH-Triggered reversible"stealth"polycationic micelles.Biomacromolecules2008;9:255-62.
47.Ding C,Gu J,Qu X,Yang Z.Preparation of multifunctional drug carrier for tumor-specific uptake and enhanced intracellular delivery through the conjugation of weak acid labile linker.Bioconjug Chem2009;20:1163-70.
48.Yang Z,Sun N,Cheng R,Zhao C,Liu Z,Li X,et al.pH multistage responsive micellar system with charge-switch and PEG layer detachment for co-delivery of paclitaxel and curcumin to synergistically eliminate breast cancer stem cells.Biomaterials 2017;147:53-67.
49.Li Y,Song L,Lin J,Ma J,Pan Z,Zhang Y,et al.Programmed nanococktail based on p H-responsive function switch for selfsynergistic tumor-targeting therapy.ACS Appl Mater Interfaces2017;9:39127-42.
50.Zhao G,Long L,Zhang L,Peng M,Cui T,Wen X,et al.Smart pH-sensitive nanoassemblies with cleavable PEGylation for tumor targeted drug delivery.Sci Rep 2017;7:3383.
51.Cheng W,Liang C,Wang X,Tsai HI,Liu G,Peng Y,et al.A drugself-gated and tumor microenvironment-responsive mesoporous silica vehicle:"four-in-one"versatile nanomedicine for targeted multidrugresistant cancer therapy.Nanoscale 2017;9:17063-73.
52.Fitzgerald KA,Malhotra M,Gooding M,Sallas F,Evans JC,Darcy R,et al.A novel,anisamide-targeted cyclodextrin nanoformulation for siRNA delivery to prostate cancer cells expressing the sigma-1receptor.Int J Pharm 2016;499:131-45.
53.Song X,Zhu JL,Wen Y,Zhao F,Zhang ZX,Li J.Thermoresponsive supramolecular micellar drug delivery system based on star-linear pseudo-block polymer consisting ofβ-cyclodextrin-poly(N-isopropylacrylamide)and adamantyl-poly(ethylene glycol).J Colloid Interface Sci 2017;490:372-9.
54.Song N,Ding M,Pan Z,Li J,Zhou L,Tan H,et al.Construction of targeting-clickable and tumor-cleavable polyurethane nanomicelles for multifunctional intracellular drug delivery.Biomacromolecules2013;14:4407-19.
55.Mo R,Sun Q,Xue J,Li N,Li W,Zhang C,et al.Multistage p H-responsive liposomes for mitochondrial-targeted anticancer drug delivery.Adv Mater 2012;24:3659-65.
56.Qhattal HS,Liu X.Characterization of CD44-mediated cancer cell uptake and intracellular distribution of hyaluronan-grafted liposomes.Mol Pharm 2011;8:1233-46.
2.Jiang BP,Zhang L,Guo XL,Shen XC,Wang Y,Zhu Y,et al.Poly(N-phenylglycine)-based nanoparticles as highly effective and targeted near-infrared photothermal therapy/photodynamic therapeutic agents for malignant melanoma.Small 2017;13:1602496.
3.Zhou Y,Quan G,Wu Q,Zhang X,Niu B,Wu B,et al.Mesoporous silica nanoparticles for drug and gene delivery.Acta Pharm Sin B2018;8:165-77.
4.Platt VM,Szoka Jr.FC.Anticancer therapeutics:targeting macromolecules and nanocarriers to hyaluronan or CD44,a hyaluronan receptor.Mol Pharm 2008;5:474-86.
5.Choi KY,Chung H,Min KH,Yoon HY,Kim K,Park JH,et al.Selfassembled hyaluronic acid nanoparticles for active tumor targeting.Biomaterials 2010;31:106-14.
6.Wang M,Li J,Li X,Mu H,Zhang X,Shi Y,et al.Magnetically and p Hdual responsive dendrosomes for tumor accumulation enhanced folatetargeted hybrid drug delivery.J Control Release 2016;232:161-74.
