Cancer nanotechnology: Opportunities and challenges

Nature Reviews Cancer

Volumn 5, Issue 3, 2005, Pages 161-171

  Ferrari, Mauro ^a,b  

^a OHIO STATE UNIVERSITY   (United States)

^b NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; CONTRAST MEDIUM;

BODY FLUID; CANCER RESEARCH; DEVICE; DRUG DELIVERY SYSTEM; EARLY DIAGNOSIS; MALIGNANT NEOPLASTIC DISEASE; NANOTECHNOLOGY; PRECANCER; PRIORITY JOURNAL; REVIEW;

ANTINEOPLASTIC AGENTS; CONTRAST MEDIA; DIAGNOSIS, DIFFERENTIAL; EQUIPMENT DESIGN; HUMANS; NANOTECHNOLOGY; NEOPLASMS;

EID: 14644439267     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc1566     Document Type: Review

References (133)

1. Langer, R. Drug delivery and targeting. Nature 392, 5-10 (1998).
2. Duncan, R. The dawning era of polymer therapeutics. Nature Rev. Drug Discov. 2, 347-360 (2003). The definitive, state-of-the-art review of polymer technology for drug-delivery application. This paper is so exhaustive that we chose not to focus on polymer nanotechnology in our review.
3. Li, K. C. P., Pandit, S. D., Guccione, S., Bednarski, M. D. Molecular imaging applications in nanomedicine. Biomed. Microdevices 6, 113-116 (2004).
4. Allen, T. M. Ligand-targeted therapeutics in anticancer therapy. Nature Rev. Drug Discov. 2, 750-763 (2002).
5. Jain, R. K. The next frontier of molecular medicine: delivery of therapeutics. Nature Med. 4, 655-657 (1998).
6. Srinivas, P. R., Barker, P. & Srivastava, S. Nanotechnology in early detection of cancer. Lab. Invest. 82, 657-662 (2002).
7. Park, J. W. Liposome-based drug delivery in breast cancer treatment. Breast Cancer Res. 4, 95-99 (2002).
8. Kircher, M. F., Mahmood, U., King, R. S., Weissleder, R. & Josephson, L. A multimodal nanoparticle for preoperative magnetic resonance imaging and intraoperative optical brain tumor delineation. Cancer Res. 63, 8122-8125 (2003).
9. Neuwalt, E. A. et al. Imaging of iron oxide nanoparticles with MR and light microscopy in patients with malignant brain tumors. Neuropathol. Appl. Neurobiol. 5, 456-471 (2004).
10. Nam, J. M. & Mirkin, C. A. Bio-barcode-based DNA detection with PCR-like sensitivity. J. Am. Chem. Soc. 126, 5932-5933 (2004). A window into the power of nanotechnology to potentially revolutionize molecular diagnostics.
11. Whitesides, G. M. The 'right' size in nanotechnology. Nature Biotechnol. 21, 1161-1165 (2003). An introduction to bionanotechnology with emphasis on the identification of its niche applications for basic research.
12. La Van, D. A., McGuire, T. & Langer R. Small-scale systems for in vivo drug delivery. Nature Biotechnol. 21, 1184-1191 (2003). Whether 'nano' or 'micro' is irrelevant, as long as actual medical problems are solved.
13. Pirollo, K. F. et al., in Vector Targeting for Therapeutic Gene Delivery (eds Curiel, D. T. & Douglas, J. T.) 33-62 (Wiley and Sons, New York 2002).
14. Gilles, E. M. & Frechet, J. M. J. Designing macromolecules for therapeutic applications: Polyester dendrimer-polyethylene oxide 'bow-tie' hybrids with tunable molecular weights and architecture. J. Am. Chem. Soc. 124, 14137-14146 (2002).
15. Oyewumi, M. O. & Mumper, R. J. Comparison of cell uptake, biodistribution and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor-bearing mice. J. Control. Rel. 24, 613-626 (2004).
16. Schellenberger, E. A. et al. Annexin V-CLIO: a nanoparticle for detecting apoptosis by MRI. Mol. Imaging 1, 102-107 (2002).
