In vitro microfluidic models of tumor microenvironment to screen transport of drugs and nanoparticles

Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology

Volumn 9, Issue 5, 2017, Pages

  Ozcelikkale, Altug ^a   Moon, Hye Ran ^a   Linnes, Michael ^a   Han, Bumsoo ^a  

^a Purdue University   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL CULTURE; CELLS; CYTOLOGY; DIAGNOSIS; DISEASES; HYDROSTATIC PRESSURE; MEDICAL NANOTECHNOLOGY; NANOPARTICLES; ONCOLOGY; PHYSIOLOGICAL MODELS; PHYSIOLOGY; SHEAR STRESS; TUMORS;

CELL MATRIX INTERACTIONS; HIGH THROUGHPUT SCREENING; MICRO FLUIDIC SYSTEM; MICROFLUIDIC TECHNOLOGIES; MULTICELLULAR TUMOR SPHEROIDS; PHYSIOLOGICAL CONDITION; TRADITIONAL CULTURES; TUMOR MICROENVIRONMENT;

MICROFLUIDICS;

NANOCARRIER; NANOPARTICLE;

CANCER THERAPY; DRUG DELIVERY SYSTEM; DRUG PENETRATION; DRUG SCREENING; DRUG TARGETING; DRUG TRANSPORT; EXTRACELLULAR MATRIX; IN VITRO STUDY; MICROFLUIDICS; NANOMEDICINE; PRIORITY JOURNAL; REVIEW; TUMOR MICROENVIRONMENT; TUMOR MODEL; TUMOR VASCULARIZATION; HUMAN;

DRUG DELIVERY SYSTEMS; HUMANS; MICROFLUIDICS; NANOMEDICINE; NANOPARTICLES; TUMOR MICROENVIRONMENT;

EID: 85013046185     PISSN: 19395116     EISSN: 19390041     Source Type: Journal    
DOI: 10.1002/wnan.1460     Document Type: Review

References (176)

1. Bao G, Mitragotri S, Tong S. Multifunctional nanoparticles for drug delivery and molecular imaging. Annu Rev Biomed Eng 2013, 15:253–282.
2. Kim BY-S, Rutka JT, Chan WCC. Nanomedicine. New Engl J Med 2010, 363:2434–2443.
3. Ozcelikkale A, Ghosh S, Han B. Multifaceted transport characteristics of nanomedicine: needs for characterization in dynamic environment. Mol Pharm 2013, 10:2111–2126.
4. Bae YH, Mrsny RJ, Park K. Cancer Targeted Drug Delivery: An Elusive Dream. Springer-Verlag New York: Springer; 2013.
5. Bae YH, Park K. Targeted drug delivery to tumors: myths, reality and possibility. J Control Release 2011, 153:198–205.
6. Kwon IK, Lee SC, Han B, Park K. Analysis on the current status of targeted drug delivery to tumors. J Control Release 2012, 164:108–114.
7. Venditto VJ, Szoka FC. Cancer nanomedicines: so many papers and so few drugs!. Adv Drug Deliv Rev 2013, 65:80–88.
8. Han B, Qu C, Park K, Konieczny SF, Korc M. Recapitulation of complex transport and action of drugs at the tumor microenvironment using tumor-microenvironment-on-chip. Cancer Lett 2016, 380:319–329.
9. Perrault SD, Walkey C, Jennings T, Fischer HC, Chan WCW. Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett 2009, 9:1909–1915.
10. Albanese A, Tang PS, Chan WC. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng 2012, 14:1–16.
11. Agarwal R, Jurney P, Raythatha M, Singh V, Sreenivasan SV, Shi L, Roy K. Effect of shape, size, and aspect ratio on nanoparticle penetration and distribution inside solid tissues using 3D spheroid models. Adv Healthc Mater 2015, 4:2269–2280.
12. Shang L, Nienhaus K, Nienhaus GU. Engineered nanoparticles interacting with cells: size matters. J Nanobiotechnol 2014, 12:5. doi:10.1186/1477-3155-12-5.
13. Stylianopoulos T, Diop-Frimpong B, Munn LL, Jain RK. Diffusion anisotropy in collagen gels and tumors: the effect of fiber network orientation. Biophys J 2010, 99:3119–3128.
14. Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Greenwald DR, Ruoslahti E. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 2010, 328:1031–1035.
15. Stirland DL, Nichols JW, Miura S, Bae YH. Mind the gap: a survey of how cancer drug carriers are susceptible to the gap between research and practice. J Control Release 2013, 172:1045–1064.
