Exploring the Tumor Microenvironment with Nanoparticles

  • Lei Miao
  • Leaf HuangEmail author
Part of the Cancer Treatment and Research book series (CTAR, volume 166)


Recent developments in nanotechnology have brought new approaches to cancer diagnosis and therapy. While enhanced permeability and retention effect (EPR) promotes nanoparticle (NP) extravasation, the abnormal tumor vasculature, high interstitial pressure and dense stroma structure limit homogeneous intratumoral distribution of NP and compromise their imaging and therapeutic effect. Moreover, heterogeneous distribution of NP in nontumor-stroma cells damages the nontumor cells, and interferes with tumor-stroma crosstalk. This can lead to inhibition of tumor progression, but can also paradoxically induce acquired resistance and facilitate tumor cell proliferation and metastasis. Overall, the tumor microenvironment plays a crucial, yet controversial role in regulating NP distribution and their biological effects. In this review, we summarize recent studies on the stroma barriers for NP extravasation, and discuss the consequential effects of NP distribution in stroma cells. We also highlight design considerations to improve NP delivery and propose potential combinatory strategies to overcome acquired resistance induced by damaged stroma cells.


Nanoparticle Tumor microenvironment Extracellular matrix Pericytes tumor-associated fibroblast 



Enhanced Permeability and Retention Effect


Extracellular Matrix


Tumor Microenvironment


Basement Membrane


Interstitial Fluidic Pressure


Tumor Associated Fibroblast


Tumor Associated Macrophage


Matrix Metalloproteinases





This work was supported by NIH grant support: CA149363, CA151652, CA149387 and DK100664. The authors thank Andrew Mackenzie Blair for his assistance in the chapter preparation.


  1. 1.
    Wang Y, Zhang L, Guo S, Hatefi A, Huang L (2013) Incorporation of histone derived recombinant protein for enhanced disassembly of core-membrane structured liposomal nanoparticles for efficient siRNA delivery. J Controlled Release Off J Controlled Release Soc 172(1):179–189. doi: 10.1016/j.jconrel.2013.08.015 CrossRefGoogle Scholar
  2. 2.
    Chang HI, Yeh MK (2012) Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy. Int J Nanomed 7:49–60. doi: 10.2147/IJN.S26766 Google Scholar
  3. 3.
    Savla R, Taratula O, Garbuzenko O, Minko T (2011) Tumor targeted quantum dot-mucin 1 aptamer-doxorubicin conjugate for imaging and treatment of cancer. J Controlled Release Off J Controlled Release Soc 153(1):16–22. doi: 10.1016/j.jconrel.2011.02.015 CrossRefGoogle Scholar
  4. 4.
    Allen PM, Liu W, Chauhan VP, Lee J, Ting AY, Fukumura D, Jain RK, Bawendi MG (2010) InAs(ZnCdS) quantum dots optimized for biological imaging in the near-infrared. J Am Chem Soc 132(2):470–471. doi: 10.1021/ja908250r PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Fang J, Nakamura H, Maeda H (2011) 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 63(3):136–151. doi: 10.1016/j.addr.2010.04.009 PubMedCrossRefGoogle Scholar
  6. 6.
    Kanapathipillai M, Brock A, Ingber DE (2014) Nanoparticle targeting of anti-cancer drugs that alter intracellular signaling or influence the tumor microenvironment. Adv Drug Deliv Rev. doi: 10.1016/j.addr.2014.05.005 PubMedGoogle Scholar
  7. 7.
    Nishihara H (2014) Human pathological basis of blood vessels and stromal tissue for nanotechnology. Adv Drug Deliv Rev 74C:19–27. doi: 10.1016/j.addr.2014.01.005 CrossRefGoogle Scholar
  8. 8.
    Kakkar V, Singh S, Singla D, Kaur IP (2011) Exploring solid lipid nanoparticles to enhance the oral bioavailability of curcumin. Mol Nutr Food Res 55(3):495–503. doi: 10.1002/mnfr.201000310 PubMedCrossRefGoogle Scholar
  9. 9.
    Knezevic NZ, Trewyn BG, Lin VS (2011) Functionalized mesoporous silica nanoparticle-based visible light responsive controlled release delivery system. Chem Commun 47(10):2817–2819. doi: 10.1039/c0cc04424e CrossRefGoogle Scholar
  10. 10.
    Elzoghby AO, Samy WM, Elgindy NA (2012) Albumin-based nanoparticles as potential controlled release drug delivery systems. J Controlled Release Off J Controlled Release Soc 157(2):168–182. doi: 10.1016/j.jconrel.2011.07.031 CrossRefGoogle Scholar
  11. 11.
    Klibanov AL, Maruyama K, Torchilin VP, Huang L (1990) Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 268(1):235–237PubMedCrossRefGoogle Scholar
  12. 12.
    Ruiz A, Hernandez Y, Cabal C, Gonzalez E, Veintemillas-Verdaguer S, Martinez E, Morales MP (2013) Biodistribution and pharmacokinetics of uniform magnetite nanoparticles chemically modified with polyethylene glycol. Nanoscale 5(23):11400–11408. doi: 10.1039/c3nr01412f PubMedCrossRefGoogle Scholar
  13. 13.