17. Harishingani, M. G. et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N. Engl. J. Med. 348, 2491-2499 (2003). A powerful illustration that for certain applications nanotechnology might be the only way to secure in vivo diagnostic information.
18. 3-integrin-targeted nanoparticles. Circulation 108, 2270-2274 (2003).
19. Perez, J. M., Josephson, L. & Weissleder, R. Viral-induced sef-assembly of magnetic nanoparticles allows the detection of viral particles in biological media. J. Am. Chem. Soc. 125, 10192-10193 (2003).
20. Zhang, Y. & Shang, M. Self-assembled coatings on individual monodisperse magnetite nanoparticles for efficient intracellular uptake. Biomed. Microdevices 6, 33-40 (2004).
21. Yan, F., Kopelman, R. & Reddy, R. Synthesis and characterization of silica-embedded iron oxide nanoparticles for magnetic resonance imaging. J. Nanosci. Nanotechnol. 4, 72-76 (2004).
22. Levy, L., Bergey E. J. & Prasad, P. N. Nanochemistry: synthesis and characterization of multifunctional nanoclinics for biological applications. Chem. Mater. 14, 3715-3721 (2002).
23. Bergey, E. J. & Prasad, P. N. DC magnetic field induced magnetocytolysis of cancer cells targeted by LH-RH magnetic nanoparticles in vitro. Biomed. Microdevices 4, 293-299 (2002).
24. May, D. J., Allen, J. S. & Ferrara, K. W. Dynamics and fragmentation of thick-shelled microbubbles. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 49, 1400-1410 (2002).
25. Bloch, S. H., Wan, M., Dayton, P. A. & Ferrara, K. W. Optical observation of lipid- and polymer-shelled ultrasound microbubble contrast agents. Appl. Phys. Lett. 84, 631-633 (2004).
26. Sullivan, D. & Ferrari, M. Nanotechnology and tumor imaging: seizing an opportunity. Mol. Imaging (in the press).
27. Nashat, A. H., Moronne, M. & Ferrari, M. Detection of functional groups and antibodies on microfabricated surfaces by confocal microscopy. Biotechnol. Bioeng. 60, 137-146 (1998).
28. Decuzzi, P., Lee, S., Bhushan, B. & Ferrari, M. Non-specific interaction of nanoparticles as drug delivery and nanoharvesting agents within the vasculature. Ann. Biomed. Eng. (in the press). Mathematical models drive the design of nanovectors for optimal use in therapeutics and diagnostics.
29. Netti, P. A. et al. Time-dependent behaviour of interstitial fluid pressure in solid tumors: implications for drug delivery. Cancer Res. 66, 5451-5458 (1995).
30. Klibanov, A. L. et al. Activity of amphipathic PEG 5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavourable for immunoliposome binding to target. Biochem. Biophys. Acta 1062, 142-148 (1991).
31. Alivisatos, P. Semiconductor clusters, nanocrystals, and quantum dots. Science 271, 933-937 (1996).
32. Chan, W. C. & Nie, S. Luminescent quantum dots for multiplexed biological detection and imaging. Curr. Opin. Biotechnol. 13, 40-46 (2002).
33. Derfus A. M., Chan, W. C. W. & Bhatia, S. N. Probing the cytotoxicity of semiconductor quantum dots. Nano Lett. 4, 11-18 (2004).
34. Voura, E. B., Jaiswal, J. K., Mattoussi, H. & Simon, S. Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy. Nature Med. 10, 993-998 (2004).
35. Kataoka, K. et al. Block copolymers micelles as vehicles. J. Control Release 24, 119-132 (1993).
36. Tomalia, D. A. et al. A new class of polymers: starburst-dendritic macromolecules. Polymer J. 17, 117-132 (1985).
37. Kobayashi, H., Choyke, P. L., Brechbiel, M. W. & Waldmann, T. A. Lymphatic drainage imaging of breast cancer in mice by micro-magnetic resonance lymphangiography using a nano-size paramagnetic contrast agent. J. Natl Cancer Inst. 96,703-708 (2004).
38. Ferrari, M. Therapeutic microdevices and methods of making and using same. US Patent 6,107,102 (2000). Early investigation of multifunctional drug-delivery nanosystems.
