Skip to main content

Advertisement

SpringerLink
Log in

Challenging the future of siRNA therapeutics against cancer: the crucial role of nanotechnology

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The identification of numerous deregulated signaling pathways on cancer cells and supportive stromal cells has revealed several molecular targets whose downregulation can elicit significant benefits for cancer treatment. In this respect, gene downregulation can be efficiently achieved by exploiting the RNA interference mechanism, particularly by the delivery of chemical synthesized small-interfering RNAs (siRNAs), which have the ability to mediate, in a specific manner, the degradation of any mRNA with complementary nucleotide sequence. However, several concerns regarding off-target effects and immune stimulation have been raised. Depending on their sequence, siRNAs can trigger an innate immune response, which might mediate undesirable side effects that ultimately compromise their clinical utility. This is a very relevant effect that will be discussed in the present manuscript. Moreover, the major drawback in the translation of siRNAs into the clinical practice is undoubtedly their inability to accumulate in tumor sites, particularly in organs other than the liver. In fact, upon systemic administration, owing to siRNAs physico-chemical features, they are rapidly cleared from the blood stream. Therefore, the development of a proper drug delivery system is of utmost importance. In this review, some of the latest advances on different nanotechnological platforms for siRNA delivery under clinical evaluation will be discussed. Along with this, targeting approaches towards cancer and/or endothelial cells will also be addressed, as these are some of the most promising strategies to enhance specific tumor accumulation while avoiding healthy tissues. Finally, clinical information on ongoing studies in patients with advanced solid tumors will be also provided.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics. CA Cancer J Clin 62(1):10–29. doi:10.3322/caac.20138

    PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    CAS  PubMed  Google Scholar 

  3. Luo J, Solimini NL, Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136(5):823–837. doi:10.1016/j.cell.2009.02.024

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Farazi TA, Spitzer JI, Morozov P, Tuschl T (2011) miRNAs in human cancer. J Pathol 223(2):102–115. doi:10.1002/path.2806

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Siolas D, Lerner C, Burchard J, Ge W, Linsley PS, Paddison PJ, Hannon GJ, Cleary MA (2005) Synthetic shRNAs as potent RNAi triggers. Nat Biotechnol 23(2):227–231. doi:10.1038/nbt1052

    CAS  PubMed  Google Scholar 

  6. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411(6836):494–498. doi:10.1038/35078107

    CAS  PubMed  Google Scholar 

  7. Aagaard L, Rossi JJ (2007) RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev 59(2–3):75–86

    CAS  PubMed Central  PubMed  Google Scholar 

  8. de Fougerolles A, Vornlocher HP, Maraganore J, Lieberman J (2007) Interfering with disease: a progress report on siRNA-based therapeutics. Nat Rev Drug Discov 6(6):443–453

    PubMed  Google Scholar 

  9. Bhindi R, Fahmy RG, Lowe HC, Chesterman CN, Dass CR, Cairns MJ, Saravolac EG, Sun LQ, Khachigian LM (2007) Brothers in arms: DNA enzymes, short interfering RNA, and the emerging wave of small-molecule nucleic acid-based gene-silencing strategies. Am J Pathol 171(4):1079–1088

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Vaishnaw AK, Gollob J, Gamba-Vitalo C, Hutabarat R, Sah D, Meyers R, de Fougerolles T, Maraganore J (2010) A status report on RNAi therapeutics. Silence 1(1):14. doi:10.1186/1758-907X-1-14

    PubMed Central  PubMed  Google Scholar 

  11. Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G, Linsley PS (2003) Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol 21(6):635–637. doi:10.1038/nbt831

    CAS  PubMed  Google Scholar 

  12. Tschuch C, Schulz A, Pscherer A, Werft W, Benner A, Hotz-Wagenblatt A, Barrionuevo LS, Lichter P, Mertens D (2008) Off-target effects of siRNA specific for GFP. BMC Mol Biol 9:60. doi:10.1186/1471-2199-9-60

    PubMed Central  PubMed  Google Scholar 

  13. Fedorov Y, Anderson EM, Birmingham A, Reynolds A, Karpilow J, Robinson K, Leake D, Marshall WS, Khvorova A (2006) Off-target effects by siRNA can induce toxic phenotype. RNA 12(7):1188–1196. doi:10.1261/rna.28106

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Mendonca LS, Firmino F, Moreira JN, Pedroso de Lima MC, Simoes S (2010) Transferrin receptor-targeted liposomes encapsulating anti-BCR-ABL siRNA or asODN for chronic myeloid leukemia treatment. Bioconjug Chem 21(1):157–168. doi:10.1021/bc9004365

    CAS  PubMed  Google Scholar 

  15. Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S, Noronha A, Manoharan M, Akira S, de Fougerolles A, Endres S, Hartmann G (2005) Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med 11(3):263–270. doi:10.1038/nm1191

    CAS  PubMed  Google Scholar 

  16. Sioud M (2009) Deciphering the code of innate immunity recognition of siRNAs. Methods Mol Biol 487:41–59

    CAS  PubMed  Google Scholar 

  17. Judge AD, Sood V, Shaw JR, Fang D, McClintock K, MacLachlan I (2005) Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol 23(4):457–462. doi:10.1038/nbt1081

    CAS  PubMed  Google Scholar 

  18. Sioud M (2005) Induction of inflammatory cytokines and interferon responses by double-stranded and single-stranded siRNAs is sequence-dependent and requires endosomal localization. J Mol Biol 348(5):1079–1090. doi:10.1016/j.jmb.2005.03.013