    Bibby DC, Talmadge JE, Dalal MK, Kurz SG, Chytil KM, Barry SE, Shand DG, Steiert M (2005) Pharmacokinetics and biodistribution of RGD-targeted doxorubicin-loaded nanoparticles in tumor-bearing mice. Int J Pharm 293(1–2):281–290. doi: 10.1016/j.ijpharm.2004.12.021 PubMedCrossRefGoogle Scholar
  14. 14.
    Jain RK, Stylianopoulos T (2010) Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 7(11):653–664. doi: 10.1038/nrclinonc.2010.139 PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Guo S, Lin CM, Xu Z, Miao L, Wang Y, Huang L (2014) Co-delivery of cisplatin and rapamycin for enhanced anticancer therapy through synergistic effects and microenvironment modulation. ACS Nano. doi: 10.1021/nn5010815 Google Scholar
  16. 16.
    Xu Z, Ramishetti S, Tseng YC, Guo S, Wang Y, Huang L (2013) Multifunctional nanoparticles co-delivering Trp2 peptide and CpG adjuvant induce potent cytotoxic T-lymphocyte response against melanoma and its lung metastasis. J Control Release 172(1):259–265. doi: 10.1016/j.jconrel.2013.08.021 PubMedCrossRefGoogle Scholar
  17. 17.
    Zhang Y, Peng L, Mumper RJ, Huang L (2013) Combinational delivery of c-myc siRNA and nucleoside analogs in a single, synthetic nanocarrier for targeted cancer therapy. Biomaterials 34(33):8459–8468. doi: 10.1016/j.biomaterials.2013.07.050 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Ashley CE, Carnes EC, Phillips GK, Padilla D, Durfee PN, Brown PA, Hanna TN, Liu J, Phillips B, Carter MB, Carroll NJ, Jiang X, Dunphy DR, Willman CL, Petsev DN, Evans DG, Parikh AN, Chackerian B, Wharton W, Peabody DS, Brinker CJ (2011) The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers. Nat Mater 10(5):389–397. doi: 10.1038/nmat2992 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Aryal S, Hu CM, Zhang L (2011) Polymeric nanoparticles with precise ratiometric control over drug loading for combination therapy. Mol Pharm 8(4):1401–1407. doi: 10.1021/mp200243k PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Kolishetti N, Dhar S, Valencia PM, Lin LQ, Karnik R, Lippard SJ, Langer R, Farokhzad OC (2010) Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy. Proc Natl Acad Sci USA 107(42):17939–17944. doi: 10.1073/pnas.1011368107 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Vivero-Escoto JL, Taylor-Pashow KM, Huxford RC, Della Rocca J, Okoruwa C, An H, Lin W, Lin W (2011) Multifunctional mesoporous silica nanospheres with cleavable Gd(III) chelates as MRI contrast agents: synthesis, characterization, target-specificity, and renal clearance. Small 7(24):3519–3528. doi: 10.1002/smll.201100521 PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Hu SH, Gao X (2010) Nanocomposites with spatially separated functionalities for combined imaging and magnetolytic therapy. J Am Chem Soc 132(21):7234–7237. doi: 10.1021/ja102489q PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Nasongkla N, Bey E, Ren J, Ai H, Khemtong C, Guthi JS, Chin SF, Sherry AD, Boothman DA, Gao J (2006) Multifunctional polymeric micelles as cancer-targeted, MRI-ultrasensitive drug delivery systems. Nano Lett 6(11):2427–2430. doi: 10.1021/nl061412u PubMedCrossRefGoogle Scholar
  24. 24.
    Nasongkla N, Shuai X, Ai H, Weinberg BD, Pink J, Boothman DA, Gao J (2004) cRGD-functionalized polymer micelles for targeted doxorubicin delivery. Angew Chem Int Ed Engl 43(46):6323–6327. doi: 10.1002/anie.200460800 PubMedCrossRefGoogle Scholar
  25. 25.
    Banerjee R, Tyagi P, Li S, Huang L (2004) Anisamide-targeted stealth liposomes: a potent carrier for targeting doxorubicin to human prostate cancer cells. Int J Cancer 112(4):693–700. doi: 10.1002/ijc.20452 PubMedCrossRefGoogle Scholar
  26. 26.
    Hu CM, Zhang L (2009) Therapeutic nanoparticles to combat cancer drug resistance. Curr Drug Metab 10(8):836–841PubMedCrossRefGoogle Scholar
  27. 27.
    Hu CM, Zhang L (2012) Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochem Pharmacol 83(8):1104–1111. doi: 10.1016/j.bcp.2012.01.008 PubMedCrossRefGoogle Scholar
  28. 28.
    Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, Castedo M, Kroemer G (2012) Molecular mechanisms of cisplatin resistance. Oncogene 31(15):1869–1883. doi: 10.1038/onc.2011.384 PubMedCrossRefGoogle Scholar
  29. 29.
    Hamelers IH, Staffhorst RW, Voortman J, de Kruijff B, Reedijk J, van Bergen en Henegouwen PM, de Kroon AI (2009) High cytotoxicity of cisplatin nanocapsules in ovarian carcinoma cells depends on uptake by caveolae-mediated endocytosis. Clinical Cancer Res Off J Am Assoc Cancer Res 15(4):1259–1268. doi: 10.1158/1078-0432.CCR-08-1702 CrossRefGoogle Scholar
  30. 30.
