Nanomedicine is an interdisciplinary field of research at the interface of science, engineering, and medicine, with broad clinical applications ranging from molecular imaging to medical diagnostics, targeted therapy, and image-guided surgery. Despite major advances during the past 20 years, there are still major fundamental and technical barriers that need to be understood and overcome. In particular, the complex behaviors of nanoparticles under physiological conditions are poorly understood, and detailed kinetic and thermodynamic principles are still not available to guide the rational design and development of nanoparticle agents. Here we discuss the interactions of nanoparticles with proteins, cells, tissues, and organs from a quantitative physical chemistry point of view. We also discuss insights and strategies on how to minimize nonspecific protein binding, how to design multistage and activatable nanostructures for improved drug delivery, and how to use the enhanced permeability and retention effect to deliver imaging agents for image-guided cancer surgery.


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Literature Cited

  1. West JL, Halas NJ. 1.  2003. Engineered nanomaterials for biophotonics applications: improving sensing, imaging, and therapeutics. Annu. Rev. Biomed. Eng. 5:285–92 [Google Scholar]
  2. Valiev R. 2.  2002. Materials science: nanomaterial advantage. Nature 419:887–89 [Google Scholar]
  3. Whitesides GM. 3.  2005. Nanoscience, nanotechnology, and chemistry. Small 1:172–79 [Google Scholar]
  4. Wagner V, Dullaart A, Bock A-K, Zweck A. 4.  2006. The emerging nanomedicine landscape. Nat. Biotechnol. 24:1211–18 [Google Scholar]
  5. Liu Z, Cai W, He L, Nakayama N, Chen K. 5.  et al. 2007. In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nat. Nanotechnol. 2:47–52 [Google Scholar]
  6. Weissleder R, Kelly K, Sun EY, Shtatland T, Josephson L. 6.  2005. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules. Nat. Biotechnol. 23:1418–23 [Google Scholar]
  7. Lee ES, Na K, Bae YH. 7.  2003. Polymeric micelle for tumor pH and folate-mediated targeting. J. Control. Release 91:103–13 [Google Scholar]
  8. Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA. 8.  et al. 2002. Tumor regression by targeted gene delivery to the neovasculature. Science 296:2404–7 [Google Scholar]
  9. Duncan R. 9.  2006. Polymer conjugates as anticancer nanomedicines. Nat. Rev. Cancer 6:688–701 [Google Scholar]
  10. Couvreur P, Vauthier C. 10.  2006. Nanotechnology: intelligent design to treat complex disease. Pharm. Res. 23:1417–50 [Google Scholar]
  11. Moghimi SM, Hunter AC, Murray JC. 11.  2001. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol. Rev. 53:283–318 [Google Scholar]
  12. Torchilin VP. 12.  2007. Micellar nanocarriers: pharmaceutical perspectives. Pharm. Res. 24:1–16 [Google Scholar]
  13. Babes L, Denizot B, Tanguy G, Le Jeune JJ, Jallet P. 13.  1999. Synthesis of iron oxide nanoparticles used as MRI contrast agents: a parametric study. J. Colloid Interface Sci. 212:474–82 [Google Scholar]
  14. Laurent S, Forge D, Port M, Roch A, Robic C. 14.  et al. 2008. Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem. Rev. 108:2064–110 [Google Scholar]
  15. Rhyner MN, Smith AM, Gao XH, Mao H, Yang L, Nie SM. 15.  2006. Quantum dots and multifunctional nanoparticles: new contrast agents for tumor imaging. Nanomedicine 1:209–17 [Google Scholar]
  16. Xing Y, Chaudry Q, Shen C, Kong KY, Zhau HE. 16.  et al. 2007. Bioconjugated quantum dots for multiplexed and quantitative immunohistochemistry. Nat. Protoc. 2:1152–65 [Google Scholar]
  17. Wu X, Liu H, Liu J, Haley KN, Treadway JA. 17.  et al. 2003. Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots. Nat. Biotechnol. 21:41–46 [Google Scholar]