39. Cohen, M. H., Melnik, K., Boiasrki, A., Ferrari, M. & Martin, F. J. Microfabrication of silicon-based nanoporous particulates for medical applications. Biomed. Microdevices 5, 253-259 (2003).
40. He, X. X. & Li J. Bioconjugated nanoparticles for DNA protection from cleavage. J. Am. Chem. Soc. 125, 7168-7169 (2003).
41. Yan, F. & Kopelman, R. The embedding of metatetra(hydroxyphenyl)- chlorin into silica nanoparticle platforms for photodynamic therapy and their singlet oxygen production and pH-dependent optical properties. Photochem. Photobiol. 78, 587-591 (2003).
42. Li, X. et al. Porosified silicon wafer structures impregnated with platinum anti-tumor compounds: fabrication, characterization, and diffusion studies. Biomed. Microdevices 2, 265-273 (2000).
43. Hirsch, L. R., Haas, N. J. & West, J. L. A whole blood immunoassay using gold nanoshells. Anal. Chem. 75, 2377-2381 (2003).
44. Hirsch, L. R., Haas, N. J. & West, J. L. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc. Natl Acad. Sci. USA 100, 13549-13554 (2003). A powerful illustration of the use of remote activation as a therapeutic targeting strategy.
45. Fodor, S. E. et al. Light-directed spatially addressable parallel chemical synthesis. Science 251, 767-773 (1991). The foundations of microarray technology.
46. Demers, L. M. et al. Direct patterning of modified oligonucleotides on metals and insulators by dip-pen nanolithography. Science 296, 1836-1838 (2002).
47. Lee, K. B. et al. Protein nanoarrays generated by dip-pen nanolithography. Science 295, 1702-1705 (2002).
48. Lee, K. B. & Mirkin, C. A. Protein nanostructures formed via direct-write dip-pen nanolithography. J. Am. Chem. Soc. 125, 5588-5589 (2003).
49. Bruckbauer, A. & Klenerman, D. An addressable antibody nanoarray produced on a nanostructured surface. J. Am. Chem. Soc. 126, 6508-6509 (2004).
50. Rosenblatt, K. P. et al. Serum proteomics in cancer diagnosis and management. Annu. Rev. Med. 55, 97-112 (2004).
51. Geho, D., Lahar, N., Ferrari, M., Petricoin, E. & Liotta, L. Opportunities for nanotechnology-based innovation in tissue proteomics. Biomed. Microdevices 6, 130-164 (2004).
52. Merchant, M. & Weinberger, S. R. Recent advancements in surface-enhanced laser desorption-ionization time-of-flight spectrometry. Electrophoresis 21, 1164-1177 (2000).
53. Hansen, K. M. et al. Cantilever-based optical deflection assay for discrimination of DNA single-nucleotide mismatches. Anal. Chem. 73, 1567-1571 (2001).
54. Wu, G. et al. Bioassay of prostate-specific antigen (PSA) using microcantilevers. Nature Biotechnol. 19, 856-880 (2001).
55. Su, M., Li, S. & Dravid, V. Microcantilever resonance-based DNA detection with nanoparticle probes. Appl. Phys. Lett. 82, 3562-62 (2003).
56. Chen, H., Han, J., Li, J. & Meyyappan, M. Microelectronic DNA assay for the detection of BRCA1 gene mutations. Biomed. Microdevices 6, 55-60 (2004).
57. Cui, Y., Qingqiao, W., Hongkun, P. & Lieber, C. M. Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species. Science 293, 1289-1292 (2001).
58. Heath, J. R., Phelps, M. E. & Hood, L. NanoSystems biology. Mol. Imaging Biol. 5, 312-325 (2003). Nanotechnology presented as the gateway for the transition from reductionist to systems biology.
59. Iijima, S. Helical microtubules of graphitic carbon. Nature 354, 56-18 (1991).
60. Kong, J. et al. Nanotube molecular wires as chemical sensors. Science 287, 622-625 (2000).
61. Star, A. et al. Preparation and properties of polymer-wrapped single-walled carbon nanotubes. Angew. Chem. Int. Engl. 40, 1721-1725 (2001).
62. Chen, R. J. & Hongjie, D. Noncovalent functionalization of carbon nanotubes for highly specific electronic biosensors. Proc. Natl Acad. Sci. USA 100, 4984-4989 (2003).
