Dual-targeting and microenvironment-responsive micelles as a gene delivery system to improve the sensitivity of glioma to radiotherapy
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摘要
Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy(RT). However, there is no effective drug delivery system to effectively overcome the blood–brain barrier(BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles(ch-Kn(s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1(LRP1) that is overexpressed on brain capillary endothelial cells(BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2(MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-Kn(s-s)R8-An micelles maintained a reasonable size(80–160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration(CMC) with positive surface charge, ranging from 15 to40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency in vitro, improved uptake in glioma cells and good biocompatibility in vitro and in vivo. In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells in vitro. Thus, ch-K5(s-s)R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells.
Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy(RT). However, there is no effective drug delivery system to effectively overcome the blood–brain barrier(BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles(ch-Kn(s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1(LRP1) that is overexpressed on brain capillary endothelial cells(BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2(MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-Kn(s-s)R8-An micelles maintained a reasonable size(80–160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration(CMC) with positive surface charge, ranging from 15 to40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency in vitro, improved uptake in glioma cells and good biocompatibility in vitro and in vivo. In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells in vitro. Thus, ch-K5(s-s)R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells.
Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy(RT). However, there is no effective drug delivery system to effectively overcome the blood–brain barrier(BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles(ch-Kn(s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1(LRP1) that is overexpressed on brain capillary endothelial cells(BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2(MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-Kn(s-s)R8-An micelles maintained a reasonable size(80–160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration(CMC) with positive surface charge, ranging from 15 to40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency in vitro, improved uptake in glioma cells and good biocompatibility in vitro and in vivo. In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells in vitro. Thus, ch-K5(s-s)R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells.
引文
1.Alifieris C,Trafalis DT.Glioblastoma multiforme:pathogenesis and treatment.Pharmacol Ther 2015;152:63-82.
2.Zhang M,Lu W.Enhanced glioma-targeting and stability ofLGICPpeptide coupled with stabilized peptideDA7R.Acta Pharm Sin B2018;8:106-15.
3.Donahue MJ,Blakeley JO,Zhou J,Pomper MG,Laterra J,van Zijl PC.Evaluation of human brain tumor heterogeneity using multiple T1-based MRI signal weighting approaches.Magn Reson Med2008;59:336-44.
4.Dutreix M,Cosset JM,Sun JS.Molecular therapy in support to radiotherapy.Mutat Res 2010;704:182-9.
5.Saad S,Wang TJ.Neurocognitive deficits after radiation therapy for brain malignancies.Am J Clin Oncol 2015;38:634-40.
6.Zhao X,Chen R,Liu M,Feng J,Chen J,Hu K.Remodeling the blood-brain barrier microenvironment by natural products for brain tumor therapy.Acta Pharm Sin B 2017;7:541-53.
7.Li J,Guo Y,Kuang Y,An S,Ma H,Jiang C.Choline transportertargeting and co-delivery system for glioma therapy.Biomaterials2013;34:9142-8.
8.Biau J,Devun F,Verrelle P,Dutreix M.Dbait:an innovative concept to inhibit DNA repair and treat cancer.Bull Cancer 2016;103:227-35.
9.Coquery N,Pannetier N,Farion R,Herbette A,Azurmendi L,Clarencon D,et al.Distribution and radiosensitizing effect of cholesterol-coupled Dbait molecule in rat model of glioblastoma.PLoS One 2012;7:e40567.
10.Devun F,Biau J,Huerre M,Croset A,Sun JS,Denys A,et al.Colorectal cancer metastasis:the DNA repair inhibitor Dbait increases sensitivity to hyperthermia and improves efficacy of radiofrequency ablation.Radiology 2014;270:736-46.
11.Quanz M,Berthault N,Roulin C,Roy M,Herbette A,Agrario C,et al.Small-molecule drugs mimicking DNA damage:a new strategy for sensitizing tumors to radiotherapy.Clin Cancer Res 2009;15:1308-16.
12.Biau J,Devun F,Jdey W,Kotula E,Quanz M,Chautard E,et al.Apreclinical study combining the DNA repair inhibitor Dbait with radiotherapy for the treatment of melanoma.Neoplasia 2014;16:835-44.