  18. Kim S, Lim YT, Soltesz EG, De Grand AM, Lee J. 18.  et al. 2004. Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat. Biotechnol. 22:93–97 [Google Scholar]
  19. Yezhelyev MV, Al-Hajj A, Morris C, Marcus AI, Liu T. 19.  et al. 2007. In situ molecular profiling of breast cancer biomarkers with multicolor quantum dots. Adv. Mater. 19:3146–51 [Google Scholar]
  20. Liu J, Lau S, Varma V, Moffitt R, Caldwell M. 20.  et al. 2010. Molecular mapping of tumor heterogeneity on clinical tissue specimens with multiplexed quantum dots. ACS Nano 4:2755–65 [Google Scholar]
  21. Gao X, Cui Y, Levenson RM, Chung LW, Nie S. 21.  2004. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat. Biotechnol. 22:969–76 [Google Scholar]
  22. Cedervall T, Lynch I, Lindman S, Berggård T, Thulin E. 22.  et al. 2007. Understanding the nanoparticle–protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc. Natl. Acad. Sci. USA 104:2050–55 [Google Scholar]
  23. Lynch I, Dawson KA, Linse S. 23.  2006. Detecting cryptic epitopes created by nanoparticles. Sci. Signal. 2006:pe14 [Google Scholar]
  24. Gref R, Lück M, Quellec P, Marchand M, Dellacherie E. 24.  et al. 2000. ‘Stealth’ corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids Surf. B 18:301–13 [Google Scholar]
  25. Cedervall T, Lynch I, Foy M, Berggård T, Donnelly SC. 25.  et al. 2007. Detailed identification of plasma proteins adsorbed on copolymer nanoparticles. Angew. Chem. Int. Ed. Engl. 46:5754–56 [Google Scholar]
  26. Lundqvist M, Stigler J, Elia G, Lynch I, Cedervall T, Dawson KA. 26.  2008. Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc. Natl. Acad. Sci. USA 105:14265–70 [Google Scholar]
  27. Vogel HG. 27.  2002. Drug Discovery and Evaluation: Pharmacological Assays Berlin: Springer-Verlag
  28. Atkins PW, De Paula J. 28.  2006. Atkins' Physical Chemistry New York: Oxford Univ. Press
  29. Astumian R, Schelly Z. 29.  1984. Geometric effects of reduction of dimensionality in interfacial reactions. J. Am. Chem. Soc. 106:304–8 [Google Scholar]
  30. Casals E, Pfaller T, Duschl A, Oostingh GJ, Puntes V. 30.  2010. Time evolution of the nanoparticle protein corona. ACS Nano 4:3623–32 [Google Scholar]
  31. Röcker C, Pötzl M, Zhang F, Parak WJ, Nienhaus GU. 31.  2009. A quantitative fluorescence study of protein monolayer formation on colloidal nanoparticles. Nat. Nanotechnol. 4:577–80 [Google Scholar]
  32. van Oss CJ. 32.  2003. Long range and short range mechanisms of hydrophobic attraction and hydrophilic repulsion in specific and aspecific interactions. J. Mol. Recognit. 16:177–90 [Google Scholar]
  33. De Young LR, Fink AL, Dill KA. 33.  1993. Aggregation of globular proteins. Acc. Chem. Res. 26:614–20 [Google Scholar]
  34. Walczyk D, Bombelli FB, Monopoli MP, Lynch I, Dawson KA. 34.  2010. What the cell “sees” in bionanoscience. J. Am. Chem. Soc. 132:5761–68 [Google Scholar]
  35. Schowalter WR, Eidsath AB. 35.  2001. Brownian flocculation of polymer colloids in the presence of a secondary minimum. Proc. Natl. Acad. Sci. USA 98:3644–51 [Google Scholar]
  36. Gessner A, Lieske A, Paulke BR, Müller RH. 36.  2002. Influence of surface charge density on protein adsorption on polymeric nanoparticles: analysis by two-dimensional electrophoresis. Eur. J. Pharm. Biopharm. 54:165–70 [Google Scholar]
  37. Vonarbourg A, Passirani C, Saulnier P, Benoit J-P. 37.  2006. Parameters influencing the stealthiness of colloidal drug delivery systems. Biomaterials 27:4356–73 [Google Scholar]
  38. Lück M, Paulke BR, Schröder W, Blunk T, Müller R. 38.  1998. Analysis of plasma protein adsorption on polymeric nanoparticles with different surface characteristics. J. Biomed. Mater. Res. 39:478–85 [Google Scholar]
  39. Jeon S, Lee J, Andrade J, de Gennes P. 39.  1991. Protein–surface interactions in the presence of polyethylene oxide: I. Simplified theory. J. Colloid Interface Sci. 142:149–58 [Google Scholar]