63. Woolley, A. et al. Direct haplotyping of kilobase-size DNA using carbon nanotube probes. Nature Biotech. 18, 760-764 (2000).
64. Brody, J. P., Yager, P., Goldstein, R. E. & Austin, R. H. Biotechnology at low Reynolds numbers. Biophys. J. 71, 3430-3441 (1996).
65. Hong, J. W. & Quake, S. R. Integrated nanoliter systems. Nature Biotechnol. 21, 1179-1183 (2003). References 64 and 65 describe microfluidics, from its firm establishment in biomedical research to current day concepts.
66. Chu, W. H., Chin, R., Huen, T. & Ferrari, M. Silicon membrane nanofilters from sacrificial oxide removal. J. Microelectromech. Syst. 8, 16-25 (1999).
67. Desai, T. A. et al. Nanopore technology for biomedical applications. Biomed. Microdevices 2, 1-40 (1999).
68. Sinha, P., Valco, G., Sharma, S., Liu, X. & Ferrari, M. Nanoengineered device for drug delivery application. Nanotechnology 15, S585-S589 (2004).
69. Han, J. & Craighead, H. G. Separation of long DNA molecules in a microfabricated entropic trap array. Science 288, 1026-1029 (2000).
70. Martin, F. J. et al. Tailoring width of microfabricated nanochannels to solute size can be used to control diffusion kinetics. J. Control. Release (in the press).
71. Desai, T. A. et al. Microfabricated biocapsules provide short-term immunoisolation of insulinoma xenografts. Biomed. Microdevices 1, 131-181 (1999).
72. Meller, A. & Branton, D. Single molecule measurement of DNA transport through a nanopore. Electrophoresis 23, 2583-2591 (2002).
73. Hayflick, L. Mortality and immortality at the cellular level. Biochemistry 62, 1180-1190 (1997).
74. Grimm, J., Perez, J. M., Josephson, L. & Weissleder, R. Novel nanosensors for rapid analysis of telomerase activity. Cancer Res. 64, 639-643 (2004).
75. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353-364 (1996).
76. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70 (2000).
77. 3-targeted magnetic resonance imaging. Nature Med. 4, 623-626 (1998).
78. 3-targeted nanoparticles. Magn. Reson. Med. 44, 433-439 (2000).
79. 3-targeted nanoparticle and 1.5 tesla magnetic resonance imaging. Cancer Res, 63, 5838-5843 (2003).
80. Morawski, A. M., Lanza, G. M. & Wickline, S. A. Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRI. Magn. Reson. Natl. 51, 480-486 (2004).
81. Desai, T. A., Hansford, D. J., Leoni, L., Essenpreis, M. & Ferrari, M. Nanoporous anti-fouling silicon membranes for implantable biosensor applications. Biosens. Bioelectron. 15, 453-462 (2000).
82. Fritz, J., et al. Translating biomolecular recognition into nanomechanics. Science 288, 316-318 (2000).
83. Majumdar, A. Bioassays based on molecular nanomechanics. Dis. Markers 16, 167-174 (2002).
84. Yue, M. A 2-D microcantilever array for multiplexed biomolecular analysis. J. Microelectromech. Syst. 13, 290-299 (2004).
85. Li, J. et al. Carbon nanotube nanoelectrode array for ultrasensitive DNA detection. Nano Lett. 3, 597-602 (2003).
86. Ferrari, M. & Weber, M. E. Determination of eigenstresses from curvature data. Smart Materials and Materials Fabrication and Materials for MEMS. MRS Bull. 276, 221-227 (1992).
87. Santra, S. & Tan, W. Conjugation of biomolecules with luminophore-doped silica nanoparticles for photostable biomarkers. Anal. Chem. 73, 4988-4993 (2001).
88. Zhao, X. & Tan, W., Ultrasensitive DNA detection using highly fluorescent bioconjugated nanoparticles. J. Am. Chem. Soc. 125, 11474-11475 (2003).
89. Wu, X. & Bruchez, M. P. Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots. Nature Biotechnol. 21, 41-46 (2003).
