Delivering nanomedicine to solid tumors

Nature Reviews Clinical Oncology

Volumn 7, Issue 11, 2010, Pages 653-664

  Jain, Rakesh K ^a   Stylianopoulos, Triantafyllos ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BLEOMYCIN; DAUNORUBICIN; DOXORUBICIN; GENEXOL PM; PACLITAXEL; TOPOTECAN; UNCLASSIFIED DRUG; VINCRISTINE;

ANTIANGIOGENIC THERAPY; BLOOD FLOW VELOCITY; BLOOD VESSEL PERMEABILITY; BREAST CANCER; CANCER MORPHOLOGY; CLINICAL TRIAL; DRUG APPROVAL; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG DOSAGE FORM COMPARISON; DRUG EFFICACY; DRUG FORMULATION; DRUG PENETRATION; DRUG TRANSPORT; ENDOCYTOSIS; EXTRACELLULAR MATRIX; HUMAN; KAPOSI SARCOMA; LYMPHATIC DRAINAGE; NANOMEDICINE; NANOTECHNOLOGY; NONHUMAN; OVARY CANCER; OVERALL SURVIVAL; PARTICLE SIZE; PRIORITY JOURNAL; REVIEW; SOLID TUMOR; TUMOR VASCULARIZATION;

BIOLOGICAL TRANSPORT; DRUG DELIVERY SYSTEMS; HUMANS; LIGANDS; LYMPHATIC SYSTEM; NANOPARTICLES; NEOPLASMS;

EID: 78049452610     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2010.139     Document Type: Review

References (155)

1. Torchilin, V. P Targeted pharmaceutical nanocarriers for cancer therapy and imaging. AAPS J. 9, E128-E147 (2007).
2. Schroeder, A., Levins, C. G., Cortez, C., Langer, R. & Anderson, D. G. Lipid-based nanotherapeutics for siRNA delivery. J. Intern. Med. 267, 9-21 (2010).
3. Wagner, V., Dullaart, A., Bock, A. K. & Zweck, A. The emerging nanomedicine landscape. Nat Biotechnol. 24, 1211-1217 (2006).
4. Duncan, R. Polymer conjugates as anticancer nanomedicines. Nat Rev. Cancer 6, 688-701 (2006).
5. Stroh, M. et al. Quantum dots spectrally distinguish multiple species within the tumor milieu in vivo. Nat Med. 11, 678-682 (2005).
6. Allen, P M. et al. inAs(ZnCdS) quantum dots optimized for biological imaging in the near-infrared. J. Am. Chem. Soc. 132, 470-471 (2010).
7. Gradishar, W. J. et al. Phase iii trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J. Clin. Oncol. 23, 7794-7803 (2005).
8. Gelderblom, H., Verweij, J., Nooter, K. & Sparreboom, A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur. J. Cancer 37, 1590-1598 (2001).
9. Weiss, R. B. et al. Hypersensitivity reactions from taxol. J. Clin. Oncol. 8, 1263-1268 (1990).
10. Davis, M. E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067-1070 (2010).
11. Hu, C. M. & Zhang, L. Therapeutic nanoparticles to combat cancer drug resistance. Curr. Drug Metab. 10, 836-841 (2009).
12. Zhang, L. et al. Nanoparticles in medicine: therapeutic applications and developments. Clin. Pharmacol. Ther. 83, 761-769 (2008).
13. Davis, M. E., Chen, Z. G. & Shin, D. M. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev. Drug Discov. 7, 771-782 (2008).
14. Gordon, A. N. et al. Recurrent epithelial ovarian carcinoma: a randomized phase iii study of pegylated liposomal doxorubicin versus topotecan. J. Clin. Oncol. 19, 3312-3322 (2001).
15. Jain, R. K. Barriers to drug delivery in solid tumors. Sci. Am. 271, 58-65 (1994).
16. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy Science 307, 58-62 (2005).
17. Boucher, Y., Baxter, L. T. & Jain, R. K. Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy Cancer Res. 50, 4478-4484 (1990).
18. Jain, R. K. Transport of molecules in the tumor interstitium: a review. Cancer Res. 47, 3039-3051 (1987).
19. Gazit, Y., Berk, D. A., Leunig, M., Baxter, L. T. & Jain, R. K. Scale-invariant behavior and vascular network formation in normal and tumor tissue. Phys. Rev. Lett. 75, 2428-2431 (1995).