  40. Lebovka NI. 40.  2014. Aggregation of charged colloidal particles. Polyelectrolyte Complexes in the Dispersed and Solid State I M Müller 57–96 New York: Springer [Google Scholar]
  41. Manciu M, Ruckenstein E. 41.  2001. Role of the hydration force in the stability of colloids at high ionic strengths. Langmuir 17:7061–70 [Google Scholar]
  42. Smith AM, Duan H, Mohs AM, Nie S. 42.  2008. Bioconjugated quantum dots for in vivo molecular and cellular imaging. Adv. Drug Deliv. Rev. 60:1226–40 [Google Scholar]
  43. Ehrenberg MS, Friedman AE, Finkelstein JN, Oberdörster G, McGrath JL. 43.  2009. The influence of protein adsorption on nanoparticle association with cultured endothelial cells. Biomaterials 30:603–10 [Google Scholar]
  44. Dill KA, Truskett TM, Vlachy V, Hribar-Lee B. 44.  2005. Modeling water, the hydrophobic effect, and ion solvation. Annu. Rev. Biophys. Biomol. Struct. 34:173–99 [Google Scholar]
  45. Brewer SH, Glomm WR, Johnson MC, Knag MK, Franzen S. 45.  2005. Probing BSA binding to citrate-coated gold nanoparticles and surfaces. Langmuir 21:9303–7 [Google Scholar]
  46. Kumar S, Nussinov R. 46.  1999. Salt bridge stability in monomeric proteins. J. Mol. Biol. 293:1241–55 [Google Scholar]
  47. Walkey CD, Olsen JB, Song F, Liu R, Guo H. 47.  et al. 2014. Protein corona fingerprinting predicts the cellular interaction of gold and silver nanoparticles. ACS Nano 8:2439–55 [Google Scholar]
  48. Kairdolf BA, Mancini MC, Smith AM, Nie S. 48.  2008. Minimizing nonspecific cellular binding of quantum dots with hydroxyl-derivatized surface coatings. Anal. Chem. 80:3029–34 [Google Scholar]
  49. Bretscher MS. 49.  1975. Mammalian plasma membranes. Nature 258:43–49 [Google Scholar]
  50. Andrade J, Hlady V. 50.  1986. Protein adsorption and materials biocompatibility: a tutorial review and suggested hypotheses. Adv. Polym. Sci. 79:1–63 [Google Scholar]
  51. Laughlin RG. 51.  1991. Fundamentals of the zwitterionic hydrophilic group. Langmuir 7:842–47 [Google Scholar]
  52. He Y, Hower J, Chen S, Bernards MT, Chang Y, Jiang S. 52.  2008. Molecular simulation studies of protein interactions with zwitterionic phosphorylcholine self-assembled monolayers in the presence of water. Langmuir 24:10358–64 [Google Scholar]
  53. Jiang S, Cao Z. 53.  2010. Ultralow fouling, functionalizable, and hydrolyzable zwitterionic materials and their derivatives for biological applications. Adv. Mater. 22:920–32 [Google Scholar]
  54. Cao Z, Jiang S. 54.  2012. Super-hydrophilic zwitterionic poly(carboxybetaine) and amphiphilic non-ionic poly(ethylene glycol) for stealth nanoparticles. Nano Today 7:404–13 [Google Scholar]
  55. Estephan ZG, Schlenoff PS, Schlenoff JB. 55.  2011. Zwitteration as an alternative to PEGylation. Langmuir 27:6794–800 [Google Scholar]
  56. Hidalgo-Álvarez R, Martín A, Fernández A, Bastos D, Martínez F, de las Nieves F. 56.  1996. Electrokinetic properties, colloidal stability and aggregation kinetics of polymer colloids. Adv. Colloid Interface Sci. 67:1–118 [Google Scholar]
  57. Leckband D. 57.  2000. Measuring the forces that control protein interactions. Annu. Rev. Biophys. Biomol. Struct. 29:1–26 [Google Scholar]
  58. Gombotz WR, Guanghui W, Horbett TA, Hoffman AS. 58.  1991. Protein adsorption to poly(ethylene oxide) surfaces. J. Biomed. Mater. Res. 25:1547–62 [Google Scholar]
  59. Abuchowski A, McCoy JR, Palczuk NC, van Es T, Davis FF. 59.  1977. Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J. Biol. Chem. 252:3582–86 [Google Scholar]
  60. Allen T, Hansen C. 60.  1991. Pharmacokinetics of stealth versus conventional liposomes: effect of dose. Biochim. Biophys. Acta Biomembr. 1068:133–41 [Google Scholar]