90. Jaiswal, J. K. & Simon, S. M. Long-term multiple color imaging of live cells using quantum dot bioconjugates. Nature Biotechnol. 21, 47-61 (2003).
91. Clark, H. A. & Kopelman, R. Optical nanosensors for chemical analysis inside single living cells. 1. Fabrication, characterization, and methods for intracellular delivery of PEBBLE sensors. Anal. Chem. 71, 4831-4836 (1999).
92. Clark, H. A., Kopelman, R. & Philbert, M. A. Optical nanosensors for chemical analysis inside single living cells. 2. Sensors for pH and calcium and the intracellular application of PEBBLE sensors. Anal. Chem. 71, 4837-4843 (1999).
93. Liotta, L. A., Ferrari, M. & Petricoin, E. Clinical proteomics: written in blood. Nature, 425, 905 (2003).
94. Lavrik, N. V., Tipple, C. A., Sepaniak, M. J. & Datskos, P. G. Gold nano-structures for transduction of bimolecular interactions into micrometer-scale movements. Biomed. Microdevices 3, 35-41 (2001).
95. Matsumura Y. & Maeda H. A new concept for macromolecular therapies in cancer chemotherapy: mechanisms of tumortropic accumulation of proteins and the antitumor agents SMANCS. Cancer Res. 6, 6397-6392 (1986).
96. Sel, Y. N. et al. Comparison of vascular permeability and enzymatic activation of the polymeric prodrug HPMA copolymer-doxorubicin (PK1) in human tumor xenografts. Proc. Am. Assoc. Cancer Res. 90, 41 (1999).
97. Jain, R. K. Delivery of molecular and cellular medicine to solid tumors. Adv. Drug Deliv. Rev. 46, 149-168 (2001). This paper sets the stage for advanced, multifunctional therapeutic delivery systems.
98. Decuzzi, P., Lee, S., Decuzzi, M. & Ferrari, M. Adhesion of micro-fabricated particles on vascular endothelium: a parametric anaysis. Ann. Biomed. Eng. 32, 793-802 (2004).
99. Quintana, A. & Baker, J. N. Jr. Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor cells through the folate receptor. Pharm. Res. 19, 1310-1316 (2002).
100. Santhakumaran, L. M. & Thomas, T. J. Enhanced cellular uptake of a triplex-forming oligonucleotide by nanoparticle formation in the presence of polypropylenimine dendrimers. Nucleic Acids Res. 32, 2102-2112 (2004).
101. Li, L. & Knox, S. J. A novel antiangiogenesis therapy using an integrin antagonist or anti-Flk-1 antibody coated 90Y-labeled nanoparticles. Int. J. Oncol. Biol. Phys. 58, 115-122 (2004).
102. Martin, F. J. & Grove, C. Microfabricated drug delivery systems: concepts to improve clinical benefits. Biomed. Microdevices 3, 97-101 (2001).
103. Tkachenko, A. G. & Feldheim, D. L. Multifunctional gold nanoparticle-peptide complexes for nuclear targeting. J. Am. Chem. Soc. 125, 4700-4701 (2003).
104. Akerman, M. E., Chan, W. C. W., Laakkonen, P., Bhatia, S. N. & Ruoslahti, E. Nanocrystal targeting in vivo. Proc. Natl Acad. Sci. USA 99, 12617-12621 (2002).
105. Roy, I., Bergey, E. J. & Prasad, P. N. Ceramic-based nanoparticles entrapping water-insoluble photosensitizing anticancer drugs: a novel drug-carrier system for photodynamic therapy. J. Am. Chem. Soc. 125, 7860-7865 (2003).
106. O'Nea, D. P., Halas, N. J. & West, J. L. Photo-thermal tumor ablation in mice using near infrared-absorbing nanoparticles. Cancer Lett. 209, 171-176 (2004).
107. Liu, J. & Wooley, K. L. Nanostructured materias designed for cell binding and transduction. Biomacromolecules 2, 362-368 (2001).
108. Potineni, A., Langer, R. & Amiji, M. M. Poly(ethylene oxide)-modifed poly(β-amino ester) nanoparticles as a pH-sensitive biodegradable system for paclitaxel delivery. J. Control. Release 86, 223-234 (2003).