7.Battogtokh G,Ko YT.Graphene oxide-incorporated pH-responsive folate-albumin-photosensitizer nanocomplex as image-guided dual therapeutics.J Control Release 2016;234:10-20.
8.Leamon CP,Low PS.Folate-mediated targeting:from diagnostics to drug and gene delivery.Drug Discov Today 2001;6:44-51.
9.Daniels TR,Bernabeu E,Rodríguez JA,Patel S,Kozman M,Chiappetta DA,et al.The transferrin receptor and the targeted delivery of therapeutic agents against cancer.BBA-Gen Subj 2012;1820:291-317.
10.Han X,Li Z,Sun J,Luo C,Li L,Liu Y,et al.Stealth CD44-targeted hyaluronic acid supramolecular nanoassemblies for doxorubicin delivery:probing the effect of uncovalent pegylation degree on cellular uptake and blood long circulation.J Control Release 2015;197:29-40.
11.Chi Y,Yin X,Sun K,Feng S,Liu J,Chen D,et al.Redox-sensitive and hyaluronic acid functionalized liposomes for cytoplasmic drug delivery to osteosarcoma in animal models.J Control Release 2017;261:113-25.
12.Choi KY,Min KH,Yoon HY,Kim K,Park JH,Kwon IC,et al.PEGylation of hyaluronic acid nanoparticles improves tumor targetability in vivo.Biomaterials 2011;32:1880-9.
13.Ran R,Liu Y,Gao H,Kuang Q,Zhang Q,Tang J,et al.Enhanced gene delivery efficiency of cationic liposomes coated with PEGylated hyaluronic acid for anti P-glycoprotein siRNA:a potential candidate for overcoming multi-drug resistance.Int J Pharm 2014;477:590-600.
14.Yoon HY,Koo H,Choi KY,Lee SJ,Kim K,Kwon IC,et al.Tumortargeting hyaluronic acid nanoparticles for photodynamic imaging and therapy.Biomaterials 2012;33:3980-9.
15.Qhattal HS,Hye T,Alali A,Liu X.Hyaluronan polymer length,grafting density,and surface poly(ethylene glycol)coating influence in vivo circulation and tumor targeting of hyaluronan-grafted liposomes.ACS Nano 2014;8:5423-40.
16.Ju Y,Cui J,Sun H,Müllner M,Dai Y,Guo J,et al.Engineered metalphenolic capsules show tunable targeted delivery to cancer cells.Biomacromolecules 2016;17:2268-76.
17.Mishra P,Nayak B,Dey RK.PEGylation in anti-cancer therapy:an overview.Asian J Pharm Sci 2016;11:337-48.
18.Tu Y,Zhu L.Enhancing cancer targeting and anticancer activity by a stimulus-sensitive multifunctional polymer-drug conjugate.J Control Release 2015;212:94-102.
19.Wang T,Wang D,Liu J,Feng B,Zhou F,Zhang H,et al.Aciditytriggered ligand-presenting nanoparticles to overcome sequential drug delivery barriers to tumors.Nano Lett 2017;17:5429-36.
20.Lv Y,Xu C,Zhao X,Lin C,Yang X,Xin X,et al.Nanoplatform assembled from a CD44-targeted prodrug and smart liposomes for dual targeting of tumor microenvironment and cancer cells.ACS Nano2018;12:1519-36.
21.Liu Y,Wang W,Yang J,Zhou C,Sun J.pH-Sensitive polymeric micelles triggered drug release for extracellular and intracellular drug targeting delivery.Asian J Pharm Sci 2013;8:159-67.
22.Li R,He Y,Zhang S,Qin J,Wang J.Cell membrane-based nanoparticles:a new biomimetic platform for tumor diagnosis and treatment.Acta Pharm Sin B 2018;8:14-22.
23.Li HJ,Du JZ,Liu J,Du XJ,Shen S,Zhu YH,et al.Smart superstructures with ultrahigh pH-sensitivity for targeting acidic tumor microenvironment:instantaneous size switching and improved tumor penetration.ACS Nano 2016;10:6753-61.