  61. Moghimi S, Szebeni J. 61.  2003. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog. Lipid Res. 42:463–78 [Google Scholar]
  62. Cheng J, Teply BA, Sherifi I, Sung J, Luther G. 62.  et al. 2007. Formulation of functionalized PLGA–PEG nanoparticles for in vivo targeted drug delivery. Biomaterials 28:869–76 [Google Scholar]
  63. Kataoka K, Harada A, Nagasaki Y. 63.  2001. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv. Drug Deliv. Rev. 47:113–31 [Google Scholar]
  64. Gao X, Cui Y, Levenson RM, Chung LW, Nie S. 64.  2004. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat. Biotechnol. 22:969–76 [Google Scholar]
  65. Niidome T, Yamagata M, Okamoto Y, Akiyama Y, Takahashi H. 65.  et al. 2006. PEG-modified gold nanorods with a stealth character for in vivo applications. J. Control. Release 114:343–47 [Google Scholar]
  66. Lee H, Lee E, Kim DK, Jang NK, Jeong YY, Jon S. 66.  2006. Antibiofouling polymer-coated superparamagnetic iron oxide nanoparticles as potential magnetic resonance contrast agents for in vivo cancer imaging. J. Am. Chem. Soc. 128:7383–89 [Google Scholar]
  67. Ikada Y. 67.  1984. Blood-compatible polymers. Adv. Polym. Sci. 57:103–40 [Google Scholar]
  68. Viegas TX, Bentley MD, Harris JM, Fang Z, Yoon K. 68.  et al. 2011. Polyoxazoline: chemistry, properties, and applications in drug delivery. Bioconjug. Chem. 22:976–86 [Google Scholar]
  69. Kopeček J, Kopečková P. 69.  2010. HPMA copolymers: origins, early developments, present, and future. Adv. Drug Deliv. Rev. 62:122–49 [Google Scholar]
  70. Kim K, Kim JH, Park H, Kim Y-S, Park K. 70.  et al. 2010. Tumor-homing multifunctional nanoparticles for cancer theragnosis: simultaneous diagnosis, drug delivery, and therapeutic monitoring. J. Control. Release 146:219–27 [Google Scholar]
  71. Mehvar R. 71.  2000. Dextrans for targeted and sustained delivery of therapeutic and imaging agents. J. Control. Release 69:1–25 [Google Scholar]
  72. Choi KY, Chung H, Min KH, Yoon HY, Kim K. 72.  et al. 2010. Self-assembled hyaluronic acid nanoparticles for active tumor targeting. Biomaterials 31:106–14 [Google Scholar]
  73. Ishida T, Atobe K, Wang X, Kiwada H. 73.  2006. Accelerated blood clearance of PEGylated liposomes upon repeated injections: effect of doxorubicin-encapsulation and high-dose first injection. J. Control. Release 115:251–58 [Google Scholar]
  74. Leger R, Arndt P, Garratty G, Armstrong J, Meiselman H, Fisher T. 74.  2001. Normal donor sera can contain antibodies to polyethylene glycol (PEG). Transfusion 41:29S–30 [Google Scholar]
  75. Romberg B, Oussoren C, Snel CJ, Carstens MG, Hennink WE, Storm G. 75.  2007. Pharmacokinetics of poly(hydroxyethyl-l-asparagine)-coated liposomes is superior over that of PEG-coated liposomes at low lipid dose and upon repeated administration. Biochim. Biophys. Acta Biomembr. 1768:737–43 [Google Scholar]
  76. Chen KL, Bothun GD. 76.  2013. Nanoparticles meet cell membranes: probing nonspecific interactions using model membranes. Environ. Sci. Technol. 48:873–80 [Google Scholar]
  77. Cho EC, Xie J, Wurm PA, Xia Y. 77.  2009. Understanding the role of surface charges in cellular adsorption versus internalization by selectively removing gold nanoparticles on the cell surface with a I2/KI etchant. Nano Lett. 9:1080–84 [Google Scholar]
  78. Chen H, Langer R, Edwards DA. 78.  1997. A film tension theory of phagocytosis. J. Colloid Interface Sci. 190:118–33 [Google Scholar]
  79. Zhang M, Desai T, Ferrari M. 79.  1998. Proteins and cells on PEG immobilized silicon surfaces. Biomaterials 19:953–60 [Google Scholar]
  80. Lesniak A, Salvati A, Santos-Martinez MJ, Radomski MW, Dawson KA, Åberg C. 80.  2013. Nanoparticle adhesion to the cell membrane and its effect on nanoparticle uptake efficiency. J. Am. Chem. Soc. 135:1438–44 [Google Scholar]