    Steichen SD, Caldorera-Moore M, Peppas NA (2012) A review of current nanoparticle and targeting moieties for the delivery of cancer therapeutics. Eur J Pharm Sci Off J Eur Fed Pharm Sci 48(3):416–427. doi: 10.1016/j.ejps.2012.12.006 Google Scholar
  31. 31.
    Davis ME, Chen ZG, Shin DM (2008) Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov 7(9):771–782. doi: 10.1038/nrd2614 PubMedCrossRefGoogle Scholar
  32. 32.
    Rink JS, Plebanek MP, Tripathy S, Thaxton CS (2013) Update on current and potential nanoparticle cancer therapies. Curr Opin Oncol 25(6):646–651. doi: 10.1097/CCO.0000000000000012 PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121(3):335–348. doi: 10.1016/j.cell.2005.02.034 PubMedCrossRefGoogle Scholar
  34. 34.
    Carmeliet P, Jain RK (2011) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10(6):417–427. doi: 10.1038/nrd3455 PubMedCrossRefGoogle Scholar
  35. 35.
    Ellem SJ, De-Juan-Pardo EM, Risbridger GP (2014) In vitro modeling of the prostate cancer microenvironment. Adv Drug Deliv Rev. doi: 10.1016/j.addr.2014.04.008 PubMedGoogle Scholar
  36. 36.
    Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM (2003) Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol 163(5):1801–1815. doi: 10.1016/S0002-9440(10)63540-7 PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Cao Y, Zhang ZL, Zhou M, Elson P, Rini B, Aydin H, Feenstra K, Tan MH, Berghuis B, Tabbey R, Resau JH, Zhou FJ, Teh BT, Qian CN (2013) Pericyte coverage of differentiated vessels inside tumor vasculature is an independent unfavorable prognostic factor for patients with clear cell renal cell carcinoma. Cancer 119(2):313–324. doi: 10.1002/cncr.27746 PubMedCrossRefGoogle Scholar
  38. 38.
    Lokody I (2014) Microenvironment: tumour-promoting tissue mechanics. Nat Rev Cancer 14(5):296. doi: 10.1038/nrc3727 PubMedCrossRefGoogle Scholar
  39. 39.
    Duyverman AM, Steller EJ, Fukumura D, Jain RK, Duda DG (2012) Studying primary tumor-associated fibroblast involvement in cancer metastasis in mice. Nat Protoc 7(4):756–762. doi: 10.1038/nprot.2012.031 PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Correia AL, Bissell MJ (2012) The tumor microenvironment is a dominant force in multidrug resistance. Drug Resist Updates Reviews Comment Antimicrob Anticancer Chemother 15(1–2):39–49. doi: 10.1016/j.drup.2012.01.006 CrossRefGoogle Scholar
  41. 41.
    Egeblad M, Rasch MG, Weaver VM (2010) Dynamic interplay between the collagen scaffold and tumor evolution. Curr Opin Cell Biol 22(5):697–706. doi: 10.1016/ PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Singleton PA, Mirzapoiazova T, Guo Y, Sammani S, Mambetsariev N, Lennon FE, Moreno-Vinasco L, Garcia JG (2010) High-molecular-weight hyaluronan is a novel inhibitor of pulmonary vascular leakiness. Am J Physiol Lung Cell Mol Physiol 299(5):L639–L651. doi: 10.1152/ajplung.00405.2009 PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487(7408):500–504. doi: 10.1038/nature11183 PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Li H, Fan X, Houghton J (2007) Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem 101(4):805–815. doi: 10.1002/jcb.21159 PubMedCrossRefGoogle Scholar
  45. 45.
    Yokoi K, Godin B, Oborn CJ, Alexander JF, Liu X, Fidler IJ, Ferrari M (2013) Porous silicon nanocarriers for dual targeting tumor associated endothelial cells and macrophages in stroma of orthotopic human pancreatic cancers. Cancer Lett 334(2):319–327. doi: 10.1016/j.canlet.2012.09.001 PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Paraiso KH, Smalley KS (2013) Fibroblast-mediated drug resistance in cancer. Biochem Pharmacol 85(8):1033–1041. doi: 10.1016/j.bcp.2013.01.018 PubMedCrossRefGoogle Scholar
  47. 47.
    Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, Rey-Giraud F, Pradel LP, Feuerhake F, Klaman I, Jones T, Jucknischke U, Scheiblich S, Kaluza K, Gorr IH, Walz A, Abiraj K, Cassier PA, Sica A, Gomez-Roca C, de Visser KE, Italiano A, Le Tourneau C, Delord JP, Levitsky H, Blay JY, Ruttinger D (2014) Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25(6):846–859. doi: 10.1016/j.ccr.2014.05.016 PubMedCrossRefGoogle Scholar
  48. 48.
    Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, LeBleu VS, Kalluri R (2014) Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25(6):719–734. doi: 10.1016/j.ccr.2014.04.005 PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, True L, Nelson PS (2012) Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med 18(9):1359–1368. doi: 10.1038/nm.2890 PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Loeffler M, Kruger JA, Niethammer AG, Reisfeld RA (2006) Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Investig 116(7):1955–1962. doi: 10.1172/JCI26532 PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Guo S, Wang Y, Miao L, Xu Z, Lin CM, Zhang Y, Huang L (2013) Lipid-coated cisplatin nanoparticles induce neighboring effect and exhibit enhanced anticancer efficacy. ACS Nano 7(11):9896–9904. doi: 10.1021/nn403606m PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Min KH, Lee HJ, Kim K, Kwon IC, Jeong SY, Lee SC (2012) The tumor accumulation and therapeutic efficacy of doxorubicin carried in calcium phosphate-reinforced polymer nanoparticles. Biomaterials 33(23):5788–5797. doi: 10.1016/j.biomaterials.2012.04.057 PubMedCrossRefGoogle Scholar
  53. 53.