    CAS  PubMed  Google Scholar 

  19. Sioud M (2006) Single-stranded small interfering RNA are more immunostimulatory than their double-stranded counterparts: a central role for 2′-hydroxyl uridines in immune responses. Eur J Immunol 36(5):1222–1230. doi:10.1002/eji.200535708

    CAS  PubMed  Google Scholar 

  20. Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BR (2003) Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 5(9):834–839. doi:10.1038/ncb1038

    CAS  PubMed  Google Scholar 

  21. Bridge AJ, Pebernard S, Ducraux A, Nicoulaz AL, Iggo R (2003) Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet 34(3):263–264. doi:10.1038/ng1173

    CAS  PubMed  Google Scholar 

  22. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S (2004) Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303(5663):1526–1529. doi:10.1126/science.1093620

    CAS  PubMed  Google Scholar 

  23. Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, Albuquerque RJ, Yamasaki S, Itaya M, Pan Y, Appukuttan B, Gibbs D, Yang Z, Kariko K, Ambati BK, Wilgus TA, DiPietro LA, Sakurai E, Zhang K, Smith JR, Taylor EW, Ambati J (2008) Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452(7187):591–597. doi:10.1038/nature06765

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Cho WG, Albuquerque RJ, Kleinman ME, Tarallo V, Greco A, Nozaki M, Green MG, Baffi JZ, Ambati BK, De Falco M, Alexander JS, Brunetti A, De Falco S, Ambati J (2009) Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth. Proc Natl Acad Sci USA 106(17):7137–7142. doi:10.1073/pnas.0812317106

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Paone A, Galli R, Gabellini C, Lukashev D, Starace D, Gorlach A, De Cesaris P, Ziparo E, Del Bufalo D, Sitkovsky MV, Filippini A, Riccioli A (2010) Toll-like receptor 3 regulates angiogenesis and apoptosis in prostate cancer cell lines through hypoxia-inducible factor 1 alpha. Neoplasia 12(7):539–549

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Judge A, MacLachlan I (2008) Overcoming the innate immune response to small interfering RNA. Hum Gene Ther 19(2):111–124. doi:10.1089/hum.2007.179

    CAS  PubMed  Google Scholar 

  27. Moreira JN, Santos A, Moura V, Pedroso de Lima MC, Simoes S (2008) Non-viral lipid-based nanoparticles for targeted cancer systemic gene silencing. J Nanosci Nanotechnol 8(5):2187–2204

    CAS  PubMed  Google Scholar 

  28. Watts JK, Deleavey GF, Damha MJ (2008) Chemically modified siRNA: tools and applications. Drug Discov Today 13(19–20):842–855. doi:10.1016/j.drudis.2008.05.007

    CAS  PubMed  Google Scholar 

  29. Jackson AL, Burchard J, Leake D, Reynolds A, Schelter J, Guo J, Johnson JM, Lim L, Karpilow J, Nichols K, Marshall W, Khvorova A, Linsley PS (2006) Position-specific chemical modification of siRNAs reduces “off-target” transcript silencing. RNA 12(7):1197–1205. doi:10.1261/rna.30706

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Chiu YL, Rana TM (2003) siRNA function in RNAi: a chemical modification analysis. RNA 9(9):1034–1048

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Morrissey DV, Lockridge JA, Shaw L, Blanchard K, Jensen K, Breen W, Hartsough K, Machemer L, Radka S, Jadhav V, Vaish N, Zinnen S, Vargeese C, Bowman K, Shaffer CS, Jeffs LB, Judge A, MacLachlan I, Polisky B (2005) Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol 23(8):1002–1007. doi:10.1038/nbt1122

    CAS  PubMed  Google Scholar 

  32. Morrissey DV, Blanchard K, Shaw L, Jensen K, Lockridge JA, Dickinson B, McSwiggen JA, Vargeese C, Bowman K, Shaffer CS, Polisky BA, Zinnen S (2005) Activity of stabilized short interfering RNA in a mouse model of hepatitis B virus replication. Hepatology 41(6):1349–1356. doi:10.1002/hep.20702

    CAS  PubMed  Google Scholar 

  33. Zimmermann TS, Lee AC, Akinc A, Bramlage B, Bumcrot D, Fedoruk MN, Harborth J, Heyes JA, Jeffs LB, John M, Judge AD, Lam K, McClintock K, Nechev LV, Palmer LR, Racie T, Rohl I, Seiffert S, Shanmugam S, Sood V, Soutschek J, Toudjarska I, Wheat AJ, Yaworski E, Zedalis W, Koteliansky V, Manoharan M, Vornlocher HP, MacLachlan I (2006) RNAi-mediated gene silencing in non-human primates. Nature 441(7089):111–114. doi:10.1038/nature04688

    CAS  PubMed  Google Scholar 

  34. Judge AD, Bola G, Lee AC, MacLachlan I (2006) Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol Ther 13(3):494–505. doi:10.1016/j.ymthe.2005.11.002

    CAS  PubMed  Google Scholar 

  35. Diebold SS, Massacrier C, Akira S, Paturel C, Morel Y, Reis e Sousa C (2006) Nucleic acid agonists for Toll-like receptor 7 are defined by the presence of uridine ribonucleotides. Eur J Immunol 36(12):3256–3267. doi:10.1002/eji.200636617

