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Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer

Liang, Gaofeng, Zhu, Yanliang, Ali, Doulathunnisa Jaffar, Tian, Tian, Xu, Huantian, Si, Ke, Sun, Bo, Chen, Baoan, Xiao, Zhongdang·2020·Journal of Nanobiotechnology
DOI 10.1186/s12951-019-0563-2PMC PMC6950820
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Abstract

Background: 5-Fluorouracil (5-FU) has been commonly prescribed for patients with colorectal cancer (CRC), but resistance to 5-FU is one of the main reasons for failure in CRC. Recently, microRNAs (miRNAs) have been established as a means of reversing the dilemma by regulating signaling pathways involved in initiation and progression of CRC. However, how to safely and effectively deliver miRNA to target cells becomes a main challenge. Results: In this study, Engineered exosomes were exploited to simultaneously deliver an anticancer drug 5-FU and miR-21 inhibitor oligonucleotide (miR-21i) to Her2 expressing cancer cells. Purified engineered exosomes from the donor cells loaded with 5-FU and miR-21i via electroporation to introduce into 5-FU-resistant colorectal cancer cell line HCT-116 5FR . Furthermore, systematic administration of 5-FU and miR-21i loaded exosomes in tumor bearing mice indicated a significantly anti-tumor effect. The results showed that the engineered exosome-based 5-FU and miR-21i co-delivery system could efficiently facilitate cellular uptake and significantly down-regulate miR-21 expression in 5-FU resistant HCT-116 5FR cell lines. Consequently, the down-regulation of miR-21 induced cell cycle arrest, reduced tumor proliferation, increased apoptosis and rescued PTEN and hMSH2 expressions, regulatory targets of miR-21. Of particular importance was the significant reduction in tumor growth in a mouse model of colon cancer with systematic administration of the targeting miR-21i. More excitedly, the combinational delivery of miR-21i and 5-FU with the engineered exosomes effectively reverse drug resistance and significantly enhanced the cytotoxicity in 5-FU-resistant colon cancer cells, compared with the single treatment with either miR-21i or 5-FU. Conclusion: The strategy for co-delivering the functional small RNA and anticancer drug by exosomes foreshadows a potential approach to reverse the drug resistance in CRC and thus to enhance the efficacy of the cancer treatment.

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Scheme 1 Engineered exosomes based nanocarrier for 5-FU and miR-21i simultaneously deliver to HCT-1165FR human colon cancer cells for enhancing chemotherapy efficacy
Scheme 1 Engineered exosomes based nanocarrier for 5-FU and miR-21i simultaneously deliver to HCT-1165FR human colon cancer cells for enhancing chemotherapy efficacyCC BY · PubMed Central
Fig. 1 Isolation and molecular characterization of engineered exosomes. a Schematics of DNA constructs used for the production of fusion proteins LG (upper) and THLG (lower). b Fluorescence images of the GFP, LG and THLG in 293T cells ( ×400). c Biomarkers of exosomes were determined by western blot analysis of exosomes. d Western blot analysis of GFP in exosomes obtained from supernatants of GFP-293T cells, LG-293T cells and THLG-293T cells. e Confocal microscopy of exosomes isolated from 0.22 filtered conditioned medium of GFP-293T cells, LG-293T cells and THLG-293T cells ( ×1000). f Transmission electron micrograph of THLG-EXO and THLG-EXO/5-FU/miR-21i. g Size distribution of THLG-EXO and THLG-EXO/5-FU/miR-21i measured by DLS
