Cell penetrating peptide

from Wikipedia, the free encyclopedia
CPP with a) double-stranded DNA or RNA, b) single-stranded DNA or RNA, c) plasmid DNA or d) proteins

A cell-penetrating peptide (engl. Cell-penetrating peptide , CPP, or protein transduction domain , transduction domain , PTD) denotes a peptide , the cell membranes penetrate through (penetrate) can. As a result, a fusion protein attached to the peptide , as well as nucleic acids or nanoparticles connected covalently or non-covalently to the cell-penetrating peptide , can be introduced into cells . With cell-penetrating peptides, small molecules such as cytostatics , antivirals , contrast media or even quantum dots were brought into cells.

This protein transduction was discovered simultaneously by two research groups in 1988 when it was discovered that the Tat protein of the human immunodeficiency virus (HIV) was taken up by different cell types in cell culture . Since then, further examples of the CPP have become known. Even with polycationic proteins, such as. B. antibodies directed against DNA or histones could be shown uptake in cells.

mechanism

Most cell-penetrating peptides consist mainly of basic and non-polar amino acids , especially lysine and arginine , tryptophan , phenylalanine , leucine and isoleucine ( polycationic type). The cationic amino acids bind to negatively charged receptors on the cell surface, e.g. B. sialic acids or heparan sulfate , while the non-polar amino acids mediate adsorption to the lipids of the cell membrane. Another type consists of alternating polar and non-polar amino acids ( amphipathic type).

Endocytic pathways
Inverted micelle

Cell-penetrating peptides have different sequences and there are three hypotheses as to how cell penetration occurs:

  • via direct penetration of the cell membrane through pore formation
  • via hygroscopic buffer effects ( proton sponge ), which after endocytosis lead to swelling of the endosome and tears in the endosome membrane .
  • via membrane insertion and the formation of inverted micelles

In some cases, the binding to cells and the endocytosis is increased by binding to receptors , e.g. B. chemokine receptors , syndecans, neuropilins, or integrins . After cell penetration occurred even without endocytosis at 4 ° C, direct penetration , as well as endocytosis- and ATP- independent penetration, was suspected, but artifacts of fixation and staining were also reported. The fact that CPP can also be distributed through ER membranes or artificial lipid bilayers speaks in favor of direct penetration . The formation of a membrane pore on the endosomal membrane or the cell membrane has been verified experimentally. However, an uneven distribution of the CPP in different cell compartments, a reduction in the distribution of the CPP penetratin when endocytosis inhibitors are added, a microscopic colocalization with caveolin and an uptake via pinocytosis speak in favor of endocytosis . It is possible that more than one uptake mechanism is running in parallel; in particular, the proportions of these mechanisms change when the size of the attached molecule or particle changes. The third mechanism presumes the formation of an inverted micelle in which the phosphate groups of the membrane lipids around the CPP and the aliphatic components are oriented outwards. This leaves the peptide in a hydrophilic environment.

Typical representatives of the cell-penetrating peptides are z. B. Penetratin, Transportan, HIV1 Tat peptide 48-60 , HIV1 Rev peptide 34-50 , Antennapedia 43-58, and octaarginine.

Applications

Covalent coupling and adsorption of CPP, A with dsDNA or dsRNA , B with ssDNA or ssRNA , C with plasmids , D with other macromolecules
Covalent coupling types of CPP to nucleic acids

Cell-penetrating peptides can be used in research and therapy as transfection reagents for the transport of RNA, DNA, PNA and morpholinos . Cyclic octaarginines were used for the endocytosis-independent transport of antigen-binding proteins. Modified CPP constructions can be activated by special enzymes such as MMP or by photonic signals and thus enable the targeted transfection of certain cell types .

Cell-penetrating peptides can be coupled to nucleic acids through various bonds, including cleavable linkers, e.g. B. with disulfide bridges , amides , thiazolidine , oximes and hydrazines . However, these groups are believed to have an impact on biological activity . Therefore non-covalent methods of connection between CPP and nucleic acids are also used. Covalent and non-covalent methods were used with siRNA . Likewise, CPP with anti-competitive DNA, plasmids , proteins, contrast agents , quantum dots , gadolinium complexes and superparamagnetic iron oxide (SPIO) were used.