13 Liu H,Cai Y,Zhang Y,Xie Y,Qiu H,Hua L,et al.Development of a hypoxic radiosensitizer-prodrug liposome delivery DNA repair inhibitor dbait combination with radiotherapy for glioma therapy.Adv Healthc Mater 2017 Available from:?https://doi.org/10.1002/adhm.201601377?.
14.Visser CC,Voorwinden LH,Crommelin DJ,Danhof M,de Boer AG.Characterization and modulation of the transferrin receptor on brain capillary endothelial cells.Pharm Res 2004;21:761-9.
15.Liu C,Liu XN,Wang GL,Hei Y,Meng S,Yang LF,et al.A dualmediated liposomal drug delivery system targeting the brain:rational construction,integrity evaluation across the blood-brain barrier,and the transporting mechanism to glioma cells.Int J Nanomed2017;12:2407-25.
16.Demeule M,Currie JC,Bertrand Y,ChéC,Nguyen T,Régina A,et al.Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2.J Neurochem2008;106:1534-44.
17.Huang S,Li J,Han L,Liu S,Ma H,Huang R,et al.Dual targeting effect of angiopep-2-modified,DNA-loaded nanoparticles for glioma.Biomaterials 2011;32:6832-8.
18.Ruan S,Yuan M,Zhang L,Hu G,Chen J,Cun X,et al.Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles.Biomaterials2015;37:425-35.
19.Kang L,Gao Z,Huang W,Jin M,Wang Q.Nanocarrier-mediated codelivery of chemotherapeutic drugs and gene agents for cancer treatment.Acta Pharm Sin B 2015;5:169-75.
20.Huang WC,Chen SH,Chiang WH,Huang CW,Lo CL,Chern CS,et al.Tumor microenvironment-responsive nanoparticle delivery of chemotherapy for enhanced selective cellular uptake and transportation within tumor.Biomacromolecules 2016;17:3883-92.
21.Liu Y,Zhang D,Qiao ZY,Qi GB,Liang XJ,Chen XG,et al.Apeptide-network weaved nanoplatform with tumor microenvironment responsiveness and deep tissue penetration capability for cancer therapy.Adv Mater 2015;27:5034-42.
22.Feng Q,Shen Y,Fu Y,Muroski ME,Zhang P,Wang Q,et al.Selfassembly of gold nanoparticles shows microenvironment-mediated dynamic switching and enhanced brain tumor targeting.Theranostics2017;7:1875-89.
23.MacEwan SR,Chilkoti A.Applications of elastin-like polypeptides in drug delivery.J Control Release 2014;190:314-30.
24.Kato T,Yamashita H,Misawa T,Nishida K,Kurihara M,Tanaka M,et al.Plasmid DNA delivery by arginine-rich cell-penetrating peptides containing unnatural amino acids.Bioorg Med Chem2016;24:2681-7.
25.Cui Y,Sui J,He M,Xu Z,Sun Y,Liang J,et al.Reduction-degradable polymeric micelles decorated with parg for improving anticancer drug delivery efficacy.ACS Appl Mater Interfaces 2016;8:2193-203.
26.Vivès E,Schmidt J,Pèlegrin A.Cell-penetrating and cell-targeting peptides in drug delivery.Biochim Biophys Acta 2008;1786:126-38.
27.Fonseca SB,Pereira MP,Kelley SO.Recent advances in the use of cell-penetrating peptides for medical and biological applications.Adv Drug Deliv Rev 2009;61:953-64.
28.Huang S,Shao K,Kuang Y,Liu Y,Li J,An S,et al.Tumor targeting and microenvironment-responsive nanoparticles for gene delivery.Biomaterials 2013;34:5294-302.
29.Yao C,Tai Z,Wang X,Liu J,Zhu Q,Wu X,et al.Reductionresponsive cross-linked stearyl peptide for effective delivery of plasmid DNA.Int J Nanomed 2015;10:3403-16.