Fig. 1 Isolation and molecular characterization of engineered exosomes. a Schematics of DNA constructs used for the production of fusion proteins LG (upper) and THLG (lower). b Fluorescence images of the GFP, LG and THLG in 293T cells ( ×400). c Biomarkers of exosomes were determined by western blot analysis of exosomes. d Western blot analysis of GFP in exosomes obtained from supernatants of GFP-293T cells, LG-293T cells and THLG-293T cells. e Confocal microscopy of exosomes isolated from 0.22 filtered conditioned medium of GFP-293T cells, LG-293T cells and THLG-293T cells ( ×1000). f Transmission electron micrograph of THLG-EXO and THLG-EXO/5-FU/miR-21i. g Size distribution of THLG-EXO and THLG-EXO/5-FU/miR-21i measured by DLSCC BY · PubMed Central
Fig. 2 The cellular tropism of THLG-EXO in vitro. a Schematics of DNA constructs used for the production of fusion proteins Her2-mCherry (upper panel); flow cytometric analyses of Her2 from SGC-7901 WT cells and Her2-mcherry-SGC-7901 cells with a FITC labeled anti-Her2 monoclonal antibody (lower panel). b Confocal microscopy images of cellular uptake of THLG-EXO or LG-EXO after 3 h incubation with SGC-7901 WT cells and Her2-mcherry-SGC-7901 cells co-culture model. red shows Her2-mcherry-SGC-7901 cells. Green represents THLG-EXO or LG-EXO. Right panel shows enlarged graphs with frame indicating internalized exosomes in cells (×400). c Flow cytometry analysis of co-culture cells after incubation with THLG-EXO or LG-EXO (upper panel); d quantification of exosomes internalization based on flow cytometry analysis (lower panel). Data are expressed as mean ± SD. n = 5; **p < 0.01
Fig. 2 The cellular tropism of THLG-EXO in vitro. a Schematics of DNA constructs used for the production of fusion proteins Her2-mCherry (upper panel); flow cytometric analyses of Her2 from SGC-7901 WT cells and Her2-mcherry-SGC-7901 cells with a FITC labeled anti-Her2 monoclonal antibody (lower panel). b Confocal microscopy images of cellular uptake of THLG-EXO or LG-EXO after 3 h incubation with SGC-7901 WT cells and Her2-mcherry-SGC-7901 cells co-culture model. red shows Her2-mcherry-SGC-7901 cells. Green represents THLG-EXO or LG-EXO. Right panel shows enlarged graphs with frame indicating internalized exosomes in cells (×400). c Flow cytometry analysis of co-culture cells after incubation with THLG-EXO or LG-EXO (upper panel); d quantification of exosomes internalization based on flow cytometry analysis (lower panel). Data are expressed as mean ± SD. n = 5; **p < 0.01CC BY · PubMed Central
Fig. 3 The results of HCT-1165FR cells treated with THLG-EXO/5-FU/miR-21i in vitro. a Real-time fluorescent quantitative PCR analysis of relative expression change of miR-21 level in HCT-1165FR cells treated with THLG-EXO/5-FU/miR-21i, THLG-EXO or miR-21i. Data were expressed as mean ± SD. n = 3. b Western blot analysis of hMSH2 and PTEN protein levels of HCT-1165FR cells treated with THLG-EXO/5-FU/miR-21i. c Flow cytometric analysis of AnnexinV-FITC/PI stained HCT-1165FR cells treated with THLG-EXO, THLG-EXO/miR-21i, THLG-EXO/5-FU or THLG/5-FU/miR-21i. d Cell cycle profiles of HCT-1165FR cells after treatment as described in c; e the proliferation of HCT-1165FR cells after treatment as described in c. Data were expressed as means ± SD. n = 5;*: significantly different from other groups (p < 0.05), **: extremely significantly different from other groups (p < 0.01)