16. Yokoi K, Chan DN, Kojic M, Milosevic M, Engler D, Matsunami R, Tanei T, Saito Y, Ferrari M, Ziemys A. Liposomal doxorubicin extravasation controlled by phenotype-specific transport properties of tumor microenvironment and vascular barrier. J Control Release 2015, 217:293–299.
17. Litzinger DC, Buiting AMJ, Vanrooijen N, Huang L. Effect of liposome size on the circulation time and intraorgan distribution of amphipathic poly(ethylene glycol)-containing liposomes. Biochim Biophys Acta 1994, 1190:99–107.
18. Lee H, Hoang B, Fonge H, Reilly RM, Allen C. In vivo distribution of polymeric nanoparticles at the whole-body, tumor, and cellular levels. Pharm Res 2010, 27:2343–2355.
19. Singh R. Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers. Proc Natl Acad Sci USA 2006, 103:3357–3362.
20. Longmire M, Choyke PL, Kobayashi H. Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine 2008, 3:703–717.
21. Choi HS, Liu W, Misra P, Tanaka E, Zimmer JP, Ipe BI, Bawendi MG, Frangioni JV. Renal clearance of quantum dots. Nat Biotechnol 2007, 25:1165–1170.
22. Li F, Zhu A, Song X, Ji L, Wang J. The internalization of fluorescence-labeled PLA nanoparticles by macrophages. Int J Pharm 2013, 453:506–513.
23. Clift MJD, Rothen-Rutishauser B, Brown DM, Duffin R, Donaldson K, Proudfoot L, Guy K, Stone V. The impact of different nanoparticle surface chemistry and size on uptake and toxicity in a murine macrophage cell line. Toxicol Appl Pharmacol 2008, 232:418–427.
24. Moghimi SM. Mechanisms of splenic clearance of blood cells and particles: towards development of new splenotropic agents. Adv Drug Deliv Rev 1995, 17:103–115.
25. dos Santos T, Varela J, Lynch I, Salvati A, Dawson KA. Quantitative assessment of the comparative nanoparticle-uptake efficiency of a range of cell lines. Small 2011, 7:3341–3349.
26. Kettler K, Giannakou C, de Jong WH, Hendriks AJ, Krystek P. Uptake of silver nanoparticles by monocytic THP-1 cells depends on particle size and presence of serum proteins. J Nanopart Res 2016, 18:286. doi:10.1007/s11051-016-3595-7.
27. Campbell RB, Fukumura D, Brown EB, Mazzola LM, Izumi Y, Jain RK, Torchilin VP, Munn LL. Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors. Cancer Res 2002, 62:6831–6836.
28. Zhang XD, Wu D, Shen X, Liu PX, Yang N, Zhao B, Zhang H, Sun YM, Zhang LA, Fan FY. Size-dependent In vivo toxicity of PEG-coated gold nanoparticles. Int J Nanomedicine 2011, 6:2071–2081.
29. Rimal B, Greenberg AK, Rom WN. Basic pathogenetic mechanisms in silicosis: current understanding. Curr Opin Pulm Med 2005, 11:169–173.
30. Nishimori H, Kondoh M, Isoda K, Tsunoda S, Tsutsumi Y, Yagi K. Silica nanoparticles as hepatotoxicants. Eur J Pharm Biopharm 2009, 72:496–501.
31. Liu T, Li L, Teng X, Huang X, Liu H, Chen D, Ren J, He J, Tang F. Single and repeated dose toxicity of mesoporous hollow silica nanoparticles in intravenously exposed mice. Biomaterials 2011, 32:1657–1668.
32. Gustafson HH, Holt-Casper D, Grainger DW, Ghandehari H. Nanoparticle uptake: the phagocyte problem. Nano Today 2015, 10:487–510.
33. Park J, Lim DH, Lim HJ, Kwon T, Choi JS, Jeong S, Choi IH, Cheon J. Size dependent macrophage responses and toxicological effects of Ag nanoparticles. Chem Commun (Camb) 2011, 47:4382–4384.
34. Park MV, Neigh AM, Vermeulen JP, de la Fonteyne LJ, Verharen HW, Briede JJ, van Loveren H, de Jong WH. The effect of particle size on the cytotoxicity, inflammation, developmental toxicity and genotoxicity of silver nanoparticles. Biomaterials 2011, 32:9810–9817.
35. Gerlowski LE, Jain RK. Microvascular permeability of normal and neoplastic tissues. Microvasc Res 1986, 31:288–305.
36. Hashizume H. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 2000, 156:1363–1380.
37. Nagy JA, Chang SH, Shih SC, Dvorak AM, Dvorak HF. Heterogeneity of the tumor vasculature. Semin Thromb Hemost 2010, 36:321–331.
38. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 2011, 10:417–427.
39. Feng D, Nagy JA, Pyne K, Hammel I, Dvorak HF, Dvorak AM. Pathways of macromolecular extravasation across microvascular endothelium in response to VPF VEGF and other vasoactive mediators. Microcirculation 1999, 6:23–44.
40. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer-chemotherapy—mechanism of tumoritropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res 1986, 46:6387–6392.
41. Holback H, Yeo Y. Intratumoral drug delivery with nanoparticulate carriers. Pharm Res 2011, 28:1819–1830.
42. Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res 2000, 60:2497–2503.
43. Choi J. Intraperitoneal immunotherapy for metastatic ovarian carcinoma: resistance of intratumoral collagen to antibody penetration. Clin Cancer Res 2006, 12:1906–1912.
44. Goodman TT, Olive PL, Pun SH. Increased nanoparticle penetration in collagenase-treated multicellullar spheroids. Int J Nanomedicine 2007, 2:265–274.
45. Jain RK. Transport of molecules, particles, and cells in solid tumors. Annu Rev Biomed Eng 1999, 1:241–263.
46. Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, Jain RK. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 2011, 91:1071–1121.
47. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012, 21:418–429.
48. Lichtenbeld HC, Yuan F, Michel CC, Jain RK. Perfusion of single tumor microvessels: application to vascular permeability measurement. Microcirculation 1996, 3:349–357.
49. Heldin CH, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer 2004, 4:806–813.
50. Kartner N, Ling V. Multidrug resistance in cancer. Sci Am 1989, 260:44–51.
51. Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov 2006, 5:219–234.
52. Sharom FJ. ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics 2008, 9:105–127.
53. Callaghan R, Stafford A, Epand RM. Increased accumulation of drugs in a multidrug resistant cell line by alteration of membrane biophysical properties. Biochim Biophys Acta 1993, 1175:277–282.
54. Teo KY, Han B. Freezing-assisted intracellular drug delivery to multidrug resistant cancer cells. J Biomech Eng 2009, 131:74513.
55. Patil Y, Sadhukha T, Ma L, Panyam J. Nanoparticle-mediated simultaneous and targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance. J Control Release 2009, 136:21–29.
56. Song XR, Cai Z, Zheng Y, He G, Cui FY, Gong DQ, Hou SX, Xiong SJ, Lei XJ, Wei YQ. Reversion of multidrug resistance by co-encapsulation of vincristine and verapamil in PLGA nanoparticles. Eur J Pharm Sci 2009, 37:300–305.
57. He Q, Gao Y, Zhang L, Zhang Z, Gao F, Ji X, Li Y, Shi J. A pH-responsive mesoporous silica nanoparticles-based multi-drug delivery system for overcoming multi-drug resistance. Biomaterials 2011, 32:7711–7720.
58. Lukianova-Hleb EY, Belyanin A, Kashinath S, Wu X, Lapotko DO. Plasmonic nanobubble-enhanced endosomal escape processes for selective and guided intracellular delivery of chemotherapy to drug-resistant cancer cells. Biomaterials 2012, 33:1821–1826.
59. Duan XP, Li YP. Physicochemical characteristics of nanoparticles affect circulation, biodistribution, cellular internalization, and trafficking. Small 2013, 9:1521–1532.
60. Dobrovolskaia MA, Shurin M, Shvedova AA. Current understanding of interactions between nanoparticles and the immune system. Toxicol Appl Pharmacol 2016, 299:78–89.
61. Lee H, Fonge H, Hoang B, Reilly RM, Allen C. The effects of particle size and molecular targeting on the intratumoral and subcellular distribution of polymeric nanoparticles. Mol Pharm 2010, 7:1195–1208.
62. Cabral H, Matsumoto Y, Mizuno K, Chen Q, Murakami M, Kimura M, Terada Y, Kano MR, Miyazono K, Uesaka M, et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat Nanotechnol 2011, 6:815–823.
63. Schadlich A, Caysa H, Mueller T, Tenambergen F, Rose C, Gopferich A, Kuntsche J, Mader K. Tumor accumulation of NIR fluorescent PEG PLA nanoparticles: impact of particle size and human xenograft tumor model. ACS Nano 2011, 5:8710–8720.
64. Geng Y, Dalhaimer P, Cai SS, Tsai R, Tewari M, Minko T, Discher DE. Shape effects of filaments versus spherical particles in flow and drug delivery. Nat Nanotechnol 2007, 2:249–255.