30.Koo AN,Min KH,Lee HJ,Lee SU,Kim K,Kwon IC,et al.Tumor accumulation and antitumor efficacy of docetaxel-loaded core-shellcorona micelles with shell-specific redox-responsive cross-links.Biomaterials 2012;33:1489-99.
31.Shao K,Zhang Y,Ding N,Huang S,Wu J,Li J,et al.Functionalized nanoscale micelles with brain targeting ability and intercellular microenvironment biosensitivity for anti-intracranial infection applications.Adv Healthc Mater 2015;4:291-300.
32.Huang J,Zhang H,Yu Y,Chen Y,Wang D,Zhang G,et al.Biodegradable self-assembled nanoparticles of poly(D,L-lactide-coglycolide)/hyaluronic acid block copolymers for target delivery of docetaxel to breast cancer.Biomaterials 2014;35:550-66.
33.Kim JS,Oh MH,Park JY,Park TG,Nam YS.Protein-resistant,reductively dissociable polyplexes for in vivo systemic delivery and tumor-targeting of siRNA.Biomaterials 2013;34:2370-9.
34.Mann A,Shukla V,Khanduri R,Dabral S,Singh H,Ganguli M.Linear short histidine and cysteine modified arginine peptides constitute a potential class of DNA delivery agents.Mol Pharm2014;11:683-96.
35.Zhang D,Wang J,Xu D.Cell-penetrating peptides as noninvasive transmembrane vectors for the development of novel multifunctional drug-delivery systems.J Control Release 2016;229:130-9.
36.Cai H,Liang Z,Huang W,Wen L,Chen G.Engineering PLGA nanobased systems through understanding the influence of nanoparticle properties and cell-penetrating peptides for cochlear drug delivery.Int J Pharm 2017;532:55-65.
37.Ding B,Wahid MA,Wang Z,Xie C,Thakkar A,Prabhu S,et al.Triptolide and celastrol loaded silk fibroin nanoparticles show synergistic effect against human pancreatic cancer cells.Nanoscale2017;9:11739-53.
38.McDuff SG,Taich ZJ,Lawson JD,Sanghvi P,Wong ET,Barker IIFG,et al.Neurocognitive assessment following whole brain radiation therapy and radiosurgery for patients with cerebral metastases.JNeurol,Neurosurg,Psychiatry 2013;84:1384-91.
39.Giovannini C,Piaggi S,Federico G,Scarpato R.High levels ofγ-H2AX foci and cell membrane oxidation in adolescents with type1 diabetes.Mutat Res 2014;770:128-35.
40.Gonzalez JE,Roch-Lefèvre SH,Mandina T,Garcia O,Roy L.Induction ofγ-H2AX foci in human exfoliated buccal cells after in vitro exposure to ionising radiation.Int J Radiat Biol 2010;86:752-9.
41.Yao H,Qiu H,Shao Z,Wang G,Wang J,Yao Y,et al.Nanoparticle formulation of small DNA molecules,Dbait,improves the sensitivity of hormone-independent prostate cancer to radiotherapy.Nanomed:Nanotechnol,Biol,Med 2016;12:2261-71.
42.Huang L,Liu M,Mao L,Zhang X,Xu D,Wan Q,et al.Polymerizable aggregation-induced emission dye for preparation of cross-linkable fluorescent nanoprobes with ultra-low critical micelle concentrations.Mater Sci Eng C,Mater Biol Appl 2017;76:586-92.
43.Cheng R,Feng F,Meng F,Deng C,Feijen J,Zhong Z.Glutathioneresponsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery.J Control Release 2011;152:2-12.
44.Klein PM,Müller K,Gutmann C,Kos P,Krhac Levacic A,Edinger D,et al.Twin disulfides as opportunity for improving stability and transfection efficiency of oligoaminoethane polyplexes.J Control Release 2015;205:109-19.
45.Velasco-Aguirre C,Morales-Zavala F,Salas-Huenuleo E,GallardoToledo E,Andonie O,Mu?oz L,et al.Improving gold nanorod delivery to the central nervous system by conjugation to the shuttle angiopep-2.Nanomedicine 2017;12:2503-17.
