Subcellular targeting: A new frontier for drug-loaded pharmaceutical nanocarriers and the concept of the magic bullet

Expert Opinion on Drug Delivery

Volumn 6, Issue 11, 2009, Pages 1135-1148

  D'Souza, Gerard Gm ^a   Weissig, Volkmar ^b  

^a MASSACHUSETTS COLLEGE OF PHARMACY AND HEALTH SCIENCES   (United States)

^b MIDWESTERN UNIVERSITY   (United States)

Author keywords

drug delivery; nanocarriers; subcellular targeting

Indexed keywords

ANTHRA[1,9 CD]PYRAZOL 6(2H) ONE; DAUNORUBICIN; DOXORUBICIN; GOLD NANOPARTICLE; INTERCELLULAR ADHESION MOLECULE 1; LIPOSOME; LOW DENSITY LIPOPROTEIN; MACROGOL; METHYLTRIPHENYLPHOSPHONIUM; MITOCHONDRIAL PERMEABILITY TRANSITION PORE; NANOCARRIER; PACLITAXEL; DRUG CARRIER; NANOMATERIAL;

CIRCULATION TIME; CONFOCAL MICROSCOPY; DNA FRAGMENTATION; DRUG BIOAVAILABILITY; DRUG CONJUGATION; DRUG DIFFUSION; DRUG DISPOSITION; DRUG PENETRATION; DRUG RETENTION; DRUG SOLUBILITY; DRUG TARGETING; DRUG TRANSPORT; ENZYME REPLACEMENT; GENE TARGETING; HUMAN; LYSOSOME STORAGE DISEASE; MAGIC BULLET; MICELLE; MOLECULAR WEIGHT; MOLECULARLY TARGETED THERAPY; NONHUMAN; NUCLEAR LOCALIZATION SIGNAL; PARTICLE SIZE; PHYSICAL CHEMISTRY; REVIEW; STRUCTURE ACTIVITY RELATION; SUBCELLULAR TARGETING; TRANSMISSION ELECTRON MICROSCOPY; ANIMAL; CELL FRACTIONATION; DRUG DELIVERY SYSTEM; DRUG EFFECT; METHODOLOGY; TISSUE DISTRIBUTION;

ANIMALS; DRUG CARRIERS; DRUG DELIVERY SYSTEMS; HUMANS; NANOSTRUCTURES; SUBCELLULAR FRACTIONS; TISSUE DISTRIBUTION;

EID: 75349103697     PISSN: 17425247     EISSN: 17447593     Source Type: Journal    
DOI: 10.1517/17425240903236101     Document Type: Review

References (137)