20. Baxter, L. T. & Jain, R. K. Transport of fluid and macromolecules in tumors. ii. Role of heterogeneous perfusion and lymphatics. Microvasc. Res. 40, 246-263 (1990).
21. Baish, J. W. et al. Role of tumor vascular architecture in nutrient and drug delivery: An invasion percolation-based network model. Microvasc. Res. 51, 327-346 (1996).
22. Jain, R. K. Determinants of tumor blood flow: a review. Cancer Res. 48, 2641-2658 (1988).
23. Vakoc, B. J. et al. Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging. Nat Med. 15, 1219-1223 (2009).
24. Jain, R. K. Transport of molecules across tumor vasculature. Cancer Metastasis Rev. 6, 559-593 (1987).
25. Roberts, W. G. & Palade, G. E. Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res. 57, 765-772 (1997).
26. Hobbs, S. K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. USA 95, 4607-4612 (1998).
27. Hashizume, H. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363-1380 (2000).
28. Padera, T. P et al. Pathology: cancer cells compress intratumour vessels. Nature 427, 695 (2004).
29. Roose, T., Netti, P A., Munn, L. L., Boucher, Y. & Jain, R. K. Solid stress generated by spheroid growth estimated using a linear poroelasticity model. Microvasc. Res. 66, 204-212 (2003).
30. Griffon-Etienne, G., Boucher, Y., Brekken, C., Suit, H. D. & Jain, R. K. Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications. Cancer Res. 59, 3776-3782 (1999).
31. Leunig, M. et al. Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCiD mice. Cancer Res. 52, 6553-6560 (1992).
32. Yuan, F. et al. Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. Cancer Res. 54, 4564-4568 (1994).
33. Kamoun, W. S. et al. Simultaneous measurement of RBC velocity, flux, hematocrit and shear rate in vascular networks in vivo. Nat Methods 7, 655-660 (2010).
34. Endrich, B., Reinhold, H. S., Gross, J. F. & Intaglietta, M. Tissue perfusion inhomogeneity during early tumor growth in rats. J. Natl Cancer Inst. 62, 387-395 (1979).
35. Padera, T. P et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296, 1883-1886 (2002).
36. Leu, A. J., Berk, D. A., Lymboussaki, A., Alitalo, K. & Jain, R. K. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res. 60, 4324-4327 (2000).
37. Hoshida, T. et al. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res. 66, 8065-8075 (2006).
38. Jain, R. K., Tong, R. T. & Munn, L. L. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res. 67, 2729-2735 (2007).
39. Dvorak, H. F., Brown, L. F., Detmar, M. & Dvorak, A. M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 146, 1029-1039 (1995).
40. Gerlowski, L. E. & Jain, R. K. Microvascular permeability of normal and neoplastic tissues. Microvasc. Res. 31, 288-305 (1986).
41. Sevick, E. M. & Jain, R. K. Measurement of capillary filtration coefficient in a solid tumor Cancer Res. 51, 1352-1355 (1991).
42. Maeda, H., Wu, J., Sawa, T., Matsumura, Y & Hori, K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control. Release 65, 271-284 (2000).
43. Yuan, F et al. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft Cancer Res. 54, 3352-3356 (1994).
44. Yuan, F et al. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 55, 3752-3756 (1995).
45. Campbell, R. B. et al. Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors. Cancer Res. 62, 6831-6836 (2002).
46. Schmitt-Sody, M. et al. Neovascular targeting therapy: paclitaxel encapsulated in cationic iposomes improves antitumoral efficacy. Clin. Cancer Res. 9, 2335-2341 (2003).
47. Dellian, M., Yuan, F, Trubetskoy, V. S., Torchilin, V. P & Jain, R. K. Vascular permeability in a human tumour xenograft: molecular charge dependence. Br. J. Cancer 82, 1513-1518 (2000).
48. Thurston, G. et al. Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice. J. Clin. Invest. 101, 1401-1413 (1998).
49. Krasnici, S. et al. Effect of the surface charge of iposomes on their uptake by angiogenic tumor essels. Int. J. Cancer 105, 561-567 (2003).
50. Yuan, F. et al. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc. Natl Acad. Sci. USA 93, 14765-14770 (1996).
51. Fukumura, D., Yuan, F., Monsky, W. L., Chen, Y. & Jain, R. K. Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. Am. J. Pathol. 151, 679-688 (1997).