46.Yang D,Yang X,Lee RJ,Liu S,Xie J.Liposomes incorporating transferrin and stearic acid-modified octa-arginine for siRNA delivery.Anticancer Res 2017;37:1759-64.
47.Aguilera TA,Olson ES,Timmers MM,Jiang T,Tsien RY.Systemic in vivo distribution of activatable cell penetrating peptides is superior to that of cell penetrating peptides.Integr Biol 2009;1:371-81.
48.He H,Zhang J,Xie Y,Lu Y,Qi J,Ahmad E,et al.Bioimaging of intravenous polymeric micelles based on discrimination of integral particles using an environment-responsive probe.Mol Pharm2016;13:4013-9.
49.He H,Jiang S,Xie Y,Lu Y,Qi J,Dong X,et al.Reassessment of long circulation via monitoring of integral polymeric nanoparticles justifies a more accurate understanding.Nanoscale Horiz 2018;3:397-407.
2.Zhang M,Lu W.Enhanced glioma-targeting and stability ofLGICPpeptide coupled with stabilized peptideDA7R.Acta Pharm Sin B2018;8:106-15.
3.Donahue MJ,Blakeley JO,Zhou J,Pomper MG,Laterra J,van Zijl PC.Evaluation of human brain tumor heterogeneity using multiple T1-based MRI signal weighting approaches.Magn Reson Med2008;59:336-44.
4.Dutreix M,Cosset JM,Sun JS.Molecular therapy in support to radiotherapy.Mutat Res 2010;704:182-9.
5.Saad S,Wang TJ.Neurocognitive deficits after radiation therapy for brain malignancies.Am J Clin Oncol 2015;38:634-40.
6.Zhao X,Chen R,Liu M,Feng J,Chen J,Hu K.Remodeling the blood-brain barrier microenvironment by natural products for brain tumor therapy.Acta Pharm Sin B 2017;7:541-53.
7.Li J,Guo Y,Kuang Y,An S,Ma H,Jiang C.Choline transportertargeting and co-delivery system for glioma therapy.Biomaterials2013;34:9142-8.
8.Biau J,Devun F,Verrelle P,Dutreix M.Dbait:an innovative concept to inhibit DNA repair and treat cancer.Bull Cancer 2016;103:227-35.
9.Coquery N,Pannetier N,Farion R,Herbette A,Azurmendi L,Clarencon D,et al.Distribution and radiosensitizing effect of cholesterol-coupled Dbait molecule in rat model of glioblastoma.PLoS One 2012;7:e40567.
10.Devun F,Biau J,Huerre M,Croset A,Sun JS,Denys A,et al.Colorectal cancer metastasis:the DNA repair inhibitor Dbait increases sensitivity to hyperthermia and improves efficacy of radiofrequency ablation.Radiology 2014;270:736-46.
11.Quanz M,Berthault N,Roulin C,Roy M,Herbette A,Agrario C,et al.Small-molecule drugs mimicking DNA damage:a new strategy for sensitizing tumors to radiotherapy.Clin Cancer Res 2009;15:1308-16.
12.Biau J,Devun F,Jdey W,Kotula E,Quanz M,Chautard E,et al.Apreclinical study combining the DNA repair inhibitor Dbait with radiotherapy for the treatment of melanoma.Neoplasia 2014;16:835-44.
13 Liu H,Cai Y,Zhang Y,Xie Y,Qiu H,Hua L,et al.Development of a hypoxic radiosensitizer-prodrug liposome delivery DNA repair inhibitor dbait combination with radiotherapy for glioma therapy.Adv Healthc Mater 2017 Available from:?https://doi.org/10.1002/adhm.201601377?.
14.Visser CC,Voorwinden LH,Crommelin DJ,Danhof M,de Boer AG.Characterization and modulation of the transferrin receptor on brain capillary endothelial cells.Pharm Res 2004;21:761-9.
15.Liu C,Liu XN,Wang GL,Hei Y,Meng S,Yang LF,et al.A dualmediated liposomal drug delivery system targeting the brain:rational construction,integrity evaluation across the blood-brain barrier,and the transporting mechanism to glioma cells.Int J Nanomed2017;12:2407-25.