65. Walkey CD, Olsen JB, Guo H, Emili A, Chan WCW. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J Am Chem Soc 2012, 134:2139–2147.
66. Wu J, Lee A, Lu Y, Lee RJ. Vascular targeting of doxorubicin using cationic liposomes. Int J Pharm 2007, 337:329–335.
67. Zhao W, Zhuang S, Qi XR. Comparative study of the in vitro and in vivo characteristics of cationic and neutral liposomes. Int J Nanomedicine 2011, 6:3087–3098.
68. Klibanov AL, Maruyama K, Torchilin VP, Huang L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 1990, 268:235–237.
69. Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev 2001, 53:283–318.
70. Park J, Fong PM, Lu J, Russell KS, Booth CJ, Saltzman WM, Fahmy TM. PEGylated PLGA nanoparticles for the improved delivery of doxorubicin. Nanomedicine 2009, 5:410–418.
71. Malugin A, Ghandehari H. Cellular uptake and toxicity of gold nanoparticles in prostate cancer cells: a comparative study of rods and spheres. J Appl Toxicol 2010, 30:212–217.
72. Dellian M, Yuan F, Trubetskoy VS, Torchilin VP, Jain RK. Vascular permeability in a human tumour xenograft: molecular charge dependence. Br J Cancer 2000, 82:1513–1518.
73. Thurston G. Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice. J Clin Invest 1998, 101:1401–1413.
74. Krasnici S. Effect of the surface charge of liposomes on their uptake by angiogenic tumor vessels. Int J Cancer 2003, 105:561–567.
75. Kostarelos K, Emfietzoglou D, Papakostas A, Yang WH, Ballangrud A, Sgouros G. Binding and interstitial penetration of liposomes within avascular tumor spheroids. Int J Cancer 2004, 112:713–721.
76. Adriani G, de Tullio MD, Ferrari M, Hussain F, Pascazio G, Liu X, Decuzzi P. The preferential targeting of the diseased microvasculature by disk-like particles. Biomaterials 2012, 33:5504–5513.
77. Decuzzi P, Pasqualini R, Arap W, Ferrari M. Intravascular delivery of particulate systems: does geometry really matter? Pharm Res 2009, 26:235–243.
78. Dreher MR, Liu W, Michelich CR, Dewhirst MW, Yuan F, Chilkoti A. Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst 2006, 98:335–344.
79. Lieleg O, Baumgartel RM, Bausch AR. Selective filtering of particles by the extracellular matrix: an electrostatic bandpass. Biophys J 2009, 97:1569–1577.
80. Padera TP. Pathology: cancer cells compress intratumour vessels. Nature 2004, 427:695.
81. 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 2000, 65:271–284.
82. Fang J, Nakamura H, Maeda H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 2011, 63:136–151.
83. Maeda H, Tsukigawa K, Fang J. A retrospective 30 years after discovery of the enhanced permeability and retention effect of solid tumors: next-generation chemotherapeutics and photodynamic therapyproblems, solutions, and prospects. Microcirculation 2016, 23:173–182.
84. Allen C. Why i'm holding onto hope for nano in oncology. Mol Pharm 2016, 13:2603–2604.
85. Florence AT. Pharmaceutical nanotechnolgy: more than size. Int J Pharm 2007, 339:1–2.
86. Frese KK, Tuveson DA. Maximizing mouse cancer models. Nat Rev Cancer 2007, 7:645–658.
87. Dozono H, Yanazume S, Nakamura H, Etrych T, Chytil P, Ulbrich K, Fang J, Arimura T, Douchi T, Kobayashi H, et al. HPMA copolymer-conjugated pirarubicin in multimodal treatment of a patient with stage IV prostate cancer and extensive lung and bone metastases. Target Oncol 2016, 11:101–106.
88. Teesalu T, Sugahara KN, Kotamraju VR, Ruoslahti E. C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc Natl Acad Sci USA 2009, 106:16157–16162.
89. Yang L, Mao H, Wang YA, Cao Z, Peng X, Wang X, Duan H, Ni C, Yuan Q, Adams G, et al. Single chain epidermal growth factor receptor antibody conjugated nanoparticles for in vivo tumor targeting and imaging. Small 2009, 5:235–243.
90. Maruyama K. Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects. Adv Drug Deliv Rev 2011, 63:161–169.
91. Huang X, Peng X, Wang Y, Wang Y, Shin DM, El-Sayed MA, Nie S. A reexamination of active and passive tumor targeting by using rod-shaped gold nanocrystals and covalently conjugated peptide ligands. ACS Nano 2010, 4:5887–5896.