1. Ehrlich P. Experimental researches on specific therapy. On immunity with special reference to the relationship between distribution and action of antigens. London: Royal Institute of Public Health 1908:107
2. Bangham AD, Standish MM, Miller N. Cation permeability of phospholipid model membranes: effect of narcotics. Nature 1965;208:1295-7
3. Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 1965;13:238-52
4. Bangham AD, Standish MM, Weissmann G. The action of steroids and streptolysin S on the permeability of phospholipid structures to cations. J Mol Biol 1965;13:253-9
5. Gregoriadis G. Letter: enzyme-carrier potential of liposomes in enzyme replacement therapy. N Engl J Med 1975;292:215
6. Gregoriadis G. The carrier potential of liposomes in biology and medicine (second of two parts). N Engl J Med 1976;295:765-70
7. Gregoriadis G. The carrier potential of liposomes in biology and medicine (first of two parts). N Engl J Med 1976;295:704-10
8. Maeda H, Wu J, Sawa T, et al. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 2000;65:271-84
9. Lopez-Berestein G, Fidler IJ. Preface. In: Lopez-Berestein G, Fidler IJ, editors, Liposomes in the therapy of infectious diseases and cancer. Lake Tahoe, CA: Alan R Liss, Inc; 1988. p. xix-xx
10. Duvvuri M, Krise JP. Intracellular drug sequestration events associated with the emergence of multidrug resistance: a mechanistic review. Front Biosci 2005;10:1499-509
11. Breunig M, Bauer S, Goepferich A. Polymers and nanoparticles: intelligent tools for intracellular targeting? Eur J Pharm Biopharm 2008;68:112-28
12. Torchilin VP. Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. Annu Rev Biomed Eng 2006;8:343-75
13. Li SD, Huang L. Pharmacokinetics and biodistribution of nanoparticles. Mol Pharm 2008;5:496-504
14. Kaufmann AM, Krise JP. Lysosomal sequestration of amine-containing drugs: analysis and therapeutic implications. J Pharm Sci 2007;96:729-46
15. Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev 2003;55:329-47
16. Weissig V. Mitochondrial-targeted drug and DNA delivery. Crit Rev Ther Drug Carrier Syst 2003;20:1-62
17. Weissig V. Targeted drug delivery to mammalian mitochondria in living cells. Expert Opin Drug Deliv 2005;2:89-102
18. Weissig V, Boddapati SV, Jabr L, D'Souza GG. Mitochondria-specific nanotechnology. Nanomedicine 2007;2:275-85
19. Weissig V, Cheng SM, D'Souza GG. Mitochondrial pharmaceutics. Mitochondrion 2004;3:229-44
20. Lim CS. Organelle-specific targeting in drug delivery and design. Adv Drug Deliv Rev 2007;59:697
21. Minton AP. How can biochemical reactions within cells differ from those in test tubes? J Cell Sci 2006;119:2863-9
22. Ellis RJ, Minton AP. Cell biology: join the crowd. Nature 2003;425:27-8
23. Sanabria H, Kubota Y, Waxham MN. Multiple diffusion mechanisms due to nanostructuring in crowded environments. Biophys J 2007;92:313-22
24. Goins AB, Sanabria H, Waxham MN. Macromolecular crowding and size effects on probe microviscosity. Biophys J 2008;95:5362-73
25. Lukacs GL, Haggie P, Seksek O, et al. Size-dependent DNA mobility in cytoplasm and nucleus. J Biol Chem 2000;275:1625-9
26. Seksek O, Biwersi J, Verkman AS. Translational diffusion of macromolecule-sized solutes in cytoplasm and nucleus. J Cell Biol 1997;138:131-42
27. Weiss M. Probing the interior of living cells with fluorescence correlation spectroscopy. Ann NY Acad Sci 2008;1130:21-7
28. Horobin RW. Uptake, distribution and accumulation of dyes and fluorescent probes within living cells: a structure-activity modelling approach. Adv Colour Sci Technol 2001;4:101-7
29. Horobin RW, Trapp S, Weissig V. Mitochondriotropics: a review of their mode of action, and their applications for drug and DNA delivery to mammalian mitochondria. J Control Release 2007;121:125-36
30. Horobin RW, Weissig V. A QSAR-modeling perspective on cationic transfection lipids. 1. Predicting efficiency and understanding mechanisms. J Gene Med 2005;7:1023-34
31. Mudhakir D, Harashima H. Learning from the viral journey: how to enter cells and how to overcome intracellular barriers to reach the nucleus. AAPS J 2009;11:65-77
32. Nori A, Kopecek J. Intracellular targeting of polymer-bound drugs for cancer chemotherapy. Adv Drug Deliv Rev 2005;57:609-36