Overview literature

Web links

Individual evidence

  1. ↑ KM Stewart, KL Horton, SO Kelley: Cell-penetrating peptides as delivery vehicles for biology and medicine. In: Organic & biomolecular chemistry. Volume 6, Number 13, July 2008, pp. 2242-2255, ISSN  1477-0520 . doi: 10.1039 / b719950c . PMID 18563254 . (Review).
  2. ↑ M. Kylie, DA Jans: Protein Transduction: Cell Penetrating Peptides and Their Therapeutic Applications. In: Current Medicinal Chemistry . Volume 13 (12), 2006, pp. 1371-1387.
  3. ↑ M. Okuyama, H. Laman et al: Small-molecule mimics of an alpha-helix for efficient transport of proteins into cells. In: Nature methods . Volume 4, Number 2, February 2007, pp. 153-159, ISSN  1548-7091 . doi: 10.1038 / nmeth997 . PMID 17220893 .
  4. ↑ A. Avrameas, T. Ternynck et al: Polyreactive anti-DNA monoclonal antibodies and a derived peptide as vectors for the intracytoplasmic and intranuclear translocation of macromolecules. In: PNAS . Volume 95, Number 10, May 1998, pp. 5601-5606, ISSN  0027-8424 . PMID 9576929 . PMC 20424 (free full text).
  5. ↑ E. Hariton-Gazal, J. Rosenbluh et al .: Direct translocation of histone molecules across cell membranes. In: Journal of cell science. Volume 116, Pt 22, November 2003, pp. 4577-4586, ISSN  0021-9533 . doi: 10.1242 / jcs.00757 . PMID 14576351 .
  6. ↑ A. Joliot, C. Pernelle and others: Antennapedia homeobox peptide regulates neural morphogenesis. In: PNAS. Volume 88, Number 5, March 1991, pp. 1864-1868, ISSN  0027-8424 . PMID 1672046 . PMC 51126 (free full text).
  7. ↑ M. Tyagi, M. Rusnati et al .: Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans. In: The Journal of biological chemistry . Volume 276, Number 5, February 2001, pp. 3254-3261, ISSN  0021-9258 . doi: 10.1074 / jbc.M006701200 . PMID 11024024 .
  8. ↑ JB Opalinska, AM Gewirtz: Nucleic-acid therapeutics: basic principles and recent applications. In: Nature reviews. Drug discovery. Volume 1, Number 7, July 2002, pp. 503-514, ISSN  1474-1776 . doi: 10.1038 / nrd837 . PMID 12120257 . (Review).
  9. ^ F. Eckstein: The versatility of oligonucleotides as potential therapeutics. In: Expert Opinion on Biological Therapy. Volume 7, Number 7, July 2007, pp. 1021-1034, ISSN  1744-7682 . doi: 10.1517 / 14712598.7.7.1021 . PMID 17665991 . (Review).
  10. ^ EL Snyder, CC Saenz, C. Denicourt, BR Meade, X.-S. Cui, IM Kaplan, SF Dowdy: Enhanced targeting and killing of tumor cells expressing the CXC chemokine receptor 4 by transducible anticancer peptides. In: Cancer Res. 65, 2005, pp. 10646-10650.
  11. ↑ T. Letoha, A. Keller-Pinter, E. Kusz, C. Koloszi, Z. Bozso, G. Toth, C. Vizier, Z. Olah, L. Szilak: Cell-penetrating peptide exploited syndecans.Biochim. In: Biophys. Acta (Biomembranes). 1798, 2010, pp. 2258-2263. doi: 10.1016 / j.bbamem.2010.01.022 .
  12. ^ GJ Prud'homme, J. Glinka: Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity. In: Oncotarget. 3, 2012, pp. 921-939.
  13. ↑ Y. Diao, W. Han, H. Zhao, S. Zhu, X. Liu, X. Feng, J. Gu, C. Yao, S. Liu, C. Sun, F. Pan: Designed synthetic analogs of the α-helical peptide temporin-La with improved antitumor efficacies via charge modification and incorporation of the integrin αvβ3 homing domain. In: J. Pept. Sci. 18, 2011, pp. 476-486.