52. Monsky, W. L. et al. Role of host microenvironment in angiogenesis and microvascular functions in human breast cancer xenografts: mammary fat pad versus cranial tumors. Clin. Cancer Res. 8, 1008-1013 (2002).
53. Baxter, L. T. & Jain, R. K. Transport of fluid and macromolecules in tumors. I. Role of interstitial pressure and convection. Microvasc. Res. 37, 77-104 (1989).
54. Boucher, Y., Kirkwood, J. M., Opacic, D., Desantis, M. & Jain, R. K. Interstitial hypertension in superficial metastatic melanomas in humans. Cancer Res. 51, 6691-6694 (1991).
55. Boucher, Y. & Jain, R. K. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res. 52, 5110-5114 (1992).
56. Less, J. R. et al. Interstitial hypertension in human breast and colorectal tumors. Cancer Res. 52, 6371-6374 (1992).
57. Willett, C. G. et al. Direct evidence that the vEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 10, 145-147 (2004).
58. Jain, R. K. & Baxter, L. T. Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res. 48, 7022-7032 (1988).
59. Baxter, L. T. & Jain, R. K. Transport of fluid and macromolecules in tumors. i V. A microscopic model of the perivascular distribution. Microvasc. Res. 41, 252-272 (1991).
60. Netti, P A., Roberge, S., Boucher, Y, Baxter, L. T. & Jain, R. K. Effect of transvascular fluid exchange on pressure-flow relationship in tumors: a proposed mechanism for tumor blood flow heterogeneity. Microvasc. Res. 52, 27-46 (1996).
61. Baish, J. W., Netti, P A. & Jain, R. K. Transmural coupling of fluid flow in microcirculatory network and interstitium in tumors. Microvasc. Res. 53, 128-141 (1997).
62. Lichtenbeld, H. C., Yuan, F., Michel, C. C. & Jain, R. K. Perfusion of single tumor microvessels: application to vascular permeability measurement. Microcirculation 3, 349-357 (1996).
63. Hagendoorn, J. et al. Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis. Cancer Res. 66, 3360-3364 (2006).
64. Nguyen, Q. T. et al. Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival. Proc. Natl Acad. Sci. USA 107, 4317-4322 (2010).
65. Olson, E. S. et al. Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases. Proc. Natl Acad. Sci. USA 107, 4311-4316 (2010)
66. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650-1659 (1986).
67. Ronnov-Jessen, L., Petersen, O. W. & Bissell, M. J. Cellular changes involved in conversion of normal to malignant breast: mportance of the stromal reaction. Physiol. Rev. 76, 69-125 (1996).
68. Krol, A., Maresca, J., Dewhirst, M. W. & Yuan, F. Available volume fraction of macromolecules in the extravascular space of a fibrosarcoma: Mplications for drug delivery. Cancer Res. 59, 4136-4141 (1999).
69. Pluen, A. et al. Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors. Proc. Natl Acad. Sci. USA 98, 4628-4633 (2001).
70. Pluen, A., Netti, P A., Jain, R. K. & Berk, D. A. Diffusion of macromolecules in agarose gels: comparison of linear and globular configurations. Biophys. J. 77, 542-552 (1999).
71. Ramanujan, S. et al. Diffusion and convection in collagen gels: implications for transport in the tumor interstitium. Biophys. J. 83, 1650-1660 (2002).
72. Alexandrakis, G. et al. Two-photon fluorescence correlation microscopy reveals the two-phase nature of transport in tumors. Nat Med. 10, 203-207 (2004).
73. McKee, T. D. et al. Degradation of fibrillar collagen in a human melanoma xenograft mproves the efficacy of an oncolytic herpes simplex virus vector. Cancer Res. 66, 2509-2513 (2006).
74. Nugent, L. J. & Jain, R. K. Extravascular diffusion in normal and neoplastic tissues. Cancer Res. 44, 238-244 (1984).
75. Netti, P A., Berk, D. A., Swartz, M. A., Grodzinsky, A. J. & Jain, R. K. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 60, 2497-2503 (2000).
76. Choi, J. et al. Intraperitoneal immunotherapy for metastatic ovarian carcinoma: resistance of intratumoral collagen to antibody penetration. Clin. Cancer Res. 12, 1906-1912 (2006).