    CAS  PubMed  Google Scholar 

  36. Sioud M, Furset G, Cekaite L (2007) Suppression of immunostimulatory siRNA-driven innate immune activation by 2′-modified RNAs. Biochem Biophys Res Commun 361(1):122–126. doi:10.1016/j.bbrc.2007.06.177

    CAS  PubMed  Google Scholar 

  37. Robbins M, Judge A, Liang L, McClintock K, Yaworski E, MacLachlan I (2007) 2′-O-methyl-modified RNAs act as TLR7 antagonists. Mol Ther 15(9):1663–1669. doi:10.1038/sj.mt.6300240

    CAS  PubMed  Google Scholar 

  38. Hamm S, Latz E, Hangel D, Muller T, Yu P, Golenbock D, Sparwasser T, Wagner H, Bauer S (2010) Alternating 2′-O-ribose methylation is a universal approach for generating non-stimulatory siRNA by acting as TLR7 antagonist. Immunobiology 215(7):559–569. doi:10.1016/j.imbio.2009.09.003

    CAS  PubMed  Google Scholar 

  39. Robbins M, Judge A, Ambegia E, Choi C, Yaworski E, Palmer L, McClintock K, MacLachlan I (2008) Misinterpreting the therapeutic effects of small interfering RNA caused by immune stimulation. Hum Gene Ther 19(10):991–999. doi:10.1089/hum.2008.131

    CAS  PubMed  Google Scholar 

  40. Ge Q, Filip L, Bai A, Nguyen T, Eisen HN, Chen J (2004) Inhibition of influenza virus production in virus-infected mice by RNA interference. Proc Natl Acad Sci USA 101(23):8676–8681. doi:10.1073/pnas.0402486101

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Tompkins SM, Lo CY, Tumpey TM, Epstein SL (2004) Protection against lethal influenza virus challenge by RNA interference in vivo. Proc Natl Acad Sci USA 101(23):8682–8686. doi:10.1073/pnas.0402630101

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Furset G, Sioud M (2007) Design of bifunctional siRNAs: combining immunostimulation and gene-silencing in one single siRNA molecule. Biochem Biophys Res Commun 352(3):642–649. doi:10.1016/j.bbrc.2006.11.059

    CAS  PubMed  Google Scholar 

  43. Iversen PO, Semaeva E, Sorensen DR, Wiig H, Sioud M (2009) Dendritic cells loaded with tumor antigens and a dual immunostimulatory and anti-interleukin 10-specific small interference RNA prime t lymphocytes against leukemic cells. Transl Oncol 2(4):242–246

    PubMed Central  PubMed  Google Scholar 

  44. Khairuddin N, Gantier MP, Blake SJ, Wu SY, Behlke MA, Williams BR, McMillan NA (2011) siRNA-induced immunostimulation through TLR7 promotes antitumoral activity against HPV-driven tumors in vivo. Immunol Cell Biol. doi:10.1038/icb.2011.19

    PubMed  Google Scholar 

  45. Lu PY, Woodle MC (2008) Delivering small interfering RNA for novel therapeutics. Methods Mol Biol 437:93–107. doi:10.1007/978-1-59745-210-6_3

    CAS  PubMed  Google Scholar 

  46. Castanotto D, Rossi JJ (2009) The promises and pitfalls of RNA-interference-based therapeutics. Nature 457(7228):426–433. doi:10.1038/nature07758

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Bumcrot D, Manoharan M, Koteliansky V, Sah DW (2006) RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol 2(12):711–719. doi:10.1038/nchembio839

    CAS  PubMed  Google Scholar 

  48. Gomes-da-Silva LC, Fonseca NA, Moura V, Pedroso de Lima MC, Simoes S, Moreira JN (2012) Lipid-based nanoparticles for siRNA delivery in cancer therapy: paradigms and challenges. Acc Chem Res 45(7):1163–1171. doi:10.1021/ar300048p

    CAS  PubMed  Google Scholar 

  49. Rossi JJ (2008) Expression strategies for short hairpin RNA interference triggers. Hum Gene Ther 19(4):313–317

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Kim DH, Rossi JJ (2007) Strategies for silencing human disease using RNA interference. Nat Rev Genet 8(3):173–184. doi:10.1038/nrg2006

    CAS  PubMed  Google Scholar 

  51. Knop K, Hoogenboom R, Fischer D, Schubert US (2010) Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew Chem Int Ed Engl 49(36):6288–6308. doi:10.1002/anie.200902672

    CAS  PubMed  Google Scholar 

  52. Heyes J, Palmer L, Bremner K, MacLachlan I (2005) Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids. J Control Release 107(2):276–287. doi:10.1016/j.jconrel.2005.06.014

    CAS  PubMed  Google Scholar 

  53. Semple SC, Akinc A, Chen J, Sandhu AP, Mui BL, Cho CK, Sah DW, Stebbing D, Crosley EJ, Yaworski E, Hafez IM, Dorkin JR, Qin J, Lam K, Rajeev KG, Wong KF, Jeffs LB, Nechev L, Eisenhardt ML, Jayaraman M, Kazem M, Maier MA, Srinivasulu M, Weinstein MJ, Chen Q, Alvarez R, Barros SA, De S, Klimuk SK, Borland T, Kosovrasti V, Cantley WL, Tam YK, Manoharan M, Ciufolini MA, Tracy MA, de Fougerolles A, MacLachlan I, Cullis PR, Madden TD, Hope MJ (2010) Rational design of cationic lipids for siRNA delivery. Nat Biotechnol 28(2):172–176. doi:10.1038/nbt.1602