24.Zhang M,Liu J,Kuang Y,Li Q,Chen H,Ye H,et al."Stealthy''chitosan/mesoporous silica nanoparticle based complex system for tumor-triggered intracellular drug release.J Mater Chem B2016;4:3387-97.
25.Zeng X,Liu G,Tao W,Ma Y,Zhang X,He F,et al.A drug-self-gated mesoporous antitumor nanoplatform based on p H-sensitive dynamic covalent bond.Adv Funct Mater 2017;27:1605985.
26.Zhao C,Deng H,Xu J,Li S,Zhong L,Shao L,et al."Sheddable"PEG-lipid to balance the contradiction of PEGylation between long circulation and poor uptake.Nanoscale 2016;8:10832-42.
27.Yang Y,Xu L,Zhu W,Feng L,Liu J,Chen Q,et al.One-pot synthesis of p H-responsive charge-switchable PEGylated nanoscale coordination polymers for improved cancer therapy.Biomaterials2018;156:121-33.
28.Chen X,Liu L,Jiang C.Charge-reversal nanoparticles:novel targeted drug delivery carriers.Acta Pharm Sin B 2016;6:261-7.
29.Zhang W,Cheng Q,Guo S,Lin D,Huang P,Liu J,et al.Gene transfection efficacy and biocompatibility of polycation/DNA complexes coated with enzyme degradable PEGylated hyaluronic acid.Biomaterials 2013;34:6495-503.
30.Shin JM,Oh SJ,Kwon S,Deepagan VG,Lee M,Song SH,et al.APEGylated hyaluronic acid conjugate for targeted cancer immunotherapy.J Control Release 2017;267:181-90.
31.Li D,Ma Y,Du J,Tao W,Du X,Yang X,et al.Tumor acidity/NIRcontrolled interaction of transformable nanoparticle with biological systems for cancer therapy.Nano Lett 2017;17:2871-8.
32.Zhu L,Wang T,Perche F,Taigind A,Torchilin VP.Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety.Proc Natl Acad Sci U S A 2013;110:17047-52.
33.Romberg B,Hennink WE,Storm G.Sheddable coatings for longcirculating nanoparticles.Pharm Res 2008;25:55-71.
34.Fay F,Hansen L,Hectors SJ,Sanchez-Gaytan BL,Zhao Y,Tang J,et al.Investigating the cellular specificity in tumors of a surfaceconverting nanoparticle by multimodal imaging.Bioconjug Chem2017;28:1413-21.
35.Yang XZ,Du JZ,Dou S,Mao CQ,Long HY,Wang J.Sheddable ternary nanoparticles for tumor acidity-targeted siRNA delivery.ACSNano 2012;6:771-81.
36.Fan Y,Li C,Li F,Chen D.p H-activated size reduction of large compound nanoparticles for in vivo nucleus-targeted drug delivery.Biomaterials 2016;85:30-9.
37.Zhao J,Liu J,Xu S,Zhou J,Han S,Deng L,et al.Graft copolymer nanoparticles with pH and reduction dual-induced disassemblable property for enhanced intracellular curcumin release.ACS Appl Mater Interfaces 2013;5:13216-26.
38.Guan X,Guo Z,Wang T,Lin L,Chen J,Tian H,et al.A pH-responsive detachable PEG shielding strategy for gene delivery system in cancer therapy.Biomacromolecules 2017;18:1342-9.
39.Vander Heiden MG,Cantley LC,Thompson CB.Understanding the Warburg effect:the metabolic requirements of cell proliferation.Science 2009;324:1029-33.
40.Lyssiotis CA,Kimmelman AC.Metabolic interactions in the tumor microenvironment.Trends Cell Biol 2017;27:863-75.
41.Yamagata M,Hasuda K,Stamato T,Tannock IF.The contribution of lactic acid to acidification of tumours:studies of variant cells lacking lactate dehydrogenase.Br J Cancer 1998;77:1726-31.