109. Juliano, R. L. & Stamp, D. Effect of particle size and charge on the clearance rates of liposomes and liposome-encapsulated drugs. Biochem. Biophys. Res. Commun. 63, 651-658 (1975).
110. Dellian, M. et al. Vascular permeability in a human tumor xenograft: molecular charge dependence. Br. J. Cancer 82, 1513-1518 (2000).
111. Sinek, J., Frieboes, H., Zheng, X. & Cristini, V. Two dimensional chemotherapy simulations demonstrate fundamental transport and tumor response limitations involving nanoparticles. Biomed. Microdevices 7, 71-79 (2005).
112. Bi-Botti, C. Y. Chronopharmaceutics: gimmick or clinically relevant approach to drug-delivery? J. Control. Release 98, 337-353 (2004).
113. Lesinski G. et al. Release of biologically functional interferon-α from a nanochannel delivery system. Biomed. Microdevices 6, 297-309 (2004).
114. Desai, T. A. & Ferrari, M. Microfabricated immunoisolating biocapsules. Biotechnol. Bioeng. 57, 118-120 (1998).
115. Bergers, G. & Hanahan, D. Cell factories for fighting cancer. Nature Biotechnol. 19, 20-21 (2001).
116. Steiniger, S. C. & Gelperina, S. E. Chemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles. Int. J. Cancer 109, 759-767 (2004).
117. Lockman, P. R. & Allen, D. D. Nanoparticle technology for drug deliver across the blood-brain barrier. Drug Dev. Ind. Pharm. 28, 1-13 (2002).
118. Lockman, P. R. & Allen, D. D. Brain uptake of thiamine-coated nanopartides. J. Control. Release 93, 271-282 (2003).
119. Koziara, J. M., Allen, D. D. & Mumper, R. J. In situ blood-brain barrier transport of nanoparticles. Pharm. Res. 20, 1772-1778 (2003).
120. Wu, J., Akaka, T. & Maeda, H. Modulation of enhanced permeability in tumor by a bradykinine antagonist, a cyclooxygenase inhibitor. Cancer Res. 58, 159-165 (1998).
121. Chen, H., Tochilin, V. & Langer, R. Lecting-bearing polymerized liposomes as potential oral vaccine carriers. Pharm. Res. 13, 1378-1383 (1996).
122. Tao, S. L., Lubeley, M. W. & Desai, T. A. Bioadhesive polymethyl methacrylate microdevices for controlled drug delivery. J. Control Rel. 88, 215-228 (2003).
123. Ferrari, M. et al. Particles for oral delivery of peptides and proteins. US Patent 6,355,270 (2002).
124. Lee, S. et al. Recognition properties of antibodies to PAMAM dendrimers and their use in immune detection of dendrimers. Biomed. Microdevices 3, 53-59 (2001).
125. Lee, S. C. et al. Biochemical and immunological properties of cytokines conjugated to dendritic polymers. Biomed. Microdevices 8, 191-202 (2004).
126. Sartinoranont, M., Rooney, F. J. & Ferrari, M. Interstitial stress and fluid pressure within a growing tumor. Ann. Biomed. Eng. 31, 327-335 (2003).
127. Qi, K. & Wooley, K. L. Determination of the bioavailability of biotin conjugated onto shell cross-linked (SCK) nanoparticles. J. Am. Chem. Soc. 128, 6599-6607 (2004).
128. Hggins, J. P. & Reed, R. A. Spectroscope approach for on-line monitoring of particle size during the processing of pharmaceutical nanoparticles. Anal. Chem. 75, 1777-1785 (2033).
129. Brocchini, S. & Duncan, R. in Encyclopedia of Controlled Drug Delivery (ed. Maliniowitz, E.) 786-816 (Wiley, New York, 1999).
130. Al Mehdi, A. B. et al. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells; a new model for metastasis. Nature Med. 8, 100-102 (2000).
131. Naumov, G. N. et al. Persistence of solitary mammary carcinoma cells in a secondary site: a possible contribution to dormancy. Cancer Res. 82, 2162-2168 (2002).
132. Brown, E. B. et al. In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy. Nature Med. 7, 864-868 (2001).
133. Wang, W. et al. Single cell behaviour in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res. 82, 6278-6288 (2002).