Fig. 3 The results of HCT-1165FR cells treated with THLG-EXO/5-FU/miR-21i in vitro. a Real-time fluorescent quantitative PCR analysis of relative expression change of miR-21 level in HCT-1165FR cells treated with THLG-EXO/5-FU/miR-21i, THLG-EXO or miR-21i. Data were expressed as mean ± SD. n = 3. b Western blot analysis of hMSH2 and PTEN protein levels of HCT-1165FR cells treated with THLG-EXO/5-FU/miR-21i. c Flow cytometric analysis of AnnexinV-FITC/PI stained HCT-1165FR cells treated with THLG-EXO, THLG-EXO/miR-21i, THLG-EXO/5-FU or THLG/5-FU/miR-21i. d Cell cycle profiles of HCT-1165FR cells after treatment as described in c; e the proliferation of HCT-1165FR cells after treatment as described in c. Data were expressed as means ± SD. n = 5;*: significantly different from other groups (p < 0.05), **: extremely significantly different from other groups (p < 0.01)CC BY · PubMed Central
Fig. 4 Tumor targeting ability of THLG-EXO in a nude mouse xenograft model using HCT-1165FR cells. a In vivo fluorescent images of HCT-1165FR-bearing nude mice after intravenous injection of DiR-labeled THLG-EXO (left panel) or LG-EXO (right panel). b Quantitative analysis showed the relative fluorescence intensities in the tumor region (upper panel) and the liver (lower panel) following administration of THLG-EXO or LG-EXO. Data were expressed as means ± SD. n = 5; *P < 0.05, **P < 0.01 versus the LG-EXO group at the same time point
Fig. 4 Tumor targeting ability of THLG-EXO in a nude mouse xenograft model using HCT-1165FR cells. a In vivo fluorescent images of HCT-1165FR-bearing nude mice after intravenous injection of DiR-labeled THLG-EXO (left panel) or LG-EXO (right panel). b Quantitative analysis showed the relative fluorescence intensities in the tumor region (upper panel) and the liver (lower panel) following administration of THLG-EXO or LG-EXO. Data were expressed as means ± SD. n = 5; *P < 0.05, **P < 0.01 versus the LG-EXO group at the same time pointCC BY · PubMed Central
Fig. 5 Antitumor activity of THLG-EXO/5-FU/miR-21i in nude mice xenograft using HCT-1165FR cells. a Representative bioluminescent images of tumor growth in nude mice treated with THLG-EXO, THLG-EXO/miR-21i, THLG-EXO/5-FU or THLG-EXO/5-FU/miR-21i at different time point. Signals were adjusted to the same color scale for the entire time course. b The mean bioluminescence intensity (BLI) for each mouse/group, line chart represented quantification of the relative bioluminescent intensity in tumor site. c Tumor weights of different treated groups. T1, T2, T3 and T4 represented the treatment of THLG-EXO, THLG-EXO/miR-21i, THLG-EXO/5-FU, THLG-EXO/5-FU/miR-21i, respectively. d TUNEL assessments of tumor tissues treated with THLG-EXO, THLG-EXO/miR-21i, THLG-EXO/5-FU, THLG-EXO/5-FU/miR-21i, respectively. e Western blot of hMSH2 and PTEN in the tissue of tumor region were performed for 24 h after administration. Data were expressed as means ± SD. n = 6; *P < 0.05, **P < 0.01 versus the THLG-EXO groups or THLG-EXO/miR-21i group, and #P < 0.05 versus the THLG-EXO/5-FU groups