    CAS  PubMed  Google Scholar 

  54. Jeffs LB, Palmer LR, Ambegia EG, Giesbrecht C, Ewanick S, MacLachlan I (2005) A scalable, extrusion-free method for efficient liposomal encapsulation of plasmid DNA. Pharm Res 22(3):362–372

    CAS  PubMed  Google Scholar 

  55. Geisbert TW, Hensley LE, Kagan E, Yu EZ, Geisbert JB, Daddario-DiCaprio K, Fritz EA, Jahrling PB, McClintock K, Phelps JR, Lee AC, Judge A, Jeffs LB, MacLachlan I (2006) Postexposure protection of guinea pigs against a lethal Ebola virus challenge is conferred by RNA interference. J Infect Dis 193(12):1650–1657. doi:10.1086/504267

    CAS  PubMed  Google Scholar 

  56. Semple SC, Klimuk SK, Harasym TO, Dos Santos N, Ansell SM, Wong KF, Maurer N, Stark H, Cullis PR, Hope MJ, Scherrer P (2001) Efficient encapsulation of antisense oligonucleotides in lipid vesicles using ionizable aminolipids: formation of novel small multilamellar vesicle structures. Biochim Biophys Acta 1510(1–2):152–166 (pii:S0005-2736(00)00343-6)

    CAS  PubMed  Google Scholar 

  57. Maurer N, Wong KF, Stark H, Louie L, McIntosh D, Wong T, Scherrer P, Semple SC, Cullis PR (2001) Spontaneous entrapment of polynucleotides upon electrostatic interaction with ethanol-destabilized cationic liposomes. Biophys J 80(5):2310–2326. doi:10.1016/S0006-3495(01)76202-9

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Ambegia E, Ansell S, Cullis P, Heyes J, Palmer L, MacLachlan I (2005) Stabilized plasmid-lipid particles containing PEG-diacylglycerols exhibit extended circulation lifetimes and tumor selective gene expression. Biochim Biophys Acta 1669(2):155–163. doi:10.1016/j.bbamem.2005.02.001

    CAS  PubMed  Google Scholar 

  59. Judge AD, Robbins M, Tavakoli I, Levi J, Hu L, Fronda A, Ambegia E, McClintock K, MacLachlan I (2009) Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice. J Clin Invest 119(3):661–673. doi:10.1172/JCI37515

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Wheeler JJ, Palmer L, Ossanlou M, MacLachlan I, Graham RW, Zhang YP, Hope MJ, Scherrer P, Cullis PR (1999) Stabilized plasmid-lipid particles: construction and characterization. Gene Ther 6(2):271–281. doi:10.1038/sj.gt.3300821

    CAS  PubMed  Google Scholar 

  61. Reddy LH, Couvreur P (2011) Nanotechnology for therapy and imaging of liver diseases. J Hepatol 55(6):1461–1466. doi:10.1016/j.jhep.2011.05.039

    CAS  PubMed  Google Scholar 

  62. Akinc A, Querbes W, De S, Qin J, Frank-Kamenetsky M, Jayaprakash KN, Jayaraman M, Rajeev KG, Cantley WL, Dorkin JR, Butler JS, Qin L, Racie T, Sprague A, Fava E, Zeigerer A, Hope MJ, Zerial M, Sah DW, Fitzgerald K, Tracy MA, Manoharan M, Koteliansky V, Fougerolles A, Maier MA (2010) Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol Ther 18(7):1357–1364. doi:10.1038/mt.2010.85

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Geisbert TW, Lee AC, Robbins M, Geisbert JB, Honko AN, Sood V, Johnson JC, de Jong S, Tavakoli I, Judge A, Hensley LE, Maclachlan I (2010) Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet 375(9729):1896–1905. doi:10.1016/S0140-6736(10)60357-1

    CAS  PubMed  Google Scholar 

  64. Lin X, Li L, Wang R, Wilcox D, Zhao X, Song J, Huang X, Hansen TM, Dande P, Wada C, Hubbard RD, Kohlbrenner WM, Fesik SW, Shen Y (2011) A robust in vivo positive-readout system for monitoring siRNA delivery to xenograft tumors. RNA 17(4):603–612. doi:10.1261/rna.2546011

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Li L, Wang R, Wilcox D, Zhao X, Song J, Lin X, Kohlbrenner WM, Fesik SW, Shen Y (2011) Tumor vasculature is a key determinant for the efficiency of nanoparticle-mediated siRNA delivery. Gene Ther. doi:10.1038/gt.2011.146

    Google Scholar 

  66. Jain RK (1994) Barriers to drug delivery in solid tumors. Sci Am 271(1):58–65

    CAS  PubMed  Google Scholar 

  67. Jain RK, Stylianopoulos T (2010) Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 7(11):653–664. doi:10.1038/nrclinonc.2010.139

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Jang SH, Wientjes MG, Lu D, Au JL (2003) Drug delivery and transport to solid tumors. Pharm Res 20(9):1337–1350

    CAS  PubMed  Google Scholar 

  69. Heddleston JM, Li Z, Lathia JD, Bao S, Hjelmeland AB, Rich JN (2010) Hypoxia inducible factors in cancer stem cells. Br J Cancer 102(5):789–795. doi:10.1038/sj.bjc.6605551

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Carmeliet P, Jain RK (2011) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10(6):417–427. doi:10.1038/nrd3455