  14. ^ D. Luo, WM Saltzman: Synthetic DNA delivery systems. In: Nature Biotechnology . Volume 18, Number 1, January 2000, pp. 33-37, ISSN  1087-0156 . doi: 10.1038 / 71889 . PMID 10625387 . (Review).
  15. ↑ E. Vivès, P. Brodin, B. Lebleu: A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. In: The Journal of biological chemistry. Volume 272, Number 25, June 1997, pp. 16010-16017, ISSN  0021-9258 . PMID 9188504 .
  16. ↑ O. Zelphati, FC Szoka: Intracellular distribution and mechanism of delivery of oligonucleotides mediated by cationic lipids. In: Pharmaceutical Research . Volume 13, Number 9, September 1996, pp. 1367-1372, ISSN  0724-8741 . PMID 8893276 .
  17. ↑ a b M. Lundberg, M. Johansson: Is VP22 nuclear homing an artifact? In: Nature biotechnology . Volume 19, Number 8, August 2001, pp. 713-714, ISSN  1087-0156 . doi: 10.1038 / 90741 . PMID 11479552 .
  18. ↑ G. Drin, S. Cottin et al: Studies on the internalization mechanism of cationic cell-penetrating peptides. In: The Journal of biological chemistry. Volume 278, Number 33, August 2003, pp. 31192-31201, ISSN  0021-9258 . doi: 10.1074 / jbc.M303938200 . PMID 12783857 .
  19. ↑ HD Herce, AE Garcia: Cell penetrating peptides: how do they do it? In: Journal of biological physics. Volume 33, Number 5-6, December 2007, pp. 345-356, ISSN  0092-0606 . doi: 10.1007 / s10867-008-9074-3 . PMID 19669523 . PMC 2565759 (free full text).
  20. ↑ HD Herce, AE Garcia: Molecular dynamics simulations suggest a mechanism for translocation of the HIV-1 TAT peptide across lipid membranes. In: PNAS. Volume 104, Number 52, December 2007, pp. 20805-20810, ISSN  1091-6490 . doi: 10.1073 / pnas.0706574105 . PMID 18093956 . PMC 2409222 (free full text).
  21. ↑ HD Herce, AE Garcia et al .: Arginine-rich peptides destabilize the plasma membrane, consistent with a pore formation translocation mechanism of cell-penetrating peptides. In: Biophysical Journal. Volume 97, Number 7, October 2009, pp. 1917-1925, ISSN  1542-0086 . doi: 10.1016 / j.bpj.2009.05.066 . PMID 19804722 . PMC 2756373 (free full text).
  22. ↑ a b A. Ferrari, V. Pellegrini et al: Caveolae-mediated internalization of extracellular HIV-1 tat fusion proteins visualized in real time. In: Molecular therapy: the journal of the American Society of Gene Therapy. Volume 8, Number 2, August 2003, pp. 284-294, ISSN  1525-0016 . PMID 12907151 .
  23. ^ AD Frankel, CO Pabo: Cellular uptake of the tat protein from human immunodeficiency virus. In: Cell . Volume 55, Number 6, December 1988, pp. 1189-1193, ISSN  0092-8674 . PMID 2849510 .
  24. ↑ M. Lundberg, S. Wikström, M. Johansson: Cell surface adherence and endocytosis of protein transduction domains. In: Molecular therapy. Volume 8, Number 1, July 2003, pp. 143-150, ISSN  1525-0016 . PMID 12842437 .
  25. ^ J. Howl, ID Nicholl, S. Jones: The many futures for cell-penetrating peptides: how soon is now? In: Biochemical Society transactions. Volume 35, 2007, pp. 767-769, ISSN  0300-5127 . doi: 10.1042 / BST0350767 . PMID 17635144 . (Review).
  26. ↑ J. Tilstra, KK Rehman et al.: Protein transduction: identification, characterization and optimization. In: Biochemical Society transactions . Volume 35, August 2007, pp. 811-815, ISSN  0300-5127 . doi: 10.1042 / BST0350811 . PMID 17635154 . (Review).