92. Juweid M, Neumann R, Paik C, Perezbacete MJ, Sato J, Vanosdol W, Weinstein JN. Micropharmacology of monoclonal-antibodies in solid tumors—direct experimental evidence for a binding-site barrier. Cancer Res 1992, 52:5144–5153.
93. Dufort S, Sancey L, Coll J-L. Physico-chemical parameters that govern nanoparticles fate also dictate rules for their molecular evolution. Adv Drug Deliv Rev 2012, 64:179–189.
94. Danhier F, Feron O, Préat V. To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release 2010, 148:135–146.
95. Huynh NT, Roger E, Lautram N, Benoit JP, Passirani C. The rise and rise of stealth nanocarriers for cancer therapy: passive versus active targeting. Nanomedicine 2010, 5:1415–1433.
96. Ganta S, Devalapally H, Shahiwala A, Amiji M. A review of stimuli-responsive nanocarriers for drug and gene delivery. J Control Release 2008, 126:187–204.
97. Medeiros SF, Santos AM, Fessi H, Elaissari A. Stimuli-responsive magnetic particles for biomedical applications. Int J Pharm 2011, 403:139–161.
98. Fleige E, Quadir MA, Haag R. Stimuli-responsive polymeric nanocarriers for the controlled transport of active compounds: concepts and applications. Adv Drug Deliv Rev 2012, 64:866–884.
99. Wong C, Stylianopoulos T, Cui JA, Martin J, Chauhan VP, Jiang W, Popovic Z, Jain RK, Bawendi MG, Fukumura D. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc Natl Acad Sci USA 2011, 108:2426–2431.
100. Tong R, Hemmati HD, Langer R, Kohane DS. Photoswitchable nanoparticles for triggered tissue penetration and drug delivery. J Am Chem Soc 2012, 134:8848–8855.
101. Han HD, Choi MS, Hwang T, Song CK, Seong H, Kim TW, Choi HS, Shin BC. Hyperthermia-induced antitumor activity of thermosensitive polymer modified temperature-sensitive liposomes. J Pharm Sci 2006, 95:1909–1917.
102. Gormley AJ, Larson N, Sadekar S, Robinson R, Ray A, Ghandehari H. Guided delivery of polymer therapeutics using plasmonic photothermal therapy. Nano Today 2012, 7:158–167.
103. Rapoport N. Physical stimuli-responsive polymeric micelles for anti-cancer drug delivery. Prog Polym Sci 2007, 32:962–990.
104. Duguet E, Vasseur S, Mornet S, Devoisselle JM. Magnetic nanoparticles and their applications in medicine. Nanomedicine 2006, 1:157–168.
105. Yoo J-W, Mitragotri S. Polymer particles that switch shape in response to a stimulus. Proc Natl Acad Sci USA 2010, 107:11205–11210.
106. Park K. Facing the Truth about Nanotechnology in Drug Delivery. ACS Nano 2013, 7:7442–7447.
107. Ruenraroengsak P, Cook JM, Florence AT. Nanosystem drug targeting: facing up to complex realities. J Control Release 2010, 141:265–276.
108. Kedem O, Katchalsky A. Thermodynamic analysis of the permeability of biological membranes to non-electrolytes. Biochim Biophys Acta 1958, 27:229–246.
109. Michel CC. Starling: the formulation of his hypothesis of microvascular fluid exchange and its significance after 100 years. Exp Physiol 1997, 82:1–30.
110. Yuan F, Dellian M, Fukumura D, Leunig M, Berk DA, Torchilin VP, Jain RK. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res 1995, 55:3752–3756.
111. Hobbs SK. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci USA 1998, 95:4607–4612.
112. Fick A. Ueber diffusion. Ann Phys 1855, 170:59–86.
113. Truskey GA, Yuan F, Katz DF. Transport Phenomena in Biological Systems. 2nd ed. Pearson Prentice Hall: Upper Saddle River, NJ; 2009.
114. Whitaker S. Flow in porous media I: a theoretical derivation of Darcy's law. Transp Porous Media 1986, 1:3–25.
115. Baish JW, Stylianopoulos T, Lanning RM, Kamoun WS, Fukumura D, Munn LL, Jain RK. Scaling rules for diffusive drug delivery in tumor and normal tissues. Proc Natl Acad Sci 2011, 108:1799–1803.
116. Zhao JB, Salmon H, Sarntinoranont M. Effect of heterogeneous vasculature on interstitial transport within a solid tumor. Microvasc Res 2007, 73:224–236.
117. Zhang AL, Mi XP, Yang G, Xu LX. Numerical study of thermally targeted liposomal drug delivery in tumor. J Heat Transfer 2009, 131:43209–43210. doi:10.1115/1.3072952.