  81. Ho K, Lapitsky Y, Shi M, Shoichet MS. 81.  2009. Tunable immunonanoparticle binding to cancer cells: thermodynamic analysis of targeted drug delivery vehicles. Soft Matter 5:1074–80 [Google Scholar]
  82. Mammen M, Choi S-K, Whitesides GM. 82.  1998. Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew. Chem. Int. Ed. Engl. 37:2754–94 [Google Scholar]
  83. Hong S, Leroueil PR, Majoros IJ, Orr BG, Baker JR Jr, Banaszak Holl MM. 83.  2007. The binding avidity of a nanoparticle-based multivalent targeted drug delivery platform. Chem. Biol. 14:107–15 [Google Scholar]
  84. Lu B, Smyth MR, O'Kennedy R. 84.  1996. Tutorial review: oriented immobilization of antibodies and its applications in immunoassays and immunosensors. Analyst 121:29R–32 [Google Scholar]
  85. Gantert M, Lewrick F, Adrian JE, Rössler J, Steenpaß T. 85.  et al. 2009. Receptor-specific targeting with liposomes in vitro based on sterol-PEG1300 anchors. Pharm. Res. 26:529–38 [Google Scholar]
  86. Salvati A, Pitek AS, Monopoli MP, Prapainop K, Bombelli FB. 86.  et al. 2013. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat. Nanotechnol. 8:137–43 [Google Scholar]
  87. Gu F, Zhang L, Teply BA, Mann N, Wang A. 87.  et al. 2008. Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers. Proc. Natl. Acad. Sci. USA 105:2586–91 [Google Scholar]
  88. Decuzzi P, Ferrari M. 88.  2007. The role of specific and non-specific interactions in receptor-mediated endocytosis of nanoparticles. Biomaterials 28:2915–22 [Google Scholar]
  89. Gao H, Shi W, Freund LB. 89.  2005. Mechanics of receptor-mediated endocytosis. Proc. Natl. Acad. Sci. USA 102:9469–74 [Google Scholar]
  90. Conway A, Vazin T, Spelke DP, Rode NA, Healy KE. 90.  et al. 2013. Multivalent ligands control stem cell behaviour in vitro and in vivo. Nat. Nanotechnol. 8:831–38 [Google Scholar]
  91. Chithrani BD, Ghazani AA, Chan WC. 91.  2006. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett. 6:662–68 [Google Scholar]
  92. Cho EC, Zhang Q, Xia Y. 92.  2011. The effect of sedimentation and diffusion on cellular uptake of gold nanoparticles. Nat. Nanotechnol. 6:385–91 [Google Scholar]
  93. Ruenraroengsak P, Novak P, Berhanu D, Thorley AJ, Valsami-Jones E. 93.  et al. 2012. Respiratory epithelial cytotoxicity and membrane damage (holes) caused by amine-modified nanoparticles. Nanotoxicology 6:94–108 [Google Scholar]
  94. Ginzburg VV, Balijepalli S. 94.  2007. Modeling the thermodynamics of the interaction of nanoparticles with cell membranes. Nano Lett. 7:3716–22 [Google Scholar]
  95. Herce HD, Garcia AE. 95.  2007. Molecular dynamics simulations suggest a mechanism for translocation of the HIV-1 TAT peptide across lipid membranes. Proc. Natl. Acad. Sci. USA 104:20805–10 [Google Scholar]
  96. Yesylevskyy S, Marrink S-J, Mark AE. 96.  2009. Alternative mechanisms for the interaction of the cell-penetrating peptides penetratin and the TAT peptide with lipid bilayers. Biophys. J. 97:40–49 [Google Scholar]
  97. Verma A, Uzun O, Hu Y, Hu Y, Han H-S. 97.  et al. 2008. Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles. Nat. Mater. 7:588–95 [Google Scholar]
  98. Van Lehn RC, Atukorale PU, Carney RP, Yang Y-S, Stellacci F. 98.  et al. 2013. Effect of particle diameter and surface composition on the spontaneous fusion of monolayer-protected gold nanoparticles with lipid bilayers. Nano Lett. 13:4060–67 [Google Scholar]
  99. Iversen T-G, Skotland T, Sandvig K. 99.  2011. Endocytosis and intracellular transport of nanoparticles: present knowledge and need for future studies. Nano Today 6:176–85 [Google Scholar]
  100. Chithrani BD, Chan WC. 100.  2007. Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes. Nano Lett. 7:1542–50 [Google Scholar]