  27. ↑ T. Plénat, S. Deshayes et al .: Interaction of primary amphipathic cell-penetrating peptides with phospholipid-supported monolayers. In: Langmuir: the ACS journal of surfaces and colloids. Volume 20, Number 21, October 2004, pp. 9255-9261, ISSN  0743-7463 . doi: 10.1021 / la048622b . PMID 15461515 .
  28. ↑ S. Deshayes, S. Gerbal-Chaloin et al: On the mechanism of non-endosomial peptide-mediated cellular delivery of nucleic acids. In: Biochimica et Biophysica Acta . Volume 1667, Number 2, December 2004, pp. 141-147, ISSN  0006-3002 . doi: 10.1016 / j.bbamem.2004.09.010 . PMID 15581849 .
  29. ↑ S. Deshayes, A. Heitz et al: Insight into the mechanism of internalization of the cell-penetrating carrier peptide Pep-1 through conformational analysis. In: Biochemistry. Volume 43, Number 6, February 2004, pp. 1449-1457, ISSN  0006-2960 . doi: 10.1021 / bi035682s . PMID 14769021 .
  30. ↑ E. Dupont, A. Prochiantz, A. Joliot: penetratin story: an overview. In: Methods in molecular biology (Clifton, NJ). Volume 683, 2011, pp. 21-29, ISSN  1940-6029 . doi : 10.1007 / 978-1-60761-919-2_2 . PMID 21053119 .
  31. ^ AT Jones, EJ Sayers: Cell entry of cell penetrating peptides: tales of tails wagging dogs. In: Journal of controlled release: official journal of the Controlled Release Society. Volume 161, Number 2, July 2012, pp. 582-591, ISSN  1873-4995 . doi: 10.1016 / j.jconrel.2012.04.003 . PMID 22516088 .
  32. ↑ H. Brooks, B. Lebleu, E. Vivès: Indeed, peptide-mediated cellular delivery: back to basics. In: Advanced drug delivery reviews. Volume 57, Number 4, February 2005, pp. 559-577, ISSN  0169-409X . doi: 10.1016 / j.addr.2004.12.001 . PMID 15722164 .
  33. ↑ a b S. Kameyama, M. Horie, T. Kikuchi, T. Omura, T. Takeuchi, I. Nakase, Y. Sugiura, S. Futaki: Effects of cell-permeating peptide binding on the distribution of 125I-labeled Fab fragment in council. In: Bioconjugate Chemistry . Volume 17, Number 3, May-Jun 2006, pp. 597-602, ISSN  1043-1802 . doi: 10.1021 / bc050258k . PMID 16704196 .
  34. ↑ S. Futaki, T. Suzuki, W. Ohashi, T. Yagami, S. Tanaka, K. Ueda, Y. Sugiura: Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. In: The Journal of biological chemistry. Volume 276, Number 8, February 2001, pp. 5836-5840, ISSN  0021-9258 . doi: 10.1074 / jbc.M007540200 . PMID 11084031 .
  35. ↑ TS Zatsepin, JJ Turner, TS Oretskaya, MJ Gait: Conjugates of oligonucleotides and analogues with cell penetrating peptides as gene silencing agents. In: Current pharmaceutical design. Volume 11, Number 28, 2005, pp. 3639-3654, PMID 16305500 .
  36. ↑ M. Pooga, U. Soomets, M. Hällbrink, A. Valkna, K. Saar, K. Rezaei, U. Kahl, JX Hao, XJ Xu, Z. Wiesenfeld-Hallin, T. Hökfelt, T. Bartfai, U Langel: Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo. In: Nature biotechnology. Volume 16, Number 9, September 1998, pp. 857-861, doi : 10.1038 / nbt0998-857 , PMID 9743120 .
  37. ↑ S. Tripathi, B. Chaubey, BE Barton, VN Pandey: Anti HIV-1 virucidal activity of polyamide nucleic acid-membrane transducing peptide conjugates targeted to primer binding site of HIV-1 genome. In: Virology. Volume 363, number 1, June 2007, pp. 91-103, doi : 10.1016 / j.virol.2007.01.016 , PMID 17320140 , PMC 2038983 (free full text).
  38. ^ BW Neuman, DA Stein, AD Kroeker, MR Hong, K. Bestwick, PL Iversen, MJ Buchmeier, Inhibition and escape of SARS-CoV treated with antisense morpholino oligomers, Adv. Exp. Med. Biol. 581 (2006) 567– 571.