    CAS  PubMed  Google Scholar 

  71. Gomes CP, Gomes-da-Silva LC, Ramalho JS, de Lima MC, Simoes S, Moreira JN (2013) Impact Of Plk-1 Silencing On Endothelial Cells And Cancer Cells Of Diverse Histological Origin. Curr Gene Ther 13(3):189–201 (pii:CGT-EPUB-20130325-3)

    Google Scholar 

  72. Fang J, Nakamura H, Maeda H (2011) The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 63(3):136–151. doi:10.1016/j.addr.2010.04.009

    CAS  PubMed  Google Scholar 

  73. Love KT, Mahon KP, Levins CG, Whitehead KA, Querbes W, Dorkin JR, Qin J, Cantley W, Qin LL, Racie T, Frank-Kamenetsky M, Yip KN, Alvarez R, Sah DW, de Fougerolles A, Fitzgerald K, Koteliansky V, Akinc A, Langer R, Anderson DG (2010) Lipid-like materials for low-dose, in vivo gene silencing. Proc Natl Acad Sci USA 107(5):1864–1869. doi:10.1073/pnas.0910603106

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Liu Y, Huang L (2010) Designer lipids advance systemic siRNA delivery. Mol Ther 18(4):669–670. doi:10.1038/mt.2010.39

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Bellocq NC, Pun SH, Jensen GS, Davis ME (2003) Transferrin-containing, cyclodextrin polymer-based particles for tumor-targeted gene delivery. Bioconjug Chem 14(6):1122–1132. doi:10.1021/bc034125f

    CAS  PubMed  Google Scholar 

  76. Davis ME (2009) The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic. Mol Pharm 6(3):659–668. doi:10.1021/mp900015y

    CAS  PubMed  Google Scholar 

  77. Heidel JD, Liu JY, Yen Y, Zhou B, Heale BS, Rossi JJ, Bartlett DW, Davis ME (2007) Potent siRNA inhibitors of ribonucleotide reductase subunit RRM2 reduce cell proliferation in vitro and in vivo. Clin Cancer Res 13(7):2207–2215. doi:10.1158/1078-0432.CCR-06-2218

    CAS  PubMed  Google Scholar 

  78. Bartlett DW, Davis ME (2008) Impact of tumor-specific targeting and dosing schedule on tumor growth inhibition after intravenous administration of siRNA-containing nanoparticles. Biotechnol Bioeng 99(4):975–985. doi:10.1002/bit.21668

    CAS  PubMed  Google Scholar 

  79. Rahman MA, Amin AR, Wang X, Zuckerman JE, Choi CH, Zhou B, Wang D, Nannapaneni S, Koenig L, Chen Z, Chen ZG, Yen Y, Davis ME, Shin DM (2012) Systemic delivery of siRNA nanoparticles targeting RRM2 suppresses head and neck tumor growth. J Control Release 159(3):384–392. doi:10.1016/j.jconrel.2012.01.045

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Santel A, Aleku M, Keil O, Endruschat J, Esche V, Fisch G, Dames S, Loffler K, Fechtner M, Arnold W, Giese K, Klippel A, Kaufmann J (2006) A novel siRNA-lipoplex technology for RNA interference in the mouse vascular endothelium. Gene Ther 13(16):1222–1234. doi:10.1038/sj.gt.3302777

    CAS  PubMed  Google Scholar 

  81. Santel A, Aleku M, Keil O, Endruschat J, Esche V, Durieux B, Loffler K, Fechtner M, Rohl T, Fisch G, Dames S, Arnold W, Giese K, Klippel A, Kaufmann J (2006) RNA interference in the mouse vascular endothelium by systemic administration of siRNA-lipoplexes for cancer therapy. Gene Ther 13(18):1360–1370. doi:10.1038/sj.gt.3302778

    CAS  PubMed  Google Scholar 

  82. Aleku M, Schulz P, Keil O, Santel A, Schaeper U, Dieckhoff B, Janke O, Endruschat J, Durieux B, Roder N, Loffler K, Lange C, Fechtner M, Mopert K, Fisch G, Dames S, Arnold W, Jochims K, Giese K, Wiedenmann B, Scholz A, Kaufmann J (2008) Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. Cancer Res 68(23):9788–9798. doi:10.1158/0008-5472.CAN-08-2428

    CAS  PubMed  Google Scholar 

  83. Santel A, Aleku M, Roder N, Mopert K, Durieux B, Janke O, Keil O, Endruschat J, Dames S, Lange C, Eisermann M, Loffler K, Fechtner M, Fisch G, Vank C, Schaeper U, Giese K, Kaufmann J (2010) Atu027 prevents pulmonary metastasis in experimental and spontaneous mouse metastasis models. Clin Cancer Res 16(22):5469–5480. doi:10.1158/1078-0432.CCR-10-1994

    CAS  PubMed  Google Scholar 

  84. Mopert K, Loffler K, Roder N, Kaufmann J, Santel A (2012) Depletion of protein kinase N3 (PKN3) impairs actin and adherens junctions dynamics and attenuates endothelial cell activation. Eur J Cell Biol 91(9):694–705. doi:10.1016/j.ejcb.2012.03.010

    PubMed  Google Scholar 

  85. Gutierrez-Puente Y, Tari AM, Stephens C, Rosenblum M, Guerra RT, Lopez-Berestein G (1999) Safety, pharmacokinetics, and tissue distribution of liposomal P-ethoxy antisense oligonucleotides targeted to Bcl-2. J Pharmacol Exp Ther 291(2):865–869