    Zhang J, Miao L, Guo S, Zhang Y, Zhang L, Satterlee A, Kim WY, Huang L (2014) Synergistic anti-tumor effects of combined gemcitabine and cisplatin nanoparticles in a stroma-rich bladder carcinoma model. J Controlled Release Off J Controlled Release Soc 182:90–96. doi: 10.1016/j.jconrel.2014.03.016 CrossRefGoogle Scholar
  54. 54.
    Armulik A, Genove G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21(2):193–215. doi: 10.1016/j.devcel.2011.07.001 PubMedCrossRefGoogle Scholar
  55. 55.
    Sims DE (1986) The pericyte—a review. Tissue Cell 18(2):153–174PubMedCrossRefGoogle Scholar
  56. 56.
    Inoue S (1989) Ultrastructure of basement membranes. Int Rev Cytol 117:57–98PubMedCrossRefGoogle Scholar
  57. 57.
    Yokoi K, Kojic M, Milosevic M, Tanei T, Ferrari M, Ziemys A (2014) Capillary-wall collagen as a biophysical marker of nanotherapeutic permeability into the tumor microenvironment. Cancer Res 74(16):4239–4246. doi: 10.1158/0008-5472.CAN-13-3494 PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Danquah MK, Zhang XA, Mahato RI (2011) Extravasation of polymeric nanomedicines across tumor vasculature. Adv Drug Deliv Rev 63(8):623–639. doi: 10.1016/j.addr.2010.11.005 PubMedCrossRefGoogle Scholar
  59. 59.
    McDonald DM, Thurston G, Baluk P (1999) Endothelial gaps as sites for plasma leakage in inflammation. Microcirculation 6(1):7–22PubMedCrossRefGoogle Scholar
  60. 60.
    Yurchenco PD, Ruben GC (1987) Basement membrane structure in situ: evidence for lateral associations in the type IV collagen network. J Cell Biol 105(6 Pt 1):2559–2568PubMedCrossRefGoogle Scholar
  61. 61.
    Accardo A, Salsano G, Morisco A, Aurilio M, Parisi A, Maione F, Cicala C, Tesauro D, Aloj L, De Rosa G, Morelli G (2012) Peptide-modified liposomes for selective targeting of bombesin receptors overexpressed by cancer cells: a potential theranostic agent. Int J Nanomed 7:2007–2017. doi: 10.2147/IJN.S29242 Google Scholar
  62. 62.
    Lu Y, Low PS (2002) Folate-mediated delivery of macromolecular anticancer therapeutic agents. Adv Drug Deliv Rev 54(5):675–693PubMedCrossRefGoogle Scholar
  63. 63.
    Zhang L, Gu FX, Chan JM, Wang AZ, Langer RS, Farokhzad OC (2008) Nanoparticles in medicine: therapeutic applications and developments. Clin Pharmacol Ther 83(5):761–769. doi: 10.1038/sj.clpt.6100400 PubMedCrossRefGoogle Scholar
  64. 64.
    Su EP, Housman LR, Masonis JL, Noble JW Jr, Engh CA (2014) Five year results of the first US FDA-approved hip resurfacing device. J Arthroplast 29(8):1571–1575. doi: 10.1016/j.arth.2014.03.021 CrossRefGoogle Scholar
  65. 65.
    Tianjiao Ji YZ, Ding Y, Nie G (2013) Using functional nanomaterials to target and regulate the tumor microenvironment: diagnostic and therapeutic applications. Adv Mater 25(26):3508–3525. doi: 10.1002/adma.201300299 PubMedCrossRefGoogle Scholar
  66. 66.
    Jain RK (1994) Barriers to drug delivery in solid tumors. Sci Am 271(1):58–65PubMedCrossRefGoogle Scholar
  67. 67.
    Boucher Y, Baxter LT, Jain RK (1990) Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res 50(15):4478–4484PubMedGoogle Scholar
  68. 68.
    Swartz MA, Lund AW (2012) Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat Rev Cancer 12(3):210–219. doi: 10.1038/nrc3186 PubMedCrossRefGoogle Scholar
  69. 69.
    Boucher Y, Jain RK (1992) Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res 52(18):5110–5114PubMedGoogle Scholar
  70. 70.
    Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK (2004) Pathology: cancer cells compress intratumour vessels. Nature 427(6976):695. doi: 10.1038/427695a PubMedCrossRefGoogle Scholar
  71. 71.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62. doi: 10.1126/science.1104819 PubMedCrossRefGoogle Scholar
  72. 72.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi: 10.1016/j.cell.2011.02.013 PubMedCrossRefGoogle Scholar
  73. 73.
    Kano MR (2014) Nanotechnology and tumor microcirculation. Adv Drug Deliv Rev 74C:2–11. doi: 10.1016/j.addr.2013.08.010 CrossRefGoogle Scholar
  74. 74.
    Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellstrom M, Backstrom G, Fredriksson S, Landegren U, Nystrom HC, Bergstrom G, Dejana E, Ostman A, Lindahl P, Betsholtz C (2003) Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 17(15):1835–1840. doi: 10.1101/gad.266803 PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Song N, Huang Y, Shi H, Yuan S, Ding Y, Song X, Fu Y, Luo Y (2009) Overexpression of platelet-derived growth factor-BB increases tumor pericyte content via stromal-derived factor-1alpha/CXCR4 axis. Cancer Res 69(15):6057–6064. doi: 10.1158/0008-5472.CAN-08-2007 PubMedCrossRefGoogle Scholar
  76. 76.
    Yu X, Radulescu A, Chen CL, James IO, Besner GE (2012) Heparin-binding EGF-like growth factor protects pericytes from injury. J Surg Res 172(1):165–176. doi: 10.1016/j.jss.2010.07.058 PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Abramsson A, Lindblom P, Betsholtz C (2003) Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Investig 112(8):1142–1151. doi: 10.1172/JCI18549 PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N, Cheresh DA (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456(7223):809–813. doi: 10.1038/nature07424 PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Furuhashi M, Sjoblom T, Abramsson A, Ellingsen J, Micke P, Li H, Bergsten-Folestad E, Eriksson U, Heuchel R, Betsholtz C, Heldin CH, Ostman A (2004) Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate. Cancer Res 64(8):2725–2733PubMedCrossRefGoogle Scholar
  80. 80.
    Hosaka K, Yang Y, Seki T, Nakamura M, Andersson P, Rouhi P, Yang X, Jensen L, Lim S, Feng N, Xue Y, Li X, Larsson O, Ohhashi T, Cao Y (2013) Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis. Nat Commun 4:2129. doi: 10.1038/ncomms3129 PubMedCrossRefGoogle Scholar
  81. 81.
    Zhang L, Nishihara H, Kano MR (2012) Pericyte-coverage of human tumor vasculature and nanoparticle permeability. Biol Pharm Bull 35(5):761–766PubMedCrossRefGoogle Scholar
  82. 82.
    Kano MR, Komuta Y, Iwata C, Oka M, Shirai YT, Morishita Y, Ouchi Y, Kataoka K, Miyazono K (2009) Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-beta receptor inhibitor on extravasation of nanoparticles from neovasculature. Cancer Sci 100(1):173–180. doi: 10.1111/j.1349-7006.2008.01003.x PubMedCrossRefGoogle Scholar
  83. 83.
    Kano MR, Bae Y, Iwata C, Morishita Y, Yashiro M, Oka M, Fujii T, Komuro A, Kiyono K, Kaminishi M, Hirakawa K, Ouchi Y, Nishiyama N, Kataoka K, Miyazono K (2007) Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling. Proc Natl Acad Sci USA 104(9):3460–3465. doi: 10.1073/pnas.0611660104 PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Liu J, Liao S, Diop-Frimpong B, Chen W, Goel S, Naxerova K, Ancukiewicz M, Boucher Y, Jain RK, Xu L (2012) TGF-beta blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc Natl Acad Sci USA 109(41):16618–16623. doi: 10.1073/pnas.1117610109
  85. 85.
    Cabral H, Matsumoto Y, Mizuno K, Chen Q, Murakami M, Kimura M, Terada Y, Kano MR, Miyazono K, Uesaka M, Nishiyama N, Kataoka K (2011) Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat Nanotechnol 6(12):815–823. doi: 10.1038/nnano.2011.166 PubMedCrossRefGoogle Scholar
  86. 86.
    Meng H, Zhao Y, Dong J, Xue M, Lin YS, Ji Z, Mai WX, Zhang H, Chang CH, Brinker CJ, Zink JI, Nel AE (2013) Two-wave nanotherapy to target the stroma and optimize gemcitabine delivery to a human pancreatic cancer model in mice. ACS Nano 7(11):10048–10065. doi: 10.1021/nn404083m PubMedCrossRefGoogle Scholar
  87. 87.
    Minowa T, Kawano K, Kuribayashi H, Shiraishi K, Sugino T, Hattori Y, Yokoyama M, Maitani Y (2009) Increase in tumour permeability following TGF-beta type I receptor-inhibitor treatment observed by dynamic contrast-enhanced MRI. Br J Cancer 101(11):1884–1890. doi: 10.1038/sj.bjc.6605367 PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Kumagai M, Kano MR, Morishita Y, Ota M, Imai Y, Nishiyama N, Sekino M, Ueno S, Miyazono K, Kataoka K (2009) Enhanced magnetic resonance imaging of experimental pancreatic tumor in vivo by block copolymer-coated magnetite nanoparticles with TGF-beta inhibitor. J Controlled Release Off J Controlled Release Soc 140(3):306–311. doi: 10.1016/j.jconrel.2009.06.002 CrossRefGoogle Scholar
  89. 89.
    Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu-Lowe DD, McDonald DM (2006) Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Investig 116(10):2610–2621. doi: 10.1172/JCI24612 PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Chauhan VP, Stylianopoulos T, Martin JD, Popovic Z, Chen O, Kamoun WS, Bawendi MG, Fukumura D, Jain RK (2012) Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol 7(6):383–388. doi: 10.1038/nnano.2012.45 PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Bauvois B (2012) New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. Biochim Biophys Acta 1825(1):29–36. doi: 10.1016/j.bbcan.2011.10.001 PubMedGoogle Scholar
  92. 92.