42.Qiu L,Zhu M,Gong K,Peng H,Ge L,Zhao L,et al.p H-Triggered degradable polymeric micelles for targeted anti-tumor drug delivery.Mat Sci Eng C:Mater Biol Appl 2017;78:912-22.
43.Guo X,Wang L,Duval K,Fan J,Zhou S,Chen Z.Dimeric drug polymeric micelles with acid-active tumor targeting and FRET-traceable drug release.Adv Mater 2018;30 Available from:?https://doi.org/10.1002/adma.201705436?.
44.Wei J,Shuai X,Wang R,He X,Li Y,Ding M,et al.Clickable and imageable multiblock polymer micelles with magnetically guided and PEG-switched targeting and release property for precise tumor theranosis.Biomaterials 2017;145:138-53.
45.Zhang J,Zheng Y,Xie X,Wang L,Su Z,Wang Y,et al.Cleavable multifunctional targeting mixed micelles with sequential pH-triggered TAT peptide activation for improved antihepatocellular carcinoma efficacy.Mol Pharm 2017;14:3644-59.
46.Gu J,Cheng WP,Liu J,Lo SY,Smith D,Qu X,et al.pH-Triggered reversible"stealth"polycationic micelles.Biomacromolecules2008;9:255-62.
47.Ding C,Gu J,Qu X,Yang Z.Preparation of multifunctional drug carrier for tumor-specific uptake and enhanced intracellular delivery through the conjugation of weak acid labile linker.Bioconjug Chem2009;20:1163-70.
48.Yang Z,Sun N,Cheng R,Zhao C,Liu Z,Li X,et al.pH multistage responsive micellar system with charge-switch and PEG layer detachment for co-delivery of paclitaxel and curcumin to synergistically eliminate breast cancer stem cells.Biomaterials 2017;147:53-67.
49.Li Y,Song L,Lin J,Ma J,Pan Z,Zhang Y,et al.Programmed nanococktail based on p H-responsive function switch for selfsynergistic tumor-targeting therapy.ACS Appl Mater Interfaces2017;9:39127-42.
50.Zhao G,Long L,Zhang L,Peng M,Cui T,Wen X,et al.Smart pH-sensitive nanoassemblies with cleavable PEGylation for tumor targeted drug delivery.Sci Rep 2017;7:3383.
51.Cheng W,Liang C,Wang X,Tsai HI,Liu G,Peng Y,et al.A drugself-gated and tumor microenvironment-responsive mesoporous silica vehicle:"four-in-one"versatile nanomedicine for targeted multidrugresistant cancer therapy.Nanoscale 2017;9:17063-73.
52.Fitzgerald KA,Malhotra M,Gooding M,Sallas F,Evans JC,Darcy R,et al.A novel,anisamide-targeted cyclodextrin nanoformulation for siRNA delivery to prostate cancer cells expressing the sigma-1receptor.Int J Pharm 2016;499:131-45.
53.Song X,Zhu JL,Wen Y,Zhao F,Zhang ZX,Li J.Thermoresponsive supramolecular micellar drug delivery system based on star-linear pseudo-block polymer consisting ofβ-cyclodextrin-poly(N-isopropylacrylamide)and adamantyl-poly(ethylene glycol).J Colloid Interface Sci 2017;490:372-9.
54.Song N,Ding M,Pan Z,Li J,Zhou L,Tan H,et al.Construction of targeting-clickable and tumor-cleavable polyurethane nanomicelles for multifunctional intracellular drug delivery.Biomacromolecules2013;14:4407-19.
55.Mo R,Sun Q,Xue J,Li N,Li W,Zhang C,et al.Multistage p H-responsive liposomes for mitochondrial-targeted anticancer drug delivery.Adv Mater 2012;24:3659-65.
56.Qhattal HS,Liu X.Characterization of CD44-mediated cancer cell uptake and intracellular distribution of hyaluronan-grafted liposomes.Mol Pharm 2011;8:1233-46.