    CAS  PubMed  Google Scholar 

  86. Landen CN Jr, Chavez-Reyes A, Bucana C, Schmandt R, Deavers MT, Lopez-Berestein G, Sood AK (2005) Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery. Cancer Res 65(15):6910–6918. doi:10.1158/0008-5472.CAN-05-0530

    CAS  PubMed  Google Scholar 

  87. Landen CN, Merritt WM, Mangala LS, Sanguino AM, Bucana C, Lu C, Lin YG, Han LY, Kamat AA, Schmandt R, Coleman RL, Gershenson DM, Lopez-Berestein G, Sood AK (2006) Intraperitoneal delivery of liposomal siRNA for therapy of advanced ovarian cancer. Cancer Biol Ther 5(12):1708–1713 (pii:3468)

    CAS  PubMed  Google Scholar 

  88. Shahzad MM, Lu C, Lee JW, Stone RL, Mitra R, Mangala LS, Lu Y, Baggerly KA, Danes CG, Nick AM, Halder J, Kim HS, Vivas-Mejia P, Landen CN, Lopez-Berestein G, Coleman RL, Sood AK (2009) Dual targeting of EphA2 and FAK in ovarian carcinoma. Cancer Biol Ther 8(11):1027–1034 (pii:8523)

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Gaspar R, Duncan R (2009) Polymeric carriers: preclinical safety and the regulatory implications for design and development of polymer therapeutics. Adv Drug Deliv Rev 61(13):1220–1231. doi:10.1016/j.addr.2009.06.003

    CAS  PubMed  Google Scholar 

  90. Karmali PP, Chaudhuri A (2007) Cationic liposomes as non-viral carriers of gene medicines: resolved issues, open questions, and future promises. Med Res Rev 27(5):696–722. doi:10.1002/med.20090

    CAS  PubMed  Google Scholar 

  91. Dams ET, Laverman P, Oyen WJ, Storm G, Scherphof GL, van Der Meer JW, Corstens FH, Boerman OC (2000) Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes. J Pharmacol Exp Ther 292(3):1071–1079

    CAS  PubMed  Google Scholar 

  92. Ishida T, Harada M, Wang XY, Ichihara M, Irimura K, Kiwada H (2005) Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes. J Control Release 105(3):305–317. doi:10.1016/j.jconrel.2005.04.003

    CAS  PubMed  Google Scholar 

  93. Ishida T, Ichihara M, Wang X, Kiwada H (2006) Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes. J Control Release 115(3):243–250. doi:10.1016/j.jconrel.2006.08.001

    CAS  PubMed  Google Scholar 

  94. Ishida T, Ichihara M, Wang X, Yamamoto K, Kimura J, Majima E, Kiwada H (2006) Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes. J Control Release 112(1):15–25. doi:10.1016/j.jconrel.2006.01.005

    CAS  PubMed  Google Scholar 

  95. Koide H, Asai T, Hatanaka K, Akai S, Ishii T, Kenjo E, Ishida T, Kiwada H, Tsukada H, Oku N (2010) T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes. Int J Pharm 392(1–2):218–223. doi:10.1016/j.ijpharm.2010.03.022

    CAS  PubMed  Google Scholar 

  96. Judge A, McClintock K, Phelps JR, Maclachlan I (2006) Hypersensitivity and loss of disease site targeting caused by antibody responses to PEGylated liposomes. Mol Ther 13(2):328–337. doi:10.1016/j.ymthe.2005.09.014

    CAS  PubMed  Google Scholar 

  97. Semple SC, Harasym TO, Clow KA, Ansell SM, Klimuk SK, Hope MJ (2005) Immunogenicity and rapid blood clearance of liposomes containing polyethylene glycol-lipid conjugates and nucleic Acid. J Pharmacol Exp Ther 312(3):1020–1026. doi:10.1124/jpet.104.078113

    CAS  PubMed  Google Scholar 

  98. Tagami T, Nakamura K, Shimizu T, Ishida T, Kiwada H (2009) Effect of siRNA in PEG-coated siRNA-lipoplex on anti-PEG IgM production. J Control Release 137(3):234–240. doi:10.1016/j.jconrel.2009.04.006

    CAS  PubMed  Google Scholar 

  99. Tagami T, Uehara Y, Moriyoshi N, Ishida T, Kiwada H (2011) Anti-PEG IgM production by siRNA encapsulated in a PEGylated lipid nanocarrier is dependent on the sequence of the siRNA. J Control Release 151(2):149–154. doi:10.1016/j.jconrel.2010.12.013

    CAS  PubMed  Google Scholar 

  100. Barros SA, Gollob JA (2012) Safety profile of RNAi nanomedicines. Adv Drug Deliv Rev 64(15):1730–1737. doi:10.1016/j.addr.2012.06.007

    CAS  PubMed  Google Scholar 

  101. Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME, Triche TJ (2005) Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing’s sarcoma. Cancer Res 65(19):8984–8992. doi:10.1158/0008-5472.CAN-05-0565

    CAS  PubMed  Google Scholar 

  102. Allen TM (2002) Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer 2(10):750–763. doi:10.1038/nrc903

    CAS  PubMed  Google Scholar 

  103. Santos AO, da Silva LC, Bimbo LM, de Lima MC, Simoes S, Moreira JN (2010) Design of peptide-targeted liposomes containing nucleic acids. Biochim Biophys Acta 1798(3):433–441. doi:10.1016/j.bbamem.2009.12.001