    Mammoto T, Jiang A, Jiang E, Panigrahy D, Kieran MW, Mammoto A (2013) Role of collagen matrix in tumor angiogenesis and glioblastoma multiforme progression. Am J Pathol 183(4):1293–1305. doi: 10.1016/j.ajpath.2013.06.026 PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Danhier F, Feron O, Preat V (2010) To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Controlled Release Off J Controlled Release Soc 148(2):135–146. doi: 10.1016/j.jconrel.2010.08.027 CrossRefGoogle Scholar
  94. 94.
    Jain RK (2013) Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol Off J Am Soc Clin Oncol 31(17):2205–2218. doi: 10.1200/JCO.2012.46.3653 CrossRefGoogle Scholar
  95. 95.
    Alderton GK (2014) Microenvironment: an exercise in restraint. Nat Rev Cancer 14(7):449. doi: 10.1038/nrc3769 PubMedCrossRefGoogle Scholar
  96. 96.
    Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK (2011) Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci USA 108 (7):2909–2914. doi: 10.1073/pnas.1018892108
  97. 97.
    Ganesh S, Gonzalez Edick M, Idamakanti N, Abramova M, Vanroey M, Robinson M, Yun CO, Jooss K (2007) Relaxin-expressing, fiber chimeric oncolytic adenovirus prolongs survival of tumor-bearing mice. Cancer Res 67(9):4399–4407. doi: 10.1158/0008-5472.CAN-06-4260 PubMedCrossRefGoogle Scholar
  98. 98.
    McKee TD, Grandi P, Mok W, Alexandrakis G, Insin N, Zimmer JP, Bawendi MG, Boucher Y, Breakefield XO, Jain RK (2006) Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. Cancer Res 66(5):2509–2513. doi: 10.1158/0008-5472.CAN-05-2242 PubMedCrossRefGoogle Scholar
  99. 99.
    Stylianopoulos T, Diop-Frimpong B, Munn LL, Jain RK (2010) Diffusion anisotropy in collagen gels and tumors: the effect of fiber network orientation. Biophys J 99(10):3119–3128. doi: 10.1016/j.bpj.2010.08.065 PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Kanapathipillai M, Mammoto A, Mammoto T, Kang JH, Jiang E, Ghosh K, Korin N, Gibbs A, Mannix R, Ingber DE (2012) Inhibition of mammary tumor growth using lysyl oxidase-targeting nanoparticles to modify extracellular matrix. Nano Lett 12(6):3213–3217. doi: 10.1021/nl301206p PubMedCrossRefGoogle Scholar
  101. 101.
    Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, Feig C, Nakagawa T, Caldwell ME, Zecchini HI, Lolkema MP, Jiang P, Kultti A, Thompson CB, Maneval DC, Jodrell DI, Frost GI, Shepard HM, Skepper JN, Tuveson DA (2013) Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62(1):112–120. doi: 10.1136/gutjnl-2012-302529 PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Provenzano PP, Hingorani SR (2013) Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br J Cancer 108(1):1–8. doi: 10.1038/bjc.2012.569 PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Chahine NO, Chen FH, Hung CT, Ateshian GA (2005) Direct measurement of osmotic pressure of glycosaminoglycan solutions by membrane osmometry at room temperature. Biophys J 89(3):1543–1550. doi: 10.1529/biophysj.104.057315 PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Ruckert F, Grutzmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324(5933):1457–1461. doi: 10.1126/science.1171362 PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Beckenlehner K, Bannke S, Spruss T, Bernhardt G, Schonenberg H, Schiess W (1992) Hyaluronidase enhances the activity of adriamycin in breast cancer models in vitro and in vivo. J Cancer Res Clin Oncol 118(8):591–596PubMedCrossRefGoogle Scholar
  106. 106.
    Brekken C, de Lange Davies C (1998) Hyaluronidase reduces the interstitial fluid pressure in solid tumours in a non-linear concentration-dependent manner. Cancer Lett 131(1):65–70PubMedCrossRefGoogle Scholar
  107. 107.
    Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, Lolkema MP, Buchholz M, Olive KP, Gress TM, Tuveson DA (2011) Stromal biology and therapy in pancreatic cancer. Gut 60(6):861–868. doi: 10.1136/gut.2010.226092 PubMedCrossRefGoogle Scholar
  108. 108.
    Thorne RG, Lakkaraju A, Rodriguez-Boulan E, Nicholson C (2008) In vivo diffusion of lactoferrin in brain extracellular space is regulated by interactions with heparan sulfate. Proc Natl Acad Sci USA 105(24):8416–8421. doi: 10.1073/pnas.0711345105 PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Yingling JM, Blanchard KL, Sawyer JS (2004) Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov 3(12):1011–1022. doi: 10.1038/nrd1580 PubMedCrossRefGoogle Scholar
  110. 110.
    Lee CG, Heijn M, di Tomaso E, Griffon-Etienne G, Ancukiewicz M, Koike C, Park KR, Ferrara N, Jain RK, Suit HD, Boucher Y (2000) Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60(19):5565–5570PubMedGoogle Scholar
  111. 111.
    Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10(2):145–147. doi: 10.1038/nm988 PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, Hambleton J, Novotny WF, Kabbinavar F (2005) Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol 23(15):3502–3508. doi: 10.1200/JCO.2005.10.017 CrossRefGoogle Scholar
  113. 113.
    Kong G, Braun RD, Dewhirst MW (2000) Hyperthermia enables tumor-specific nanoparticle delivery: effect of particle size. Cancer Res 60(16):4440–4445PubMedGoogle Scholar
  114. 114.
    Hainfeld JF, Dilmanian FA, Slatkin DN, Smilowitz HM (2008) Radiotherapy enhancement with gold nanoparticles. J Pharm Pharmacol 60(8):977–985. doi: 10.1211/jpp.60.8.0005 PubMedCrossRefGoogle Scholar
  115. 115.
    Mok W, Boucher Y, Jain RK (2007) Matrix metalloproteinases-1 and -8 improve the distribution and efficacy of an oncolytic virus. Cancer Res 67(22):10664–10668. doi: 10.1158/0008-5472.CAN-07-3107 PubMedCrossRefGoogle Scholar
  116. 116.
    Dreher MR, Liu W, Michelich CR, Dewhirst MW, Yuan F, Chilkoti A (2006) Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst 98(5):335–344. doi: 10.1093/jnci/djj070 PubMedCrossRefGoogle Scholar
  117. 117.
    Campbell RB, Fukumura D, Brown EB, Mazzola LM, Izumi Y, Jain RK, Torchilin VP, Munn LL (2002) Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors. Cancer Res 62(23):6831–6836PubMedGoogle Scholar
  118. 118.
    Stylianopoulos T, Poh MZ, Insin N, Bawendi MG, Fukumura D, Munn LL, Jain RK (2010) Diffusion of particles in the extracellular matrix: the effect of repulsive electrostatic interactions. Biophys J 99(5):1342–1349. doi: 10.1016/j.bpj.2010.06.016 PubMedCentralPubMedCrossRefGoogle Scholar
  119. 119.
    Pluen A, Netti PA, Jain RK, Berk DA (1999) Diffusion of macromolecules in agarose gels: comparison of linear and globular configurations. Biophys J 77(1):542–552. doi: 10.1016/S0006-3495(99)76911-0 PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Wong C, Stylianopoulos T, Cui J, Martin J, Chauhan VP, Jiang W, Popovic Z, Jain RK, Bawendi MG, Fukumura D (2011) Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc Natl Acad Sci USA 108(6):2426–2431. doi: 10.1073/pnas.1018382108 PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Huang S, Fang R, Xu J, Qiu S, Zhang H, Du J, Cai S (2011) Evaluation of the tumor targeting of a FAPalpha-based doxorubicin prodrug. J Drug Target 19(7):487–496. doi: 10.3109/1061186X.2010.511225 PubMedCrossRefGoogle Scholar
  122. 122.
    Aggarwal S, Brennen WN, Kole TP, Schneider E, Topaloglu O, Yates M, Cotter RJ, Denmeade SR (2008) Fibroblast activation protein peptide substrates identified from human collagen I derived gelatin cleavage sites. Biochemistry 47(3):1076–1086. doi: 10.1021/bi701921b PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Hatakeyama H, Akita H, Harashima H (2011) A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: a strategy for overcoming the PEG dilemma. Adv Drug Deliv Rev 63(3):152–160. doi: 10.1016/j.addr.2010.09.001 PubMedCrossRefGoogle Scholar
  124. 124.
    LeBeau AM, Brennen WN, Aggarwal S, Denmeade SR (2009) Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin. Mol Cancer Ther 8(5):1378–1386. doi: 10.1158/1535-7163.MCT-08-1170 PubMedCentralPubMedCrossRefGoogle Scholar
  125. 125.
    Lim EK, Huh YM, Yang J, Lee K, Suh JS, Haam S (2011) pH-triggered drug-releasing magnetic nanoparticles for cancer therapy guided by molecular imaging by MRI. Adv Mater 23(21):2436–2442. doi: 10.1002/adma.201100351 PubMedCrossRefGoogle Scholar
  126. 126.
    Chen W, Meng F, Cheng R, Zhong Z (2010) pH-Sensitive degradable polymersomes for triggered release of anticancer drugs: a comparative study with micelles. J Controlled Release Off J Controlled Release Soc 142(1):40–46. doi: 10.1016/j.jconrel.2009.09.023 CrossRefGoogle Scholar
  127. 127.
    Ge J, Neofytou E, Cahill TJ 3rd, Beygui RE, Zare RN (2012) Drug release from electric-field-responsive nanoparticles. ACS Nano 6(1):227–233. doi: 10.1021/nn203430m
  128. 128.
    Oliveira H, Perez-Andres E, Thevenot J, Sandre O, Berra E, Lecommandoux S (2013) Magnetic field triggered drug release from polymersomes for cancer therapeutics. J Control Release Off J Controlled Release Soc 169(3):165–170. doi: 10.1016/j.jconrel.2013.01.013 CrossRefGoogle Scholar
  129. 129.
    Zderic V (2008) Ultrasound-enhanced drug and gene delivery: a review. In: conference proceedings: annual international conference of the IEEE engineering in medicine and biology society IEEE engineering in medicine and biology society annual conference, p 4472. doi: 10.1109/IEMBS.2008.4650205
  130. 130.