  39. ↑ Q. Ge, M. Pastey, D. Kobasa, P. Puthavathana, C. Lupfer, RK Bestwick, PL Iversen, J. Chen, DA Stein, Inhibition of multiple subtypes of influenza Avirus in cell cultures with morpholino oligomers, Antimicrob. Agents Chemother. 50 (2006) 3724-3733.
  40. ↑ B. Wu, HM Moulton, PL Iversen, J. Jiang, J. Li, J. Li, CF Spurney, A. Sali, AD Guerron, K. Nagaraju, T. Doran, P. Lu, X. Xiao, QL Lu, Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer, Proc Natl Acad Sci US A. 105 (2008) 14814-14819.
  41. ^ Siegmund Reissmann: Cell penetration: scope and limitations by the application of cell-penetrating peptides. In: J. Pept. Sci. Volume 20, 2014, pp. 760-784, doi: 10.1002 / psc.2672
  42. ↑ MC Morris, S. Deshayes, F. Simeoni, G. Aldrian-Herrada, F. Heitz, G. Divita, A noncovalent peptide-based strategy for peptide and short interfering RNA delivery, in: Ü. Langel (Ed.), Cell-penetrating peptides, 2007, pp. 387-408.
  43. ↑ S. El-Andaloussi, T. Holm, Ü. Langel, Cell-penetrating peptides: mechanism and applications, Curr. Pharma. Design 11 (2005) 3597-3611.
  44. ^ J. Gariepy, K. Kawamura, Vectorial delivery of macromolecules into cells using peptide-based vehicles, Trends Biotechnol. 19 (2000) 21-28.
  45. ↑ Henry D. Herce, Dominik Schumacher, Anselm FL Schneider, Anne K. Ludwig, Florian A. Mann: Cell-permeable nanobodies for targeted immunolabelling and antigen manipulation in living cells . In: Nature Chemistry . tape 9 , no. 8 , 2017, ISSN  1755-4349 , p. 762-771 , doi : 10.1038 / nchem.2811 ( nature.com [accessed November 24, 2017]).
  46. ↑ Emilia S. Olson, Todd A. Aguilera, Tao Jiang, Lesley G. Ellies, Quyen T. Nguyen, Edmund Wong, Larry Gross, Roger Y. Tsien: In vivo characterization of activatable cell penetrating peptides for targeting protease activity in cancer. In: Integr Biol (Camb). Volume 1, Issue 5-6, 2009, pp. 382-393. doi: 10.1039 / b904890a , PMC 2796841 (free full text).
  47. ↑ John J. Turner, Andrey A. Arzumanov, Gabriela Ivanova, Martin Fabani, and Michael J. Gait; Peptide Conjugates of Oligonucleotide Analogs and siRNA for Gene Expression Modulation; in: Ü Langel. Handbook of Cell-Penetrating Peptides, Second Edition, 2007
  48. ↑ Stetsenko, DA and Gait, MJ, Efficient conjugation of peptides to oligonucleotides by 'native ligation', J. Org. Chem., 65, 4900, 2000.
  49. ↑ BR Meade, SF Dowdy, Exogenous siRNA delivery using peptide transduction domains / cell penetrating peptides, Adv. Drug Deliv. Rev. 59 (2007) 134-140.
  50. ↑ MC Morris, P. Vidal, L. Chaloin, F. Heitz, G. Divita, A new peptide vector for efficient delivery of oligonucleotides into mammalian cells, Nucleic Acids Res. 25 (1997) 2730-2736.
  51. ↑ F. Simeoni, MC Morris, F. Heitz, G. Divita, Insight into the mechanism of the peptide-based gene delivery system MPG: implications for delivery of siRNA into mammalian cells, Nucleic Acids Res. 31 (2003) 2717-2724 .
  52. ↑ Muratovska, A. and Eccles, MR, Conjugate for efficient delivery of short interfering RNA (siRNA) into mammalian cells, FEBS Lett., 558, 63, 2004.
  53. ↑ Chiu, Y.-L. et al., Visualizing a correlation between siRNA, localization, cellular uptake and RNAi in living cells, Chem. Biol., 11, 1165, 2004.