16.Demeule M,Currie JC,Bertrand Y,ChéC,Nguyen T,Régina A,et al.Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2.J Neurochem2008;106:1534-44.
17.Huang S,Li J,Han L,Liu S,Ma H,Huang R,et al.Dual targeting effect of angiopep-2-modified,DNA-loaded nanoparticles for glioma.Biomaterials 2011;32:6832-8.
18.Ruan S,Yuan M,Zhang L,Hu G,Chen J,Cun X,et al.Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles.Biomaterials2015;37:425-35.
19.Kang L,Gao Z,Huang W,Jin M,Wang Q.Nanocarrier-mediated codelivery of chemotherapeutic drugs and gene agents for cancer treatment.Acta Pharm Sin B 2015;5:169-75.
20.Huang WC,Chen SH,Chiang WH,Huang CW,Lo CL,Chern CS,et al.Tumor microenvironment-responsive nanoparticle delivery of chemotherapy for enhanced selective cellular uptake and transportation within tumor.Biomacromolecules 2016;17:3883-92.
21.Liu Y,Zhang D,Qiao ZY,Qi GB,Liang XJ,Chen XG,et al.Apeptide-network weaved nanoplatform with tumor microenvironment responsiveness and deep tissue penetration capability for cancer therapy.Adv Mater 2015;27:5034-42.
22.Feng Q,Shen Y,Fu Y,Muroski ME,Zhang P,Wang Q,et al.Selfassembly of gold nanoparticles shows microenvironment-mediated dynamic switching and enhanced brain tumor targeting.Theranostics2017;7:1875-89.
23.MacEwan SR,Chilkoti A.Applications of elastin-like polypeptides in drug delivery.J Control Release 2014;190:314-30.
24.Kato T,Yamashita H,Misawa T,Nishida K,Kurihara M,Tanaka M,et al.Plasmid DNA delivery by arginine-rich cell-penetrating peptides containing unnatural amino acids.Bioorg Med Chem2016;24:2681-7.
25.Cui Y,Sui J,He M,Xu Z,Sun Y,Liang J,et al.Reduction-degradable polymeric micelles decorated with parg for improving anticancer drug delivery efficacy.ACS Appl Mater Interfaces 2016;8:2193-203.
26.Vivès E,Schmidt J,Pèlegrin A.Cell-penetrating and cell-targeting peptides in drug delivery.Biochim Biophys Acta 2008;1786:126-38.
27.Fonseca SB,Pereira MP,Kelley SO.Recent advances in the use of cell-penetrating peptides for medical and biological applications.Adv Drug Deliv Rev 2009;61:953-64.
28.Huang S,Shao K,Kuang Y,Liu Y,Li J,An S,et al.Tumor targeting and microenvironment-responsive nanoparticles for gene delivery.Biomaterials 2013;34:5294-302.
29.Yao C,Tai Z,Wang X,Liu J,Zhu Q,Wu X,et al.Reductionresponsive cross-linked stearyl peptide for effective delivery of plasmid DNA.Int J Nanomed 2015;10:3403-16.
30.Koo AN,Min KH,Lee HJ,Lee SU,Kim K,Kwon IC,et al.Tumor accumulation and antitumor efficacy of docetaxel-loaded core-shellcorona micelles with shell-specific redox-responsive cross-links.Biomaterials 2012;33:1489-99.
31.Shao K,Zhang Y,Ding N,Huang S,Wu J,Li J,et al.Functionalized nanoscale micelles with brain targeting ability and intercellular microenvironment biosensitivity for anti-intracranial infection applications.Adv Healthc Mater 2015;4:291-300.
32.Huang J,Zhang H,Yu Y,Chen Y,Wang D,Zhang G,et al.Biodegradable self-assembled nanoparticles of poly(D,L-lactide-coglycolide)/hyaluronic acid block copolymers for target delivery of docetaxel to breast cancer.Biomaterials 2014;35:550-66.
33.Kim JS,Oh MH,Park JY,Park TG,Nam YS.Protein-resistant,reductively dissociable polyplexes for in vivo systemic delivery and tumor-targeting of siRNA.Biomaterials 2013;34:2370-9.