    CAS  PubMed  Google Scholar 

  104. Woll PJ, Rozengurt E (1990) A neuropeptide antagonist that inhibits the growth of small cell lung cancer in vitro. Cancer Res 50(13):3968–3973

    CAS  PubMed  Google Scholar 

  105. Mishra S, Webster P, Davis ME (2004) PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. Eur J Cell Biol 83(3):97–111

    CAS  PubMed  Google Scholar 

  106. Li SD, Chen YC, Hackett MJ, Huang L (2008) Tumor-targeted delivery of siRNA by self-assembled nanoparticles. Mol Ther 16(1):163–169. doi:10.1038/sj.mt.6300323

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Li SD, Chono S, Huang L (2008) Efficient oncogene silencing and metastasis inhibition via systemic delivery of siRNA. Mol Ther 16(5):942–946. doi:10.1038/mt.2008.51

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Gao J, Liu W, Xia Y, Li W, Sun J, Chen H, Li B, Zhang D, Qian W, Meng Y, Deng L, Wang H, Chen J, Guo Y (2011) The promotion of siRNA delivery to breast cancer overexpressing epidermal growth factor receptor through anti-EGFR antibody conjugation by immunoliposomes. Biomaterials 32(13):3459–3470. doi:10.1016/j.biomaterials.2011.01.034

    CAS  PubMed  Google Scholar 

  109. Gao J, Yu Y, Zhang Y, Song J, Chen H, Li W, Qian W, Deng L, Kou G, Chen J, Guo Y (2012) EGFR-specific PEGylated immunoliposomes for active siRNA delivery in hepatocellular carcinoma. Biomaterials 33(1):270–282. doi:10.1016/j.biomaterials.2011.09.035

    CAS  PubMed  Google Scholar 

  110. Mendonca LS, Moreira JN, de Lima MC, Simoes S (2010) Co-encapsulation of anti-BCR-ABL siRNA and imatinib mesylate in transferrin receptor-targeted sterically stabilized liposomes for chronic myeloid leukemia treatment. Biotechnol Bioeng 107(5):884–893. doi:10.1002/bit.22858

    CAS  PubMed  Google Scholar 

  111. Chiu SJ, Liu S, Perrotti D, Marcucci G, Lee RJ (2006) Efficient delivery of a Bcl-2-specific antisense oligodeoxyribonucleotide (G3139) via transferrin receptor-targeted liposomes. J Control Release 112(2):199–207. doi:10.1016/j.jconrel.2006.02.011

    CAS  PubMed  Google Scholar 

  112. Chiu SJ, Marcucci G, Lee RJ (2006) Efficient delivery of an antisense oligodeoxyribonucleotide formulated in folate receptor-targeted liposomes. Anticancer Res 26(2A):1049–1056

    CAS  PubMed  Google Scholar 

  113. Yang L, Li J, Zhou W, Yuan X, Li S (2004) Targeted delivery of antisense oligodeoxynucleotides to folate receptor-overexpressing tumor cells. J Control Release 95(2):321–331. doi:10.1016/j.jconrel.2003.11.021

    CAS  PubMed  Google Scholar 

  114. Feng C, Wang T, Tang R, Wang J, Long H, Gao X, Tang S (2010) Silencing of the MYCN gene by siRNA delivered by folate receptor-targeted liposomes in LA-N-5 cells. Pediatr Surg Int 26(12):1185–1191. doi:10.1007/s00383-010-2703-5

    PubMed  Google Scholar 

  115. Cardoso AL, Simoes S, de Almeida LP, Pelisek J, Culmsee C, Wagner E, Pedroso de Lima MC (2007) siRNA delivery by a transferrin-associated lipid-based vector: a non-viral strategy to mediate gene silencing. J Gene Med 9(3):170–183. doi:10.1002/jgm.1006

    CAS  PubMed  Google Scholar 

  116. Davis ME, Zuckerman JE, Choi CH, Seligson D, Tolcher A, Alabi CA, Yen Y, Heidel JD, Ribas A (2010) Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464(7291):1067–1070. doi:10.1038/nature08956

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Lu W, Zhang G, Zhang R, Flores LG 2nd, Huang Q, Gelovani JG, Li C (2010) Tumor site-specific silencing of NF-kappaB p65 by targeted hollow gold nanosphere-mediated photothermal transfection. Cancer Res 70(8):3177–3188. doi:10.1158/0008-5472.CAN-09-3379

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Sapra P, Allen TM (2003) Ligand-targeted liposomal anticancer drugs. Prog Lipid Res 42(5):439–462 (pii:S0163782703000328)

    CAS  PubMed  Google Scholar 

  119. Sapra P, Tyagi P, Allen TM (2005) Ligand-targeted liposomes for cancer treatment. Curr Drug Deliv 2(4):369–381

    CAS  PubMed  Google Scholar 

  120. Zhu Q, Feng C, Liao W, Zhang Y, Tang S (2013) Target delivery of MYCN siRNA by folate-nanoliposomes delivery system in a metastatic neuroblastoma model. Cancer Cell Int 13(1):65. doi:10.1186/1475-2867-13-65

    CAS  PubMed Central  PubMed  Google Scholar 

  121. da Cruz MT, Simoes S, Pires PP, Nir S, de Lima MC (2001) Kinetic analysis of the initial steps involved in lipoplex–cell interactions: effect of various factors that influence transfection activity. Biochim Biophys Acta 1510(1–2):136–151 (pii:S0005273600003424)