  101. Jin H, Heller DA, Sharma R, Strano MS. 101.  2009. Size-dependent cellular uptake and expulsion of single-walled carbon nanotubes: single particle tracking and a generic uptake model for nanoparticles. ACS Nano 3:149–58 [Google Scholar]
  102. Iversen T-G, Frerker N, Sandvig K. 102.  2010. Endocytosis and intracellular trafficking of quantum dot–ligand bioconjugates. Organelle-Specific Pharmaceutical Nanotechnology V Weissig, GGM D'Souza 55–72 New York: Wiley [Google Scholar]
  103. Lai SK, Hida K, Man ST, Chen C, Machamer C. 103.  et al. 2007. Privileged delivery of polymer nanoparticles to the perinuclear region of live cells via a non-clathrin, non-degradative pathway. Biomaterials 28:2876–84 [Google Scholar]
  104. Hu Y, Litwin T, Nagaraja AR, Kwong B, Katz J. 104.  et al. 2007. Cytosolic delivery of membrane-impermeable molecules in dendritic cells using pH-responsive core-shell nanoparticles. Nano Lett. 7:3056–64 [Google Scholar]
  105. Nishiyama N, Morimoto Y, Jang W-D, Kataoka K. 105.  2009. Design and development of dendrimer photosensitizer-incorporated polymeric micelles for enhanced photodynamic therapy. Adv. Drug Deliv. Rev. 61:327–38 [Google Scholar]
  106. Decuzzi P, Ferrari M. 106.  2008. The receptor-mediated endocytosis of nonspherical particles. Biophys. J. 94:3790–97 [Google Scholar]
  107. Ferrari M. 107.  2008. Nanogeometry: beyond drug delivery. Nat. Nanotechnol. 3:131–32 [Google Scholar]
  108. Cho EC, Au L, Zhang Q, Xia Y. 108.  2010. The effects of size, shape, and surface functional group of gold nanostructures on their adsorption and internalization by cells. Small 6:517–22 [Google Scholar]
  109. Gratton SE, Ropp PA, Pohlhaus PD, Luft JC, Madden VJ. 109.  et al. 2008. The effect of particle design on cellular internalization pathways. Proc. Natl. Acad. Sci. USA 105:11613–18 [Google Scholar]
  110. Yang Q, Jones SW, Parker CL, Zamboni WC, Bear JE, Lai SK. 110.  2014. Evading immune cell uptake and clearance requires PEG grafting at densities substantially exceeding the minimum for brush conformation. Mol. Pharm. 11:1250–58 [Google Scholar]
  111. Garg A, Tisdale AW, Haidari E, Kokkoli E. 111.  2009. Targeting colon cancer cells using PEGylated liposomes modified with a fibronectin-mimetic peptide. Int. J. Pharm. 366:201–10 [Google Scholar]
  112. Demirgoż DN, Garg A, Kokkoli E. 112.  2008. PR_b-targeted PEGylated liposomes for prostate cancer therapy. Langmuir 24:13518–24 [Google Scholar]
  113. Sawant RR, Sawant RM, Kale AA, Torchilin VP. 113.  2008. The architecture of ligand attachment to nanocarriers controls their specific interaction with target cells. J. Drug Target. 16:596–600 [Google Scholar]
  114. Gabizon A, Horowitz AT, Goren D, Tzemach D, Shmeeda H, Zalipsky S. 114.  2003. In vivo fate of folate-targeted polyethylene-glycol liposomes in tumor-bearing mice. Clin. Cancer Res. 9:6551–59 [Google Scholar]
  115. Jain RK. 115.  1987. Transport of molecules across tumor vasculature. Cancer Metastasis Rev. 6:559–93 [Google Scholar]
  116. Bhave G, Neilson EG. 116.  2011. Body fluid dynamics: back to the future. J. Am. Soc. Nephrol. 22:2166–81 [Google Scholar]
  117. Monsky WL, Fukumura D, Gohongi T, Ancukiewcz M, Weich HA. 117.  et al. 1999. Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. Cancer Res. 59:4129–35 [Google Scholar]
  118. Boucher Y, Jain RK. 118.  1992. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res. 52:5110–14 [Google Scholar]
  119. Iyer AK, Khaled G, Fang J, Maeda H. 119.  2006. Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov. Today 11:812–18 [Google Scholar]
  120. Maeda H. 120.  2001. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv. Enzyme Regul. 41:189–207 [Google Scholar]
  121. Epenetos AA, Snook D, Durbin H, Johnson PM, Taylor-Papadimitriou J. 121.  1986. Limitations of radiolabeled monoclonal antibodies for localization of human neoplasms. Cancer Res. 46:3183–91 [Google Scholar]