34.Mann A,Shukla V,Khanduri R,Dabral S,Singh H,Ganguli M.Linear short histidine and cysteine modified arginine peptides constitute a potential class of DNA delivery agents.Mol Pharm2014;11:683-96.
35.Zhang D,Wang J,Xu D.Cell-penetrating peptides as noninvasive transmembrane vectors for the development of novel multifunctional drug-delivery systems.J Control Release 2016;229:130-9.
36.Cai H,Liang Z,Huang W,Wen L,Chen G.Engineering PLGA nanobased systems through understanding the influence of nanoparticle properties and cell-penetrating peptides for cochlear drug delivery.Int J Pharm 2017;532:55-65.
37.Ding B,Wahid MA,Wang Z,Xie C,Thakkar A,Prabhu S,et al.Triptolide and celastrol loaded silk fibroin nanoparticles show synergistic effect against human pancreatic cancer cells.Nanoscale2017;9:11739-53.
38.McDuff SG,Taich ZJ,Lawson JD,Sanghvi P,Wong ET,Barker IIFG,et al.Neurocognitive assessment following whole brain radiation therapy and radiosurgery for patients with cerebral metastases.JNeurol,Neurosurg,Psychiatry 2013;84:1384-91.
39.Giovannini C,Piaggi S,Federico G,Scarpato R.High levels ofγ-H2AX foci and cell membrane oxidation in adolescents with type1 diabetes.Mutat Res 2014;770:128-35.
40.Gonzalez JE,Roch-Lefèvre SH,Mandina T,Garcia O,Roy L.Induction ofγ-H2AX foci in human exfoliated buccal cells after in vitro exposure to ionising radiation.Int J Radiat Biol 2010;86:752-9.
41.Yao H,Qiu H,Shao Z,Wang G,Wang J,Yao Y,et al.Nanoparticle formulation of small DNA molecules,Dbait,improves the sensitivity of hormone-independent prostate cancer to radiotherapy.Nanomed:Nanotechnol,Biol,Med 2016;12:2261-71.
42.Huang L,Liu M,Mao L,Zhang X,Xu D,Wan Q,et al.Polymerizable aggregation-induced emission dye for preparation of cross-linkable fluorescent nanoprobes with ultra-low critical micelle concentrations.Mater Sci Eng C,Mater Biol Appl 2017;76:586-92.
43.Cheng R,Feng F,Meng F,Deng C,Feijen J,Zhong Z.Glutathioneresponsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery.J Control Release 2011;152:2-12.
44.Klein PM,Müller K,Gutmann C,Kos P,Krhac Levacic A,Edinger D,et al.Twin disulfides as opportunity for improving stability and transfection efficiency of oligoaminoethane polyplexes.J Control Release 2015;205:109-19.
45.Velasco-Aguirre C,Morales-Zavala F,Salas-Huenuleo E,GallardoToledo E,Andonie O,Mu?oz L,et al.Improving gold nanorod delivery to the central nervous system by conjugation to the shuttle angiopep-2.Nanomedicine 2017;12:2503-17.
46.Yang D,Yang X,Lee RJ,Liu S,Xie J.Liposomes incorporating transferrin and stearic acid-modified octa-arginine for siRNA delivery.Anticancer Res 2017;37:1759-64.
47.Aguilera TA,Olson ES,Timmers MM,Jiang T,Tsien RY.Systemic in vivo distribution of activatable cell penetrating peptides is superior to that of cell penetrating peptides.Integr Biol 2009;1:371-81.
48.He H,Zhang J,Xie Y,Lu Y,Qi J,Ahmad E,et al.Bioimaging of intravenous polymeric micelles based on discrimination of integral particles using an environment-responsive probe.Mol Pharm2016;13:4013-9.
49.He H,Jiang S,Xie Y,Lu Y,Qi J,Dong X,et al.Reassessment of long circulation via monitoring of integral polymeric nanoparticles justifies a more accurate understanding.Nanoscale Horiz 2018;3:397-407.