Fig. 5 Antitumor activity of THLG-EXO/5-FU/miR-21i in nude mice xenograft using HCT-1165FR cells. a Representative bioluminescent images of tumor growth in nude mice treated with THLG-EXO, THLG-EXO/miR-21i, THLG-EXO/5-FU or THLG-EXO/5-FU/miR-21i at different time point. Signals were adjusted to the same color scale for the entire time course. b The mean bioluminescence intensity (BLI) for each mouse/group, line chart represented quantification of the relative bioluminescent intensity in tumor site. c Tumor weights of different treated groups. T1, T2, T3 and T4 represented the treatment of THLG-EXO, THLG-EXO/miR-21i, THLG-EXO/5-FU, THLG-EXO/5-FU/miR-21i, respectively. d TUNEL assessments of tumor tissues treated with THLG-EXO, THLG-EXO/miR-21i, THLG-EXO/5-FU, THLG-EXO/5-FU/miR-21i, respectively. e Western blot of hMSH2 and PTEN in the tissue of tumor region were performed for 24 h after administration. Data were expressed as means ± SD. n = 6; *P < 0.05, **P < 0.01 versus the THLG-EXO groups or THLG-EXO/miR-21i group, and #P < 0.05 versus the THLG-EXO/5-FU groupsCC BY · PubMed Central
Fig. 6 The systematic toxicity assessment of THLG-EXO. Histopathological analysis of heart, lung, liver, kidney and spleen sections stained with hematoxylin and eosin of BALB/c mice post-intravenous injection of 20 mg/kg THLG-EXO or PBS for 7 days (one dose every other day). Images were obtained under Nikon Ti microscope using a × 40 objective
Fig. 6 The systematic toxicity assessment of THLG-EXO. Histopathological analysis of heart, lung, liver, kidney and spleen sections stained with hematoxylin and eosin of BALB/c mice post-intravenous injection of 20 mg/kg THLG-EXO or PBS for 7 days (one dose every other day). Images were obtained under Nikon Ti microscope using a × 40 objectiveCC BY · PubMed Central

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Cites

Research works printed but not linked: 45

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30. · DOI
  2. Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci. 2000;11:265–83. · DOI
  3. Baker EK, El-Osta A. The rise of DNA methylation and the importance of chromatin on multidrug resistance in cancer. Exp Cell Res. 2003;290:177–94. · DOI
  4. To KK, Polgar O, Huff LM, Morisaki K, Bates SE. Histone modifications at the ABCG2 promoter following treatment with histone deacetylase inhibitor mirror those in multidrug-resistant cells. Mol Cancer Res. 2008;6:151–64. · DOI
  5. Wang S, Su X, Bai H, Zhao J, Duan J, An T, Zhuo M, Wang Z, Wu M, Li Z, et al. Identification of plasma microRNA profiles for primary resistance to EGFR-TKIs in advanced non-small cell lung cancer (NSCLC) patients with EGFR activating mutation. J Hematol Oncol. 2015;8:127. · DOI
  6. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJA. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29:U341–U179. · DOI · Paper page
  7. Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, Sumani KM, Alder H, Amadori D, Patel T, et al. MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proc Natl Acad Sci USA. 2010;107:21098–103. · DOI
  8. Mitamura T, Watari H, Wang L, Kanno H, Hassan MK, Miyazaki M, Katoh Y, Kimura T, Tanino M, Nishihara H, et al. Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET. Oncogenesis. 2013;2:e40. · DOI
  9. Kovalchuk O, Filkowski J, Meservy J, Ilnytskyy Y, Tryndyak VP, Chekhun VF, Pogribny IP. Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther. 2008;7:2152–9. · DOI
  10. Tian Y, Li S, Song J, Ji T, Zhu M, Anderson GJ, Wei J, Nie G. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials. 2014;35:2383–90. · DOI
  11. Dai X, Tan C. Combination of microRNA therapeutics with small-molecule anticancer drugs: mechanism of action and co-delivery nanocarriers. Adv Drug Deliv Rev. 2015;81:184–97. · DOI
  12. Gandhi NS, Tekade RK, Chougule MB. Nanocarrier mediated delivery of siRNA/miRNA in combination with chemotherapeutic agents for cancer therapy: current progress and advances. J Control Release. 2014;194:238–56. · DOI