118. Chauhan VP, Stylianopoulos T, Martin JD, Popovic Z, Chen O, Kamoun WS, Bawendi MG, Fukumura D, Jain RK. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol 2012, 7:383–388.
119. Thurber GM, Schmidt MM, Wittrup KD. Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance. Adv Drug Deliv Rev 2008, 60:1421–1434.
120. Schmidt MM, Wittrup KD. A modeling analysis of the effects of molecular size and binding affinity on tumor targeting. Mol Cancer Ther 2009, 8:2861–2871.
121. Le VM, Lang MD, Shi WB, Liu JW. A collagen-based multicellular tumor spheroid model for evaluation of the efficiency of nanoparticle drug delivery. Artif Cells Nanomed Biotechnol 2016, 44:540–544.
122. Huh D, Hamilton GA, Ingber DE. From 3D cell culture to organs-on-chips. Trends Cell Biol 2011, 21:745–754.
123. Elliott NT, Yuan F. A microfluidic system for investigation of extravascular transport and cellular uptake of drugs in tumors. Biotechnol Bioeng 2012, 109:1326–1335.
124. Goodman TT, Ng CP, Pun SH. 3-D tissue culture systems for the evaluation and optimization of nanoparticle-based drug carriers. Bioconjug Chem 2008, 19:1951–1959.
125. Polacheck WJ, Charest JL, Kamm RD. Interstitial flow influences direction of tumor cell migration through competing mechanisms. Proc Natl Acad Sci USA 2011, 108:11115–11120.
126. Kwak B, Ozcelikkale A, Shin CS, Park K, Han B. Simulation of Complex Transport of Nanoparticles around a Tumor Using Tumor-microenvironment-on-chip. Journal of Controlled Release 2014, 194:157–167.
127. Shin CS, Kwak B, Han B, Park K. Development of an in vitro 3D tumor model to study therapeutic efficiency of an anticancer drug. Mol Pharm 2013, 10:2167–2175.
128. Wang Y, Tang XL, Feng XJ, Liu C, Chen P, Chen DJ, Liu BF. A microfluidic digital single-cell assay for the evaluation of anticancer drugs. Anal Bioanal Chem 2015, 407:1139–1148.
129. Du GS, Pan JZ, Zhao SP, Zhu Y, den Toonder JMJ, Fang Q. Cell-based drug combination screening with a microfluidic droplet array system. Anal Chem 2013, 85:6740–6747.
130. An D, Kim K, Kim J. Microfluidic system based high throughput drug screening system for curcumin/TRAIL combinational chemotherapy in human prostate cancer PC3 cells. Biomol Ther 2014, 22:355–362.
131. Wang ZH, Liu ZX, Li LL, Liang QL. Investigation into the hypoxia-dependent cytotoxicity of anticancer drugs under oxygen gradient in a microfluidic device. Microfluid Nanofluidics 2015, 19:1271–1279.
132. Li YW, Chen DJ, Zhang YF, Liu C, Chen P, Wang Y, Feng XJ, Du W, Liu BF. High-throughput single cell multidrug resistance analysis with multifunctional gradients-customizing microfluidic device. Sens Actuators B Chem 2016, 225:563–571.
133. Das T, Meunier L, Barbe L, Provencher D, Guenat O, Gervais T, Mes-Masson AM. Empirical chemosensitivity testing in a spheroid model of ovarian cancer using a microfluidics-based multiplex platform. Biomicrofluidics 2013, 7:011805.
134. Ruppen J, Cortes-Dericks L, Marconi E, Karoubi G, Schmid RA, Peng RW, Marti TM, Guenat OT. A microfluidic platform for chemoresistive testing of multicellular pleural cancer spheroids. Lab Chip 2014, 14:1198–1205.
135. Chen YL, Gao D, Liu HX, Lin S, Jiang YY. Drug cytotoxicity and signaling pathway analysis with three-dimensional tumor spheroids in a microwell-based microfluidic chip for drug screening. Anal Chim Acta 2015, 898:85–92.
136. Liu WM, Xu J, Li TB, Zhao L, Ma C, Shen SF, Wang JY. Monitoring tumor response to anticancer drugs using stable three-dimensional culture in a recyclable microfluidic platform. Anal Chem 2015, 87:9752–9760.
137. Ruppen J, Wildhaber FD, Strub C, Hall SRR, Schmid RA, Geiser T, Guenat OT. Towards personalized medicine: chemosensitivity assays of patient lung cancer cell spheroids in a perfused microfluidic platform. Lab Chip 2015, 15:3076–3085.