  122. Khawli LA, Miller GK, Epstein AL. 122.  1994. Effect of seven new vasoactive immunoconjugates on the enhancement of monoclonal antibody uptake in tumors. Cancer 73:824–31 [Google Scholar]
  123. Sinha R, Kim GJ, Nie S, Shin DM. 123.  2006. Nanotechnology in cancer therapeutics: bioconjugated nanoparticles for drug delivery. Mol. Cancer Ther. 5:1909–17 [Google Scholar]
  124. Stohrer M, Boucher Y, Stangassinger M, Jain RK. 124.  2000. Oncotic pressure in solid tumors is elevated. Cancer Res. 60:4251–55 [Google Scholar]
  125. Baish JW, Stylianopoulos T, Lanning RM, Kamoun WS, Fukumura D. 125.  et al. 2011. Scaling rules for diffusive drug delivery in tumor and normal tissues. Proc. Natl. Acad. Sci. USA 108:1799–803 [Google Scholar]
  126. Nagamitsu A, Greish K, Maeda H. 126.  2009. Elevating blood pressure as a strategy to increase tumor-targeted delivery of macromolecular drug SMANCS: cases of advanced solid tumors. Jpn. J. Clin. Oncol. 39:756–66 [Google Scholar]
  127. Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK. 127.  2000. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 60:2497–503 [Google Scholar]
  128. Jain RK. 128.  2005. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62 [Google Scholar]
  129. Jain RK, Tong RT, Munn LL. 129.  2007. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res. 67:2729–35 [Google Scholar]
  130. McKee TD, Grandi P, Mok W, Alexandrakis G, Insin N. 130.  et al. 2006. Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. Cancer Res. 66:2509–13 [Google Scholar]
  131. Lammers T, Hennink W, Storm G. 131.  2008. Tumour-targeted nanomedicines: principles and practice. Br. J. Cancer 99:392–97 [Google Scholar]
  132. Byrne JD, Betancourt T, Brannon-Peppas L. 132.  2008. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv. Drug Deliv. Rev. 60:1615–26 [Google Scholar]
  133. Bartlett DW, Su H, Hildebrandt IJ, Weber WA, Davis ME. 133.  2007. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc. Natl. Acad. Sci. USA 104:15549–54 [Google Scholar]
  134. Huang X, Peng X, Wang Y, Wang Y, Shin DM. 134.  et al. 2010. A reexamination of active and passive tumor targeting by using rod-shaped gold nanocrystals and covalently conjugated peptide ligands. ACS Nano 4:5887–96 [Google Scholar]
  135. Choi CHJ, Alabi CA, Webster P, Davis ME. 135.  2010. Mechanism of active targeting in solid tumors with transferrin-containing gold nanoparticles. Proc. Natl. Acad. Sci. USA 107:1235–40 [Google Scholar]
  136. Davis ME. 136.  2009. The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic. Mol. Pharm. 6:659–68 [Google Scholar]
  137. Allen TM. 137.  2002. Ligand-targeted therapeutics in anticancer therapy. Nat. Rev. Cancer 2:750–63 [Google Scholar]
  138. Adams GP, Schier R, McCall AM, Simmons HH, Horak EM. 138.  et al. 2001. High affinity restricts the localization and tumor penetration of single-chain Fv antibody molecules. Cancer Res. 61:4750–55 [Google Scholar]
  139. Albanese A, Lam AK, Sykes EA, Rocheleau JV, Chan WC. 139.  2013. Tumour-on-a-chip provides an optical window into nanoparticle tissue transport. Nat. Commun. 4:2718 [Google Scholar]
  140. Davis ME. 140.  2008. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat. Rev. Drug Discov. 7:771–82 [Google Scholar]
  141. Schrama D, Reisfeld RA, Becker JC. 141.  2006. Antibody targeted drugs as cancer therapeutics. Nat. Rev. Drug Discov. 5:147–59 [Google Scholar]
  142. Weiner LM, Adams GP. 142.  2000. New approaches to antibody therapy. Oncogene 19:6144–51 [Google Scholar]
  143. Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. 143.  2007. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2:751–60 [Google Scholar]
  144. Romberg B, Hennink WE, Storm G. 144.  2008. Sheddable coatings for long-circulating nanoparticles. Pharm. Res. 25:55–71 [Google Scholar]