    PubMed  Google Scholar 

  122. Bartlett DW, Su H, Hildebrandt IJ, Weber WA, Davis ME (2007) Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc Natl Acad Sci USA 104(39):15549–15554. doi:10.1073/pnas.0707461104

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Iyer AK, Khaled G, Fang J, Maeda H (2006) Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today 11(17–18):812–818. doi:10.1016/j.drudis.2006.07.005

    CAS  PubMed  Google Scholar 

  124. Li SD, Huang L (2008) Pharmacokinetics and biodistribution of nanoparticles. Mol Pharm 5(4):496–504. doi:10.1021/mp800049w

    CAS  PubMed  Google Scholar 

  125. Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29(6 Suppl 16):15–18. doi:10.1053/sonc.2002.37263

    CAS  PubMed  Google Scholar 

  126. Abdollahi A, Folkman J (2010) Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist Updat 13(1–2):16–28. doi:10.1016/j.drup.2009.12.001

    CAS  PubMed  Google Scholar 

  127. Simone E, Ding BS, Muzykantov V (2009) Targeted delivery of therapeutics to endothelium. Cell Tissue Res 335(1):283–300. doi:10.1007/s00441-008-0676-7

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Ding BS, Dziubla T, Shuvaev VV, Muro S, Muzykantov VR (2006) Advanced drug delivery systems that target the vascular endothelium. Mol Interv 6(2):98–112. doi:10.1124/mi.6.2.7

    CAS  PubMed  Google Scholar 

  129. Hajitou A, Pasqualini R, Arap W (2006) Vascular targeting: recent advances and therapeutic perspectives. Trends Cardiovasc Med 16(3):80–88. doi:10.1016/j.tcm.2006.01.003

    CAS  PubMed  Google Scholar 

  130. Chen Y, Wu JJ, Huang L (2010) Nanoparticles targeted with NGR motif deliver c-myc siRNA and doxorubicin for anticancer therapy. Mol Ther 18(4):828–834. doi:10.1038/mt.2009.291

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Porkka K, Laakkonen P, Hoffman JA, Bernasconi M, Ruoslahti E (2002) A fragment of the HMGN2 protein homes to the nuclei of tumor cells and tumor endothelial cells in vivo. Proc Natl Acad Sci USA 99(11):7444–7449. doi:10.1073/pnas.062189599

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Christian S, Pilch J, Akerman ME, Porkka K, Laakkonen P, Ruoslahti E (2003) Nucleolin expressed at the cell surface is a marker of endothelial cells in angiogenic blood vessels. J Cell Biol 163(4):871–878. doi:10.1083/jcb.200304132

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Gomes-da-Silva LC, Santos AO, Bimbo LM, Moura V, Ramalho JS, Pedroso de Lima MC, Simoes S, Moreira JN (2012) Toward a siRNA-containing nanoparticle targeted to breast cancer cells and the tumor microenvironment. Int J Pharm 434(1–2):9–19. doi:10.1016/j.ijpharm.2012.05.018

    CAS  PubMed  Google Scholar 

  134. Gomes-da-Silva LC, Fernandez Y, Abasolo I, Schwartz S, Ramalho JS, Pedroso de Lima MC, Simoes S, Moreira JN (2013) Efficient intracellular delivery of siRNA with a safe multitargeted lipid-based nanoplatform. Nanomedicine (Lond). doi:10.2217/nnm.12.174

    Google Scholar 

  135. Gomes-da-Silva LC, Ramalho JS, Pedroso de Lima MC, Simoes S, Moreira JN (2013) Impact of anti-PLK1 siRNA-containing F3-targeted liposomes on the viability of both cancer and endothelial cells. Eur J Pharm Biopharm. doi:10.1016/j.ejpb.2013.04.007

    PubMed  Google Scholar 

  136. Moura V, Lacerda M, Figueiredo P, Corvo ML, Cruz ME, Soares R, de Lima MC, Simoes S, Moreira JN (2012) Targeted and intracellular triggered delivery of therapeutics to cancer cells and the tumor microenvironment: impact on the treatment of breast cancer. Breast Cancer Res Treat 133(1):61–73. doi:10.1007/s10549-011-1688-7

    CAS  PubMed  Google Scholar 

  137. Strumberg D, Schultheis B, Traugott U, Vank C, Santel A, Keil O, Giese K, Kaufmann J, Drevs J (2012) Phase I clinical development of Atu027, a siRNA formulation targeting PKN3 in patients with advanced solid tumors. Int J Clin Pharmacol Ther 50(1):76–78 (pii:9341)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge Nuno Fonseca for his help with Fig. 1. The work performed by the authors was supported by the Portugal–Spain capacitation program in Nanoscience and Nanotechnology (ref.: NANO/NMed-AT/0042/2007) and grant PEst-C/SAU/LA0001/2011.

Author information

Authors and Affiliations

  1. CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Lígia Catarina Gomes-da-Silva, Sérgio Simões & João Nuno Moreira

  2. FFUC - Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

    Lígia Catarina Gomes-da-Silva, Sérgio Simões & João Nuno Moreira

Authors
  1. Lígia Catarina Gomes-da-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sérgio Simões
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. João Nuno Moreira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to João Nuno Moreira.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gomes-da-Silva, L.C., Simões, S. & Moreira, J.N. Challenging the future of siRNA therapeutics against cancer: the crucial role of nanotechnology. Cell. Mol. Life Sci. 71, 1417–1438 (2014). https://doi.org/10.1007/s00018-013-1502-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-013-1502-2

Keywords

Search

Navigation