138. Fan YT, Nguyen DT, Akay Y, Xu F, Akay M. Engineering a brain cancer chip for high-throughput drug screening. Sci Rep 2016, 6:25062.
139. Patra B, Peng CC, Liao WH, Lee CH, Tung YC. Drug testing and flow cytometry analysis on a large number of uniform sized tumor spheroids using a microfluidic device. Sci Rep 2016, 6:21061.
140. Cunha-Matos CA, Millington OR, Wark AW, Zagnoni M. Real-time assessment of nanoparticle-mediated antigen delivery and cell response. Lab Chip 2016, 16:3374–3381.
141. Bhatia SN, Ingber DE. Microfluidic organs-on-chips. Nat Biotechnol 2014, 32:760–772.
142. Shin K, Klosterhoff BS, Han B. Characterization of Cell-Type-Specific Drug Transport and Resistance of Breast Cancers Using Tumor-Microenvironment-on-Chip. Molecular Pharmaceutics 2016, 13:2214–2223.
143. Bruce A, Evans R, Mezan R, Shi L, Moses BS, Martin KH, Gibson LF, Yang Y. Three-dimensional microfluidic tri-culture model of the bone marrow microenvironment for study of acute lymphoblastic leukemia. PLoS One 2015, 10:e0140506.
144. Huang CP, Lu J, Seon H, Lee AP, Flanagan LA, Kim HY, Putnam AJ, Jeon NL. Engineering microscale cellular niches for three-dimensional multicellular co-cultures. Lab Chip 2009, 9:1740–1748.
145. Clay NE, Shin K, Ozcelikkale A, Lee MK, Rich MH, Kim DH, Han B, Kong H. Modulation of matrix softness and interstitial flow for 3D cell culture using a cell-microenvironment-on-a-chip system. ACS Biomater Sci Eng 2016, 2:1968–1975.
146. Bersini S, Jeon JS, Dubini G, Arrigoni C, Chung S, Charest JL, Moretti M, Kamm RD. A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone. Biomaterials 2014, 35:2454–2461.
147. Zervantonakis IK, Hughes-Alford SK, Charest JL, Condeelis JS, Gertler FB, Kamm RD. Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function. Proc Natl Acad Sci USA 2012, 109:13515–13520.
148. Soroush F, Zhang T, King DJ, Tang Y, Deosarkar S, Prabhakarpandian B, Kilpatrick LE, Kiani MF. A novel microfluidic assay reveals a key role for protein kinase C delta in regulating human neutrophil-endothelium interaction. J Leukoc Biol 2016 (http://www.jleukbio.org/content/early/2016/05/11/jlb.3MA0216-087R.full.pdf+html).
149. Bagley AF, Scherz-Shouval R, Galie PA, Zhang AQ, Wyckoff J, Whitesell L, Chen CS, Lindquist S, Bhatia SN. Endothelial thermotolerance impairs nanoparticle transport in tumors. Cancer Res 2015, 75:3255–3267.
150. Bai J, Tu TY, Kim C, Thiery JP, Kamm RD. Identification of drugs as single agents or in combination to prevent carcinoma dissemination in a microfluidic 3D environment. Oncotarget 2015, 6:36603–36614.
151. Hasan A, Paul A, Memic A, Khademhosseini A. A multilayered microfluidic blood vessel-like structure. Biomed Microdevices 2015, 17:88.
152. Prabhakarpandian B, Shen MC, Nichols JB, Garson CJ, Mills IR, Matar MM, Fewell JG, Pant K. Synthetic tumor networks for screening drug delivery systems. J Control Release 2015, 201:49–55.
153. Jin D, Ma XC, Luo Y, Fang SM, Xie ZR, Li XJ, Qi DY, Zhang FY, Kong J, Li J, et al. Application of a microfluidic-based perivascular tumor model for testing drug sensitivity in head and neck cancers and toxicity in endothelium. RSC Adv 2016, 6:29598–29607.
154. Bischel LL, Beebe DJ, Sung KE. Microfluidic model of ductal carcinoma in situ with 3D, organotypic structure. BMC Cancer 2015, 15:12. doi:10.1186/s12885-015-1007-5.
155. Toley BJ, Lovatt ZGT, Harrington JL, Forbes NS. Microfluidic technique to measure intratumoral transport and calculate drug efficacy shows that binding is essential for doxorubicin and release hampers Doxil. Integr Biol 2013, 5:1184–1196.
156. Kolhar P, Anselmo AC, Gupta V, Pant K, Prabhakarpandian B, Ruoslahti E, Mitragotri S. Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium. Proc Natl Acad Sci USA 2013, 110:10753–10758.