  13. Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–79. · DOI
  14. Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM, Baty CJ, Gibson GA, Erdos G, Wang Z, et al. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood. 2012;119:756–66. · DOI · Paper page
  15. Gross JC, Chaudhary V, Bartscherer K, Boutros M. Active Wnt proteins are secreted on exosomes. Nat Cell Biol. 2012;14:1036–45. · DOI
  16. Liang G, Li J, Sun B, Li S, Lu L, Wang Y, Chen B, Xiao Z. Deep sequencing reveals complex mechanisms of microRNA deregulation in colorectal cancer. Int J Oncol. 2014;45:603–10. · DOI
  17. Yang T, Martin P, Fogarty B, Brown A, Schurman K, Phipps R, Yin VP, Lockman P, Bai S. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm Res. 2015;32:2003–144. · DOI
  18. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29:341–5. · DOI · Paper page
  19. Shtam TA, Kovalev RA, Varfolomeeva EY, Makarov EM, Kil YV, Filatov MV. Exosomes are natural carriers of exogenous siRNA to human cells in vitro. Cell Commun Signal. 2013;11:88. · DOI · Paper page
  20. Liang G, Kan S, Zhu Y, Feng S, Feng W, Gao S. Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells. Int J Nanomed. 2018;13:585–99. · DOI · Paper page
  21. Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T, Ohgi T, Ochiya T, et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther. 2013;21:185–91. · DOI · Paper page
  22. Gong C, Tian J, Wang Z, Gao Y, Wu X, Ding X, Qiang L, Li G, Han Z, Yuan Y, Gao S. Functional exosome-mediated co-delivery of doxorubicin and hydrophobically modified microRNA 159 for triple-negative breast cancer therapy. J Nanobiotechnol. 2019;17(1):93. · DOI
  23. Hung ME, Leonard JN. Stabilization of exosome-targeting peptides via engineered glycosylation. J Biol Chem. 2015;290:8166–72. · DOI
  24. Zheng P, Chen L, Yuan X, Luo Q, Liu Y, Xie G, Ma Y, Shen L. Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells. J Exp Clin Cancer Res. 2017;36:53. · DOI
  25. Rehemtulla A, Stegman LD, Cardozo SJ, Gupta S, Hall DE, Contag CH, Ross BD. Rapid and quantitative assessment of cancer treatment response using in vivo bioluminescence imaging. Neoplasia. 2000;2:491–5. · DOI
  26. Vooijs M, Jonkers J, Lyons S, Berns A. Noninvasive imaging of spontaneous retinoblastoma pathway-dependent tumors in mice. Cancer Res. 2002;62:1862–7.
  27. Suk JS, Xu Q, Kim N, Hanes J, Ensign LM. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev. 2016;99:28–51. · DOI · Paper page
  28. Moridikia A, Mirzaei H, Sahebkar A, Salimian J. MicroRNAs: potential candidates for diagnosis and treatment of colorectal cancer. J Cell Physiol. 2018;233:901–13. · DOI
  29. Shi GH, Ye DW, Yao XD, Zhang SL, Dai B, Zhang HL, Shen YJ, Zhu Y, Zhu YP, Xiao WJ, Ma CG. Involvement of microRNA-21 in mediating chemo-resistance to docetaxel in androgen-independent prostate cancer PC3 cells. Acta Pharmacol Sin. 2010;31:867–73. · DOI
  30. Shi L, Chen J, Yang J, Pan T, Zhang S, Wang Z. MiR-21 protected human glioblastoma U87MG cells from chemotherapeutic drug temozolomide induced apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 activity. Brain Res. 2010;1352:255–64. · DOI
  31. Zhang JG, Wang JJ, Zhao F, Liu Q, Jiang K, Yang GH. MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC). Clin Chim Acta. 2010;411:846–52. · DOI
  32. Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, Sumani KM, Alder H, Amadori D, Patel T, et al. MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proc Natl Acad Sci U S A. 2010;107:21098–103. · DOI