  145. Kale AA, Torchilin VP. 145.  2007. Enhanced transfection of tumor cells in vivo using “smart” pH-sensitive TAT-modified pegylated liposomes. J. Drug Targeting 15:538–45 [Google Scholar]
  146. Schmaljohann D. 146.  2006. Thermo- and pH-responsive polymers in drug delivery. Adv. Drug Deliv. Rev. 58:1655–70 [Google Scholar]
  147. Sershen S, Westcott S, Halas N, West J. 147.  2000. Temperature sensitive polymer–nanoshell composites for photothermally modulated drug delivery. J. Biomed. Mater. Res. 51:293–98 [Google Scholar]
  148. Yavuz MS, Cheng Y, Chen J, Cobley CM, Zhang Q. 148.  et al. 2009. Gold nanocages covered by smart polymers for controlled release with near-infrared light. Nat. Mater. 8:935–39 [Google Scholar]
  149. McBain SC, Yiu HH, Dobson J. 149.  2008. Magnetic nanoparticles for gene and drug delivery. Int. J. Nanomed. 3:169–80 [Google Scholar]
  150. Wilson MW, Kerlan RK Jr, Fidelman NA, Venook AP, LaBerge JM. 150.  et al. 2004. Hepatocellular carcinoma: regional therapy with a magnetic targeted carrier bound to doxorubicin in a dual MR imaging/conventional angiography suite: initial experience with four patients. Radiology 230:287–93 [Google Scholar]
  151. Hilger I, Hiergeist R, Hergt R, Winnefeld K, Schubert H, Kaiser WA. 151.  2002. Thermal ablation of tumors using magnetic nanoparticles: an in vivo feasibility study. Investig. Radiol. 37:580–86 [Google Scholar]
  152. Cheng R, Meng F, Deng C, Klok H-A, Zhong Z. 152.  2013. Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials 34:3647–57 [Google Scholar]
  153. Cheng Z, Al Zaki A, Hui JZ, Muzykantov VR, Tsourkas A. 153.  2012. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science 338:903–10 [Google Scholar]
  154. Zhou K, Liu H, Zhang S, Huang X, Wang Y. 154.  et al. 2012. Multicolored pH-tunable and activatable fluorescence nanoplatform responsive to physiologic pH stimuli. J. Am. Chem. Soc. 134:7803–11 [Google Scholar]
  155. Wang Y, Zhou K, Huang G, Hensley C, Huang X. 155.  et al. 2014. A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals. Nat. Mater. 13:204–12 [Google Scholar]
  156. Sheridan C. 156.  2012. Proof of concept for next-generation nanoparticle drugs in humans. Nat. Biotechnol. 30:471–73 [Google Scholar]
  157. Godin B, Tasciotti E, Liu X, Serda RE, Ferrari M. 157.  2011. Multistage nanovectors: from concept to novel imaging contrast agents and therapeutics. Acc. Chem. Res. 44:979–89 [Google Scholar]
  158. Wong C, Stylianopoulos T, Cui J, Martin J, Chauhan VP. 158.  et al. 2011. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl. Acad. Sci. USA 108:2426–31 [Google Scholar]
  159. Chou LYT, Zagorovsky K, Chan WCW. 159.  2014. DNA assembly of nanoparticle superstructures for controlled biological delivery and elimination. Nat. Nanotechnol. 9:148–55 [Google Scholar]
  160. Choi HS, Liu W, Liu F, Nasr K, Misra P. 160.  et al. 2009. Design considerations for tumour-targeted nanoparticles. Nat. Nanotechnol. 5:42–47 [Google Scholar]
  161. Choi HS, Frangioni JV. 161.  2010. Nanoparticles for biomedical imaging: fundamentals of clinical translation. Mol. Imaging 9:291–310 [Google Scholar]
  162. Okusanya OT, Holt D, Heitjan D, Deshpande C, Venegas O. 162.  et al. 2014. Intraoperative near-infrared imaging can identify pulmonary nodules. Ann. Thorac. Surg. 98:1223–30 [Google Scholar]
  163. Holt D, Okusanya O, Judy R, Venegas O, Liang J. 163.  et al. 2014. Intraoperative near-infrared imaging can distinguish cancer from normal tissue but not inflammation. PLoS ONE 9:e103342 [Google Scholar]
  164. van Dam GM, Themelis G, Crane CMA, Harlaar NJ, Pleijhuis RG. 164.  et al. 2011. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results. Nat. Med. 17:1315–19 [Google Scholar]

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