157. Kim S, Lee H, Chung M, Jeon NL. Engineering of functional, perfusable 3D microvascular networks on a chip. Lab Chip 2013, 13:1489–1500.
158. Zheng Y, Chen J, Craven M, Choi NW, Totorica S, Diaz-Santana A, Kermani P, Hempstead B, Fischbach-Teschl C, López JA, et al. In vitro microvessels for the study of angiogenesis and thrombosis. Proc Natl Acad Sci 2012, 109:9342–93427.
159. Rios-Mondragon I, Wang X, Gerdes HH. Spatio-temporal analysis of tamoxifen-induced bystander effects in breast cancer cells using microfluidics. Biomicrofluidics 2012, 6:024128. doi:10.1063/1.4726349.
160. Chang CW, Cheng YJ, Tu M, Chen YH, Peng CC, Liao WH, Tung YC. A polydimethylsiloxane-polycarbonate hybrid microfluidic device capable of generating perpendicular chemical and oxygen gradients for cell culture studies. Lab Chip 2014, 14:3762–3772.
161. Kuo CT, Chiang CL, Chang CH, Liu HK, Huang GS, Huang RYJ, Lee H, Huang CS, Wo AM. Modeling of cancer metastasis and drug resistance via biomimetic nano-cilia and microfluidics. Biomaterials 2014, 35:1562–1571.
162. Uzel SGM, Amadi OC, Pearl TM, Lee RT, So PTC, Kamm RD. Simultaneous or Sequential orthogonal gradient formation in a 3D cell culture microfluidic platform. Small 2016, 12:612–622.
163. Grist SM, Schmok JC, Liu MC, Chrostowski L, Cheung KC. Designing a microfluidic device with integrated ratiometric oxygen sensors for the long-term control and monitoring of chronic and cyclic hypoxia. Sensors 2015, 15:20030–20052.
164. Wu Q, Ren WQ, Yu ZL, Dong EB, Zhang SW, Xu RX. Microfabrication of polydimethylsiloxane phantoms to simulate tumor hypoxia and vascular anomaly. J Biomed Opt 2015, 20:121308.
165. Hsu YH, Moya ML, Abiri P, Hughes CCW, George SC, Lee AP. Full range physiological mass transport control in 3D tissue cultures. Lab Chip 2013, 13:81–89.
166. Cao JT, Zhu YD, Rana RK, Zhu JJ. Microfluidic chip integrated with flexible PDMS-based electrochemical cytosensor for dynamic analysis of drug-induced apoptosis on HeLa cells. Biosens Bioelectron 2014, 51:97–102.
167. Lei KF, Wu MH, Hsu CW, Chen YD. Real-time and non-invasive impedimetric monitoring of cell proliferation and chemosensitivity in a perfusion 3D cell culture microfluidic chip. Biosens Bioelectron 2014, 51:16–21.
168. Weltin A, Slotwinski K, Kieninger J, Moser I, Jobst G, Wego M, Ehret R, Urban GA. Cell culture monitoring for drug screening and cancer research: a transparent, microfluidic, multi-sensor microsystem. Lab Chip 2014, 14:138–146.
169. Zervantonakis IK, Arvanitis CD. Controlled drug release and chemotherapy response in a novel acoustofluidic 3D tumor platform. Small 2016, 12:2616–2626.
170. Moraes C, Labuz JM, Leung BM, Inoue M, Chun T-H, Takayama S. On being the right size: scaling effects in designing a human-on-a-chip. Integr Biol 2013, 5:1149–1161.
171. Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 2010, 18:884–901.
172. Wiig H, Aukland K, Tenstad O. Isolation of interstitial fluid from rat mammary tumors by a centrifugation method. Am J Physiol Heart Circ Physiol 2003, 284:H416–H424.
173. Gress TM, Müller-Pillasch F, Lerch MM, Friess H, Büchler M, Adler G. Expression and in situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer. Int J Cancer 1995, 62:407–413.
174. Yoshida E, Kudo D, Nagase H, Shimoda H, Suto S, Negishi M, Kakizaki I, Endo M, Hakamada K. Antitumor effects of the hyaluronan inhibitor, 4-methylumbelliferone, on pancreatic cancer. Oncol Lett 2016, 12:2337–2344.
175. Theocharis AD, Tsara ME, Papageorgacopoulou N, Karavias DD, Theocharis DA. Pancreatic carcinoma is characterized by elevated content of hyaluronan and chondroitin sulfate with altered disaccharide composition. Biochim Biophys Acta 2000, 1502:201–206.
176. Wiig H, Swartz MA. Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiol Rev 2012, 92:1005–1060.