77. Stylianopoulos, T., Diop-Frimpong, B., Munn, L. L. & Jain, R. K. Diffusion anisotropy in collagen gels and tumors: the effect of fiber network orientation. Biophys. J. (in press).
78. Stylianopoulos, T. et al. Diffusion of particles in the extracellular matrix: the effect of repulsive electrostatic interactions. Biophys. J. (in press).
79. Mok, W., Boucher, Y. & Jain, R. K. Matrix metalloproteinases-1 and-8 improve the distribution and efficacy of an oncolytic virus. Cancer Res. 67, 10664-10668 (2007).
80. Lieleg, O., Baumgartel, R. M. & Bausch, A. R. Selective filtering of particles by the extracellular matrix: an electrostatic bandpass. Biophys. J. 97, 1569-1577 (2009).
81. Thorne, R. G., Lakkaraju, A., Rodriguez-Boulan, E. & Nicholson, C. In vivo diffusion of lactoferrin in brain extracellular space is regulated by interactions with heparan sulfate. Proc. Natl Acad. Sci. USA 105, 8416-8421 (2008).
82. Dowd, C. J., Cooney, C. L. & Nugent, M. A. Heparan sulfate mediates bFGF transport through basement membrane by diffusion with rapid reversible binding. J. Biol. Chem. 274, 5236-5244 (1999).
83. Chauhan, V. P et al. Multiscale measurements distinguish cellular and interstitial hindrances to diffusion in vivo. Biophys. J. 97, 330-336 (2009).
84. Carmeliet, P & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249-257 (2000).
85. Yancopoulos, G. D. et al. Vascular-specific growth factors and blood vessel formation. Nature 407, 242-248 (2000).
86. Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 7, 987-989 (2001).
87. Tong, R. T. et al. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 64, 3731-3736 (2004).
88. Winkler, F et al. Kinetics of vascular normalization by vEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553-563 (2004).
89. Wildiers, H. et al. Effect of antivascular endothelial growth factor treatment on the ntratumoral uptake of CPT-11. Br. J. Cancer 88, 1979-1986 (2003).
90. Lee, C. G. et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 60, 5565-5570 (2000).
91. Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R. K. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279-280 (2002).
92. Mazzone, M. et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136, 839-851 (2009).
93. Jain, R. K. A new target for tumor therapy N. Engl. J. Med. 360, 2669-2671 (2009).
94. Batchelor, T. T. et al. AZD2171, a pan-vEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83-95 (2007).
95. Olive, K. P et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457-1461 (2009).
96. Magzoub, M., Jin, S. & verkman, A. S. Enhanced macromolecule diffusion deep in tumors after enzymatic digestion of extracellular matrix collagen and its associated proteoglycan decorin. FASEB J. 22, 276-284 (2008).
97. Mok, W., Stylianopoulos, T., Boucher, Y & Jain, R. K. Mathematical modeling of herpes simplex virus distribution in solid tumors: mplications for cancer gene therapy. Clin. Cancer Res. 15, 2352-2360 (2009).
98. Brown, E. et al. Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation. Nat Med. 9, 796-800 (2003).
99. Perentes, J. Y et al. In vivo imaging of extracellular matrix remodeling by tumor-associated fibroblasts. Nat Methods 6, 143-145 (2009).
100. Sugahara, K. N. et al. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328, 1031-1035 (2010).
101. Choi, H. S. et al. Renal clearance of quantum dots. Nat Biotechnol. 25, 1165-1170 (2007).
102. Choi, H. S. et al. Design considerations for tumour-targeted nanoparticles. Nat Nanotechnol. 5, 42-47 (2010).
103. Geng, Y et al. Shape effects of filaments versus spherical particles in flow and drug delivery. Nat Nanotechnol. 2, 249-255 (2007).
104. Singh, R. et al. Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers. Proc. Natl Acad. Sci. USA 103, 3357-3362 (2006).
105. Longmire, M., Choyke, P L. & Kobayashi, H. Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine (Lond.) 3, 703-717 (2008).
106. Franzen, S. & Lommel, S. A. Targeting cancer with 'smart bombs': equipping plant virus nanoparticles for a 'seek and destroy' mission. Nanomedicine (Lond.) 4, 575-588 (2009).
107. Klibanov, A. L., Maruyama, K., Torchilin, V. P & Huang, L. Amphipathic polyethyleneglycols effectively prolong the circulation time of iposomes. FEBS Lett 268, 235-237 (1990).