33. Cho YW, Kim JD, Park K. Polycation gene delivery systems: escape from endosomes to cytosol. J Pharm Pharmacol 2003;55:721-34
34. Bareford LM, Swaan PW. Endocytic mechanisms for targeted drug delivery. Adv Drug Deliv Rev 2007;59:748-58
35. Gregoriadis G, Ryman BE. Liposomes as carriers of enzymes or drugs: a new approach to the treatment of storage diseases. Biochem J 1971;124:58P
36. Castino R, Demoz M, Isidoro C. Destination 'lysosome': a target organelle for tumour cell killing? J Mol Recognit 2003;16:337-48
37. Tate BA, Mathews PM. Targeting the role of the endosome in the pathophysiology of Alzheimer's disease: a strategy for treatment. Sci Aging Knowledge Environ 2006;28(10):re2
38. Dermaut B, Norga KK, Kania A, et al. Aberrant lysosomal carbohydrate storage accompanies endocytic defects and neurodegeneration in Drosophila benchwarmer. J Cell Biol 2005;170:127-39
39. Dhami R, Schuchman EH. Mannose 6-phosphate receptor-mediated uptake is defective in acid sphingomyelinase-deficient macrophages: implications for Niemann-Pick disease enzyme replacement therapy. J Biol Chem 2004;279:1526-32
40. Monroy MA, Ross FP, Teitelbaum SL, Sands MS. Abnormal osteoclast morphology and bone remodeling in a murine model of a lysosomal storage disease. Bone 2002;30:352-9
41. Muro S, Schuchman EH, Muzykantov VR. Lysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis. Mol Ther 2006;13:135-41
42. Muro S, Garnacho C, Champion JA, et al. Control of endothelial targeting and intracellular delivery of therapeutic enzymes by modulating the size and shape of ICAM-1-targeted carriers. Mol Ther 2008;16:1450-8
43. Qian ZM, Li H, Sun H, Ho K. Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol Rev 2002;54:561-87
44. Stoorvogel W, Geuze HJ, Strous GJ. Sorting of endocytosed transferrin and asialoglycoprotein occurs immediately after internalization in HepG2 cells. J Cell Biol 1987;104:1261-8
45. Trinder D, Baker E. Transferrin receptor 2: a new molecule in iron metabolism. Int J Biochem Cell Biol 2003;35:292-6
46. Calzolari A, Oliviero I, Deaglio S, et al. Transferrin receptor 2 is frequently expressed in human cancer cell lines. Blood Cells Mol Dis 2007;39:82-91
47. Eavarone DA, Yu X, Bellamkonda RV. Targeted drug delivery to C6 glioma by transferrin-coupled liposomes. J Biomed Mater Res 2000;51:10-4
48. Dufes C, Muller JM, Couet W, et al. Anticancer drug delivery with transferrin targeted polymeric chitosan vesicles. Pharm Res 2004;21:101-7
49. Glickson JD, Lund-Katz S, Zhou R, et al. Lipoprotein nanoplatform for targeted delivery of diagnostic and therapeutic agents. Mol Imaging 2008;7:101-10
50. Glickson JD, Lund-Katz S, Zhou R, et al. Lipoprotein nanoplatform for targeted delivery of diagnostic and therapeutic agents. Adv Exp Med Biol 2009;645:227-39
51. Zheng G, Chen J, Li H, Glickson JD. Rerouting lipoprotein nanoparticles to selected alternate receptors for the targeted delivery of cancer diagnostic and therapeutic agents. Proc Natl Acad Sci USA 2005;102:17757-62
52. Zheng G, Li H, Zhang M, et al. Low-density lipoprotein reconstituted by pyropheophorbide cholesteryl oleate as target-specific photosensitizer. Bioconjug Chem 2002;13:392-6
53. Boddapati SV, D'Souza GG, Erdogan S, et al. Organelle-targeted nanocarriers: specific delivery of liposomal ceramide to mitochondria enhances its cytotoxicity in vitro and in vivo. Nano Lett 2008;8:2559-63
54. Boddapati SV, Tongcharoensirikul P, Hanson RN, et al. Mitochondriotropic liposomes. J Liposome Res 2005;15:49-58
55. Liberman EA, Topaly VP, Tsofina LM, et al. Mechanism of coupling of oxidative phosphorylation and the membrane potential of mitochondria. Nature 1969;222:1076-8
56. Murphy MP. Targeting lipophilic cations to mitochondria. Biochim Biophys Acta 2008;1777:1028-31
57. Murphy MP, Smith RA. Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol Toxicol 2007;47:629-56
58. Ross MF, Prime TA, Abakumova I, et al. Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells. Biochem J 2008;411:633-45
59. Smith RA, Porteous CM, Gane AM, Murphy MP. Delivery of bioactive molecules to mitochondria in vivo. Proc Natl Acad Sci USA 2003;100:5407-12