  33. Tai W, Mahato R, Cheng K. The role of HER2 in cancer therapy and targeted drug delivery. J Control Release. 2010;146:264–75. · DOI
  34. Zindy P, Berge Y, Allal B, Filleron T, Pierredon S, Cammas A, Beck S, Mhamdi L, Fan L, Favre G, et al. Formation of the eIF4F translation-initiation complex determines sensitivity to anticancer drugs targeting the EGFR and HER2 receptors. Cancer Res. 2011;71:4068–73. · DOI
  35. Alric C, Herve-Aubert K, Aubrey N, Melouk S, Lajoie L, Meme W, Meme S, Courbebaisse Y, Ignatova AA, Feofanov AV, et al. Targeting HER2-breast tumors with scFv-decorated bimodal nanoprobes. J Nanobiotechno. 2018;16:18. · DOI
  36. Zahmatkeshan M, Gheybi F, Rezayat SM, Jaafari MR. Improved drug delivery and therapeutic efficacy of PEgylated liposomal doxorubicin by targeting anti-HER2 peptide in murine breast tumor model. Eur J Pharm Sci. 2016;86:125–35. · DOI
  37. Mu Q, Kievit FM, Kant RJ, Lin G, Jeon M, Zhang M. Anti-HER2/neu peptide-conjugated iron oxide nanoparticles for targeted delivery of paclitaxel to breast cancer cells. Nanoscale. 2015;7:18010–4. · DOI
  38. Soni KS, Lei F, Desale SS, Marky LA, Cohen SM, Bronich TK. Tuning polypeptide-based micellar carrier for efficient combination therapy of ErbB2-positive breast cancer. J Control Release. 2017;264:276–87. · DOI
  39. Lai CP, Kim EY, Badr CE, Weissleder R, Mempel TR, Tannous BA, Breakefield XO. Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters. Nat Commun. 2015;6:7029. · DOI · Paper page
  40. Lai CP, Mardini O, Ericsson M, Prabhakar S, Maguire C, Chen JW, Tannous BA, Breakefield XO. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano. 2014;8:483–94. · DOI
  41. Chen F, Ma M, Wang J, Wang F, Chern SX, Zhao ER, Jhunjhunwala A, Darmadi S, Chen H, Jokerst JV. Exosome-like silica nanoparticles: a novel ultrasound contrast agent for stem cell imaging. Nanoscale. 2017;9:402–11. · DOI
  42. Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, Patel T, Piroyan A, Sokolsky M, Kabanov AV, Batrakova EV. Exosomes as drug delivery vehicles for Parkinson's disease therapy. J Control Release. 2015;207:18–30. · DOI · Paper page
  43. Busato A, Bonafede R, Bontempi P, Scambi I, Schiaffino L, Benati D, Malatesta M, Sbarbati A, Marzola P, Mariotti R. Magnetic resonance imaging of ultrasmall superparamagnetic iron oxide-labeled exosomes from stem cells: a new method to obtain labeled exosomes. Int J Nanomedicine. 2016;11:2481–90.
  44. Kooijmans SAA, Stremersch S, Braeckmans K, de Smedt SC, Hendrix A, Wood MJA, Schiffelers RM, Raemdonck K, Vader P. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J Control Release. 2013;172:229–38. · DOI · Paper page
  45. de Angelis PM, Fjell B, Kravik KL, Haug T, Tunheim SH, Reichelt W, Beigi M, Clausen OP, Galteland E, Stokke T. Molecular characterizations of derivatives of HCT116 colorectal cancer cells that are resistant to the chemotherapeutic agent 5-fluorouracil. Int J Oncol. 2004;24:1279–88.

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Metadata

Authors
Liang, G., Zhu, Y., Ali, D. J., Tian, T., Xu, H., Si, K., Sun, B., Chen, B., & Xiao, Z.
Venue
Journal of Nanobiotechnology
Publisher
Springer Science and Business Media LLC
Published
2020-01-09
Volume
18
Issue
1
ISSN
1477-3155
DOI
10.1186/s12951-019-0563-2
PMC
PMC6950820
Cited by
619
References
6
Language
en
Licence
Funders
  • Chinese National Postdoctoral Science Foundation (2017M611661)
  • National Natural Science Foundation of China (81671807, 81741147)

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