108. Peracchia, M. T. et al. Stealth PEGylated polycyanoacrylate nanoparticles for intravenous administration and splenic targeting. J. Control. Release 60, 121-128 (1999).
109. Storm, G., Belliot, S. O., Daemen, T. & Lasic, D. D. Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system. Adv. Drug Deliv. Rev. 17, 31-48 (1995).
110. Decuzzi, P, Pasqualini, R., Arap, W. & Ferrari, M. Intravascular delivery of particulate systems: does geometry really matter? Pharm. Res. 26, 235-243 (2009).
111. Rejman, J., Oberle, V., Zuhorn, I. S. & Hoekstra, D. Size-dependent internalization of particles via the pathways of clathrin-and caveolae-mediated endocytosis. Biochem. J. 377, 159-169 (2004).
112. Chithrani, B. D., Ghazani, A. A. & Chan, W. C. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano. Lett. 6, 662-668 (2006).
113. Gao, H., Shi, W. & Freund, L. B. Mechanics of receptor-mediated endocytosis. Proc. Natl Acad. Sci. USA 102, 9469-9474 (2005).
114. Foged, C., Brodin, B., Frokjaer, S. & Sundblad, A. Particle size and surface charge affect particle uptake by human dendritic cells in an in vitro model. Int. J. Pharm. 298, 315-322 (2005).
115. Jiang, W., Kim, B. Y., Rutka, J. T. & Chan, W. C. Nanoparticle-mediated cellular response is size-dependent. Nat Nanotechnol. 3, 145-150 (2008).
116. Champion, J. A. & Mitragotri, S. Role of target geometry in phagocytosis. Proc. Natl Acad. Sci. USA 103, 4930-4934 (2006).
117. Gratton, S. E. et al. The effect of particle design on cellular internalization pathways. Proc. Natl Acad. Sci. USA 105, 11613-11618 (2008).
118. Wagner, E. Programmed drug delivery: nanosystems for tumor targeting. Expert Opin. Biol. Ther. 7, 587-593 (2007).
119. 2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med. 3, 177-182 (1997).
120. Kale, A. A. & Torchilin, V. P. Environment-responsive multifunctional liposomes. Methods Mol. Biol. 605, 213-242 (2010).
121. Meyer, O., Papahadjopoulos, D. & Leroux, J. C. Copolymers of N-isopropylacrylamide can trigger pH sensitivity to stable liposomes. FEBS Lett. 421, 61-64 (1998).
122. Leroux, J., Roux, E., Le Garrec, D., Hong, K. & Drummond, D. C. N-isopropylacrylamide copolymers for the preparation of pH-sensitive iposomes and polymeric micelles. J. Control. Release 72, 71-84 (2001).
123. Meyer, M. & Wagner, E. PH-responsive shielding of non-viral gene vectors. Expert Opin. Drug Deliv. 3, 563-571 (2006).
124. Harris, T. J., von Maltzahn, G., Derfus, A. M., Ruoslahti, E. & Bhatia, S. N. Proteolytic actuation of nanoparticle self-assembly. Angew. Chem. Int. Ed. Engl. 45, 3161-3165 (2006).
125. Lee, S. et al. A near-infrared-fluorescence-quenched gold-nanoparticle imaging probe for in vivo drug screening and protease activity determination. Angew. Chem. Int. Ed. Engl. 47, 2804-2807 (2008).
126. Mu, C. J., Lavan, D. A., Langer, R. S. & Zetter, B. R. Self-assembled gold nanoparticle molecular probes for detecting proteolytic activity in vivo. ACS Nano. 4, 1511-1520 (2010).
127. Goto, T. et al. Highly efficient electro-gene therapy of solid tumor by using an expression plasmid for the herpes simplex virus thymidine kinase gene. Proc. Natl Acad. Sci. USA 97, 354-359 (2000).
128. Heller, L. C. & Heller, R. In vivo electroporation for gene therapy. Hum. Gene Ther. 17, 890-897 (2006).
129. Scherer, F. et al. Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo. Gene Ther. 9, 102-109 (2002).
130. Manome, Y., Nakamura, M., Ohno, T. & Furuhata, H. Ultrasound facilitates transduction of naked plasmid DNA into colon carcinoma cells in vitro and in vivo. Hum. Gene Ther. 11, 1521-1528 (2000).