60. Stover TC, Sharma A, Robertson GP, Kester M. Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin Cancer Res 2005;11:3465-74
61. Wei Q, Wei A. Plasmon-resonant gold nanorods: photophysical properties applied toward biological imaging and therapy. In: Mattousi H, Cheon J, editors, Inorganic nanoprobes for biological sensing and imaging. Boston, London: Artech House; 2009. p. 197-233
62. Ghosh P, Han G, De M, et al. Gold nanoparticles in delivery applications. Adv Drug Deliv Rev 2008;60:1307-15
63. Salnikov V, Lukyanenko YO, Frederick CA, et al. Probing the outer mitochondrial membrane in cardiac mitochondria with nanoparticles. Biophys J 2007;92:1058-71
64. Parfenov AS, Salnikov V, Lederer WJ, Lukyanenko V. Aqueous diffusion pathways as a part of the ventricular cell ultrastructure. Biophys J 2006;90:1107-19
65. Ju-Nam Y, Bricklebank N, Allen DW, et al. Phosphonioalkylthiosulfate zwitterions-new masked thiol ligands for the formation of cationic functionalised gold nanoparticles. Org Biomol Chem 2006;4:4345-51
66. Tkachenko AG, Xie H, Liu Y, et al. Cellular trajectories of peptide-modified gold particle complexes: comparison of nuclear localization signals and peptide transduction domains. Bioconjug Chem 2004;15:482-90
67. Xie W, Wang L, Zhang Y, et al. Nuclear targeted nanoprobe for single living cell detection by surface-enhanced Raman scattering. Bioconjug Chem 2009;20:768-73
68. Zanta MA, Belguise-Valladier P, Behr JP. Gene delivery: a single nuclear localization signal peptide is sufficient to carry DNA to the cell nucleus. Proc Natl Acad Sci USA 1999;96:91-6
69. Wagner E. Ligand-Polycation conjugates for receptor-targeted gene transfer. In: Huang L, Hung M-C, Wagner E, editors, Nonviral vectors for gene therapy. San Diego, London, Boston, New York, Sydney, Tokyo, Toronto: Academic Press; 1999. p. 207-27
70. Meyer M, Dohmen C, Philipp A, et al. Synthesis and biological evaluation of a bioresponsive and endosomolytic siRNA-polymer conjugate. Mol Pharm 2009;6:752-62
71. Kloeckner J, Boeckle S, Persson D, et al. DNA polyplexes based on degradable oligoethylenimine-derivatives: combination with EGF receptor targeting and endosomal release functions. J Control Release 2006;116:115-22
72. Wagner E, Culmsee C, Boeckle S. Targeting of polyplexes: toward synthetic virus vector systems. Adv Genet 2005;53PA:333-54
73. Wagner E. Strategies to improve DNA polyplexes for in vivo gene transfer: will 'artificial viruses' be the answer? Pharm Res 2004;21:8-14
74. Lee M, Choi JS, Choi MJ, et al. DNA delivery to the mitochondria sites using mitochondrial leader peptide conjugated polyethylenimine. J Drug Target 2007;15:115-22
75. Boussif O, Lezoualc'H F, Zanta MA, et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc Natl Acad Sci USA 1995;92:7297-301
76. Demeneix B, Behr JP. Polyethylenimine (PEI). Adv Genet 2005;53:217-30
77. Seibel P, Trappe J, Villani G, et al. Transfection of mitochondria: strategy towards a gene therapy of mitochondrial DNA diseases. Nucleic Acids Res 1995;23:10-7
78. Weissig V, Torchilin VP. Mitochondriotropic cationic vesicles: a strategy towards mitochondrial gene therapy. Curr Pharm Biotechnol 2000;1:325-46
79. Weissig V, Torchilin VP. Towards mitochondrial gene therapy: DQAsomes as a strategy. J Drug Target 2001;9:1-13
80. Weissig V, Torchilin VP. Cationic bolasomes with delocalized charge centers as mitochondria-specific DNA delivery systems. Adv Drug Deliv Rev 2001;49:127-49
81. Ellouze S, Augustin S, Bouaita A, et al. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet 2008;83:373-87
82. Oca-Cossio J, Kenyon L, Hao H, Moraes CT. Limitations of allotopic expression of mitochondrial genes in mammalian cells. Genetics 2003;165:707-20
83. Zullo SJ. Gene therapy of mitochondrial DNA mutations: a brief, biased history of allotopic expression in mammalian cells. Semin Neurol 2001;21:327-35
84. Gray RE, Law RH, Devenish RJ, Nagley P. Allotopic expression of mitochondrial ATP synthase genes in nucleus of Saccharomyces cerevisiae. Methods Enzymol 1996;264:369-89
85. Rowe TC, Weissig V, Lawrence JW. Mitochondrial DNA metabolism targeting drugs. Adv Drug Deliv Rev 2001;49:175-87