  54. ↑ D. Zeineddine, E. Papadimou, K. Chebli, M. Gineste, J. Liu, C. Gray, S. Thurig, A. Behfar, VA Wallace, IS Skerjanc, M. Puceat, Oct-3/4 dose dependently regulates specification of embryonic stem cells toward a cardiac lineage and early heart development, Dev. Cell. 11 (2006) 535-546
  55. ↑ Morishita, R., Gibbons, GH, Horiuchi, M., Ellison, KE, Nakama, M., Zhang, L., Kaneda, Y., Ogihara, T. and Dzau, VJ (1995) Proc. Natl. Acad. Sci. USA 92, 5855-5859
  56. ↑ Fisher L, Soomets U, Cortes Toro V, Chilton L, Jiang Y, Langel Ü, Iverfeldt K: Cellular delivery of a double-stranded oligonucleotide NFkappaB decoy by hybridization to complementary PNA linked to a cell-penetrating peptide. Gene Ther 2004, 11: 1264-1272.
  57. ↑ El-Andaloussi S, Johansson H, Magnusdottir A, Jä rver P, Lundberg P, Langel Ü: TP10, a delivery vector for decoy oligonucleotides targeting the Myc protein. J Control Release 2005, 110: 189-201.
  58. ↑ Liu, Z., Li, M., Cui, D. and Fei, J. (2005) J. Controlled Release 102, 699-710
  59. ↑ C. Rudolph et al., Oligomers of the arginine-rich motif of the HIV-1 TAT protein are capable of transferring plasmid DNA into cells. J. Biol. Chem. 278 (2003), pp. 11411-11418
  60. ↑ Wadia JS, Stan RV, Dowdy SF: Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis. Nat Med 2004, 10: 310-315.
  61. ↑ HD Herce, D. Schumacher, AFL Schneider, AK Ludwig, FA Mann, M. Fillies, M.-A. Kasper, S. Reinke, E. Krause, H. Leonhardt, MC Cardoso, CPR Hackenberger: Cell-permeable nanobodies for targeted immunolabelling and antigen manipulation in living cells . In: Nat. Chem. . No. 9, 2017, pp. 762–771. doi : 10.1038 / nchem.2811 .
  62. ↑ S. Kameyama, M. Horie, T. Kikuchi, T. Omura, T. Takeuchi, I. Nakase, Y. Sugiura and S. Futaki, Bioconjugate Chem., 2006, 17, 597-602.
  63. ^ Cheng, RP, SH Gellman, and WF DeGrado. 2001. Peptides: from structure to function. Chem. Rev. 101: 3219-3232.
  64. ↑ Seebach, D., S. Abele, JV Schreiber, B. Martinoni, AK Nussbaum, H. Schild, H. Schulz, H. Hennecke, R. Woessner, and F. Bitsch. 1998. Biological and pharmacokinetic studies with β-peptides. Chimica 1998 (52) 734-739.
  65. ↑ Akkarawongsa, R., Terra B. Potocky, T., B., English, E., B., Gellman, S., H., and Brandt, C., R., ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2008, 2120 -2129.
  66. ↑ Delehanty, J., B., Medintz, I., L., Pons, T., Brunel, F., M., Dawson P., E., Mattoussi, H., Bioconjugate Chem. 2006, 17, 920 -927.
  67. ↑ Alivisatos, AP, Gu, W., and Larabell, CA, Annu. Rev. Biomed. Closely. 2005 (7), 55-76.
  68. ↑ Alivisatos, P., Nat. Biotechnol. 2004 (22,) 47-52.
  69. ↑ Medintz, IL, Uyeda, Nat. Mater. 4, 435-446.
  70. ↑ Parak, WJ, Gerion, D., Pellegrino, T., Zanchet, D., Micheel, C., Williams, SC, Boudreau, R., Le Gros, MA, Larabell, CA, and Alivisatos, AP, Nanotechnology ( 2003) 14, R15-R27.
  71. ↑ Parak, W., Pellegrino, T., and Plank, C., Nanotechnology 2005 (16), R9-R25.
  72. ↑ Lewis, BK, Zywicke, H., Miller, B., van Gelderen, P., Moskowitz, BM, Duncan, ID, and Frank, JA, Nat. Biotechnol. 2001 (19), 1141-1147.
  73. ↑ Pittet, MJ, Swirski, PK, Reynolds, F., Josephson, L., and Weissleder, R., Nat. Protoc. 2006 (1), 73-78.
  74. ↑ Foster, PJ, Dunn, EA, Karl, KE, Snir, JA, Nycz, CM, Harvey, AJ, and Pettis, RJ, Neoplasia 2008 (10), 207-216.
  75. ↑ Martin, A., L., Bernas, L., M., Rutt, B., K., Foster, P., J., Gillies, E., R., Bioconjugate Chem. 2008 (19), 2375 -2384.