131. Zintchenko, A., Ogris, M. & Wagner, E. Temperature dependent gene expression induced by PNiPAM-based copolymers: potential of hyperthermia in gene transfer. Bioconjug. Chem. 17, 766-772 (2006).
132. Kloeckner, J., Prasmickaite, L., Hogset, A., Berg, K. & Wagner, E. Photochemically enhanced gene delivery of EGF receptor-targeted DNA polyplexes. J. Drug Target. 12, 205-213 (2004).
133. Lu, J. et al. Mesoporous silica nanoparticles for cancer therapy: energy-dependent cellular uptake and delivery of paclitaxel to cancer cells. Nanobiotechnology 3, 89-95 (2007).
134. Tanaka, T. et al. Sustained small interfering RNA delivery by mesoporous silicon particles. Cancer Res. 70, 3687-3696 (2010).
135. Lei, C. et al. Local release of highly loaded antibodies from functionalized nanoporous support for cancer immunotherapy. J. Am. Chem. Soc. 132, 6906-6907 (2010).
136. Ruoslahti, E., Bhatia, S. N. & Sailor, M. J. Targeting of drugs and nanoparticles to tumors. J. Cell Biol. 188, 759-768 (2010).
137. Hood, J. D. et al. Tumor regression by targeted gene delivery to the neovasculature. Science 296, 2404-2407 (2002).
138. Murphy, E. A. et al. Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis. Proc. Natl Acad. Sci. USA 105, 9343-9348 (2008).
139. Sugahara, K. N. et al. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16, 510-520 (2009).
140. Pirollo, K. F. & Chang, E. H. Does a targeting ligand influence nanoparticle tumor localization or uptake? Trends Biotechnol. 26, 552-558 (2008).
141. Karmali, P P. et al. Targeting of albumin-embedded paclitaxel nanoparticles to tumors. Nanomedicine 5, 73-82 (2009).
142. Jain, R. K. Delivery of molecular and cellular medicine to solid tumors. Adv. Drug Deliv. Rev. 46, 149-168 (2001).
143. Jain, R. K. Taming vessels to treat cancer. Sci. Am. 298, 56-63 (2008).
144. Northfelt, D. W. et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AiDS-related Kaposi's sarcoma: results of a randomized phase iii clinical trial. J. Clin. Oncol. 16, 2445-2451 (1998).
145. O'Brien, M. E. et al. Reduced cardiotoxicity and comparable efficacy in a phase iii trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann. Oncol. 15, 440-449 (2004).
146. Gill, P S. et al. Randomized phase iii trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AiDS-related Kaposi's sarcoma. J. Clin. Oncol. 14, 2353-2364 (1996).
147. Lee, K. S. et al. Multicenter phase ii trial of Genexol-PM, a Cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer. Breast Cancer Res. Treat 108, 241-250 (2008).
148. Kim, J. & Shin, S. Cost-effectiveness of Genexol-PM for treating metastatic breast cancer. J. Breast Cancer 13, 104-110 (2010).
149. Sevick, E. M. & Jain, R. K. Blood flow and venous pH of tissue-isolated Walker 256 carcinoma during hyperglycemia. Cancer Res. 48, 1201-1207 (1988).
150. Sevick, E. M. & Jain, R. K. Geometric resistance to blood flow in solid tumors perfused ex vivo: effects of tumor size and perfusion pressure. Cancer Res. 49, 3506-3512 (1989).
151. Sevick, E. M. & Jain, R. K. Viscous resistance to blood flow in solid tumors: effect of hematocrit on intratumor blood viscosity. Cancer Res. 49, 3513-3519 (1989).
152. Less, J. R., Skalak, T. C., Sevick, E. M. & Jain, R. K. Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions. Cancer Res. 51, 265-273 (1991).
153. Baish, J. W. & Jain, R. K. Fractals and cancer. Cancer Res. 60, 3683-3688 (2000).
154. Less, J. R., Posner, M. C., Skalak, T. C., Wolmark, N. & Jain, R. K. Geometric resistance and microvascular network architecture of human colorectal carcinoma. Microcirculation 4, 25-33 (1997).
155. Sun, C., Jain, R. K. & Munn, L. L. Non-uniform plasma leakage affects local hematocrit and blood flow: implications for inflammation and tumor perfusion. Ann. Biomed. Eng. 35, 2121-2129 (2007).