86. Weissig V, Lasch J, Erdos G, et al. DQAsomes: a novel potential drug and gene delivery system made from Dequalinium. Pharm Res 1998;15:334-7
87. D'Souza GG, Boddapati SV, Weissig V. Mitochondrial leader sequence-plasmid DNA conjugates delivered into mammalian cells by DQAsomes co-localize with mitochondria. Mitochondrion 2005;5:352-8
88. D'Souza GG, Rammohan R, Cheng SM, et al. DQAsome-mediated delivery of plasmid DNA toward mitochondria in living cells. J Control Release 2003;92:189-97
89. Weissig V, D'Souza GG, Torchilin VP. DQAsome/DNA complexes release DNA upon contact with isolated mouse liver mitochondria. J Control Release 2001;75:401-8
90. Weissig V, Lizano C, Torchilin VP. Selective DNA release from DQAsome/DNA complexes at mitochondria-like membranes. Drug Deliv 2000;7:1-5
91. Cheng SM, Pabba S, Torchilin VP, et al. Towards mitochondria-specific delivery of apoptosis-inducing agents: DQAsomal incorporated paclitaxel. J Drug Del Sci Tech 2005;15:81-6
92. D'Souza GG, Cheng SM, Boddapati SV, et al. Nanocarrier-assisted sub-cellular targeting to the site of mitochondria improves the pro-apoptotic activity of paclitaxel. J Drug Target 2008;16:578-85
93. Seligson AL, Terry RC, Bressi JC, et al. A new prodrug of paclitaxel: synthesis of protaxel. Anticancer Drugs 2001;12:305-13
94. Fan W. Possible mechanisms of paclitaxel-induced apoptosis. Biochem Pharmacol 1999;57:1215-21
95. Wang TH, Wang HS, Soong YK. Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer 2000;88:2619-28
96. Andre N, Braguer D, Brasseur G, et al. Paclitaxel induces release of cytochrome c from mitochondria isolated from human neuroblastoma cells'. Cancer Res 2000;60:5349-53
97. Andre N, Carre M, Brasseur G, et al. Paclitaxel targets mitochondria upstream of caspase activation in intact human neuroblastoma cells. FEBS Lett 2002;532:256-60
98. Vaidya BPR, Rai S, Khatri K, et al. Cell-selective mitochondrial targeting: a new approach for cancer therapy. Cancer Ther 2009;7:141-8
99. Sega EI, Low PS. Tumor detection using folate receptor-targeted imaging agents. Cancer Metastasis Rev 2008;27:655-64
100. Zhao XB, Lee RJ. Tumor-selective targeted delivery of genes and antisense oligodeoxyribonucleotides via the folate receptor. Adv Drug Deliv Rev 2004;56:1193-204
101. Ke CY, Mathias CJ, Green MA. The folate receptor as a molecular target for tumor-selective radionuclide delivery. Nucl Med Biol 2003;30:811-7
102. Esmaeili F, Ghahremani MH, Ostad SN, et al. Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA-PEG-folate conjugate. J Drug Target 2008;16:415-23
103. Kim SH, Jeong JH, Mok H, et al. Folate receptor targeted delivery of polyelectrolyte complex micelles prepared from ODN-PEG-folate conjugate and cationic lipids. Biotechnol Prog 2007;23:232-7
104. Leamon CP, Reddy JA, Vlahov IR, et al. Preclinical antitumor activity of a novel folate-targeted dual drug conjugate. Mol Pharm 2007;4:659-67
105. Bae Y, Nishiyama N, Fukushima S, et al. Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy. Bioconjug Chem 2005;16:122-30
106. Maysinger D, Lovric J, Eisenberg A, Savic R. Fate of micelles and quantum dots in cells. Eur J Pharm Biopharm 2007;65:270-81
107. Savic R, Azzam T, Eisenberg A, Maysinger D. Assessment of the integrity of poly (caprolactone)-b-poly(ethylene oxide) micelles under biological conditions: a fluorogenic-based approach. Langmuir 2006;22:3570-8
108. Savic R, Azzam T, Eisenberg A, et al. Block-copolymer micelles as carriers of cell signaling modulators for the inhibition of JNK in human islets of Langerhans. Biomaterials 2009;30(21):3597-604
109. Xiong XB, Mahmud A, Uludag H, Lavasanifar A. Multifunctional polymeric micelles for enhanced intracellular delivery of doxorubicin to metastatic cancer cells. Pharm Res 2008;25:2555-66
110. Hirano T, Klesse W, Ringsdorf H. Polymeric derivatives of activated cyclophosphamide as drug delivery systems in antitumor chemotherapy- pharmacologically active polymeres. Macromol Chem Macromol Chem Phys 1979;180:1125-31
111. Savic R, Eisenberg A, Maysinger D. Block copolymer micelles as delivery vehicles of hydrophobic drugs: micelle-cell interactions. J Drug Target 2006;14:343-55
112. Savic R, Luo L, Eisenberg A, Maysinger D. Micellar nanocontainers distribute to defined cytoplasmic organelles. Science 2003;300:615-8
113. Ruan G, Agrawal A, Marcus AI, Nie S. Imaging and tracking of tat peptide-conjugated quantum dots in living cells: new insights into nanoparticle uptake, intracellular transport, and vesicle shedding. J Am Chem Soc 2007;129:14759-66
114. Akita H, Kudo A, Minoura A, et al. Multi-layered nanoparticles for penetrating the endosome and nuclear membrane via a step-wise membrane fusion process. Biomaterials 2009;30:2940-9
115. Yamada Y, Harashima H. Mitochondrial drug delivery systems for macromolecule and their therapeutic application to mitochondrial diseases. Adv Drug Deliv Rev 2008;60:1439-62
116. Yamada Y, Akita H, Kamiya H, et al. MITO-Porter: a liposome-based carrier system for delivery of macromolecules into mitochondria via membrane fusion. Biochim Biophys Acta 2008;1778:423-32
117. Xu ZP, Niebert M, Porazik K, et al. Subcellular compartment targeting of layered double hydroxide nanoparticles. J Control Release 2008;130:86-94
118. Nakai K, Horton P. Computational prediction of subcellular localization. Methods Mol Biol 2007;390:429-66
119. Yacobi NR, Malmstadt N, Fazlollahi F, et al. Mechanisms of alveolar epithelial translocation of a defined population of nanoparticles. Am J Respir Cell Mol Biol 2009 [Epub ahead of print]
120. Hillaireau H, Couvreur P. Nanocarriers' entry into the cell: relevance to drug delivery. Cell Mol Life Sci 2009;66(17):2873-96
121. Smirnov P. Cellular magnetic resonance imaging using superparamagnetic anionic iron oxide nanoparticles: applications to in vivo trafficking of lymphocytes and cell-based anticancer therapy. Methods Mol Biol 2009;512:333-53
122. Harush-Frenkel O, Altschuler Y, Benita S. Nanoparticle-cell interactions: drug delivery implications. Crit Rev Ther Drug Carrier Syst 2008;25:485-544
123. Huser T. Nano-biophotonics: new tools for chemical nano-analytics. Curr Opin Chem Biol 2008;12:497-04
124. Vasir JK, Labhasetwar V. Quantification of the force of nanoparticle-cell membrane interactions and its influence on intracellular trafficking of nanoparticles. Biomaterials 2008;29:4244-52
125. Rajan SS, Liu HY, Vu TQ. Ligand-bound quantum dot probes for studying the molecular scale dynamics of receptor endocytic trafficking in live cells. ACS Nano 2008;2:1153-66
126. Perrine KA, Lamarche BL, Hopkins DF, et al. High speed method for in situ multispectral image registration. Microsc Res Tech 2007;70:382-9
127. Rabut G, Ellenberg J. Automatic real-time three-dimensional cell tracking by fluorescence microscopy. J Microsc 2004;216:131-7
128. Sunaguchi M, Nishi M, Mizobe T, Kawata M. Real-time imaging of green fluorescent protein-tagged beta 2-adrenergic receptor distribution in living cells. Brain Res 2003;984:21-32
129. Jester JV, Andrews PM, Petroll WM, et al. In vivo, real-time confocal imaging. J Electron Microsc Tech 1991;18:50-60
130. Byrne GD, Pitter MC, Zhang J, et al. Total internal reflection microscopy for live imaging of cellular uptake of sub-micron non-fluorescent particles. J Microsc 2008;231:168-79
131. Matthaus C, Kale A, Chernenko T, et al. New ways of imaging uptake and intracellular fate of liposomal drug carrier systems inside individual cells, based on Raman microscopy. Mol Pharm 2008;5:287-93
132. Fujita K, Smith NI. Label-free molecular imaging of living cells. Mol Cells 2008;26:530-5
133. Freudiger CW, Min W, Saar BG, et al. Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy. Science 2008;322:1857-61
134. Ray PC, Yu H, Fu PP. Toxicity and environmental risks of nanomaterials: challenges and future needs. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2009;27:1-35
135. Fischer HC, Chan WC. Nanotoxicity: the growing need for in vivo study. Curr Opin Biotechnol 2007;18:565-71
136. Hoet P, Legiest B, Geys J, Nemery B. Do nanomedicines require novel safety assessments to ensure their safety for long-term human use? Drug Saf 2009;32:625-36
137. Klaine SJ, Alvarez PJ, Batley GE, et al. Nanomaterials in the environment: behavior, fate, bioavailability, and effects. Environ Toxicol Chem 2008;27:1825-51