    Huschka R, Zuloaga J, Knight MW, Brown LV, Nordlander P, Halas NJ (2011) Light-induced release of DNA from gold nanoparticles: nanoshells and nanorods. J Am Chem Soc 133(31):12247–12255. doi: 10.1021/ja204578e PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Manzoor AA, Lindner LH, Landon CD, Park JY, Simnick AJ, Dreher MR, Das S, Hanna G, Park W, Chilkoti A, Koning GA, ten Hagen TL, Needham D, Dewhirst MW (2012) Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors. Cancer Res 72(21):5566–5575. doi: 10.1158/0008-5472.CAN-12-1683 PubMedCentralPubMedCrossRefGoogle Scholar
  132. 132.
    Kim HR, Gil S, Andrieux K, Nicolas V, Appel M, Chacun H, Desmaele D, Taran F, Georgin D, Couvreur P (2007) Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells. Cell Mol Life Sci CMLS 64(3):356–364. doi: 10.1007/s00018-007-6390-x PubMedCrossRefGoogle Scholar
  133. 133.
    Agemy L, Friedmann-Morvinski D, Kotamraju VR, Roth L, Sugahara KN, Girard OM, Mattrey RF, Verma IM, Ruoslahti E (2011) Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma. Proc Natl Acad Sci USA 108(42):17450–17455. doi: 10.1073/pnas.1114518108 PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    Murphy EA, Majeti BK, Barnes LA, Makale M, Weis SM, Lutu-Fuga K, Wrasidlo W, Cheresh DA (2008) Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis. Proc Natl Acad Sci USA 105(27):9343–9348. doi: 10.1073/pnas.0803728105 PubMedCentralPubMedCrossRefGoogle Scholar
  135. 135.
    Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Girard OM, Hanahan D, Mattrey RF, Ruoslahti E (2009) Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16(6):510–520. doi: 10.1016/j.ccr.2009.10.013 PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Lee HY, Li Z, Chen K, Hsu AR, Xu C, Xie J, Sun S, Chen X (2008) PET/MRI dual-modality tumor imaging using arginine-glycine-aspartic (RGD)-conjugated radiolabeled iron oxide nanoparticles. J Nucl Med Off Publ Soc Nucl Med 49(8):1371–1379. doi: 10.2967/jnumed.108.051243 Google Scholar
  137. 137.
    Cui Z, Hsu CH, Mumper RJ (2003) Physical characterization and macrophage cell uptake of mannan-coated nanoparticles. Drug Dev Ind Pharm 29(6):689–700. doi: 10.1081/DDC-120021318 PubMedCrossRefGoogle Scholar
  138. 138.
    Zhu S, Niu M, O’Mary H, Cui Z (2013) Targeting of tumor-associated macrophages made possible by PEG-sheddable, mannose-modified nanoparticles. Mol Pharm 10(9):3525–3530. doi: 10.1021/mp400216r PubMedCentralPubMedCrossRefGoogle Scholar
  139. 139.
    Weissleder R, Nahrendorf M, Pittet MJ (2014) Imaging macrophages with nanoparticles. Nat Mater 13(2):125–138. doi: 10.1038/nmat3780 PubMedCrossRefGoogle Scholar
  140. 140.
    Yamashita M, Ogawa T, Zhang X, Hanamura N, Kashikura Y, Takamura M, Yoneda M, Shiraishi T (2012) Role of stromal myofibroblasts in invasive breast cancer: stromal expression of alpha-smooth muscle actin correlates with worse clinical outcome. Breast Cancer 19(2):170–176. doi: 10.1007/s12282-010-0234-5 PubMedCrossRefGoogle Scholar
  141. 141.
    Siemann DW (2011) Tumor microenvironment. Wiley, ChichesterGoogle Scholar
  142. 142.
    Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, Teichmann SA, Janowitz T, Jodrell DI, Tuveson DA, Fearon DT (2013) Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA 110(50):20212–20217. doi: 10.1073/pnas.1320318110 PubMedCentralPubMedCrossRefGoogle Scholar
  143. 143.
    Murakami M, Ernsting MJ, Undzys E, Holwell N, Foltz WD, Li SD (2013) Docetaxel conjugate nanoparticles that target alpha-smooth muscle actin-expressing stromal cells suppress breast cancer metastasis. Cancer Res 73(15):4862–4871. doi: 10.1158/0008-5472.CAN-13-0062 PubMedCrossRefGoogle Scholar
  144. 144.
    Guo S, Miao L, Wang Y, Huang L (2014) Unmodified drug used as a material to construct nanoparticles: delivery of cisplatin for enhanced anti-cancer therapy. J Control Release 174:137–142. doi: 10.1016/j.jconrel.2013.11.019 PubMedCentralPubMedCrossRefGoogle Scholar
  145. 145.
    Li J, Yang Y, Huang L (2012) Calcium phosphate nanoparticles with an asymmetric lipid bilayer coating for siRNA delivery to the tumor. J Control Release Off J Control Release Soc 158(1):108–114. doi: 10.1016/j.jconrel.2011.10.020 CrossRefGoogle Scholar
  146. 146.
    Guo S, Lin CM, Xu Z, Miao L, Wang Y, Huang L (2014) Co-delivery of cisplatin and rapamycin for enhanced anticancer therapy through synergistic effects and microenvironment modulation. ACS Nano 8(5):4996–5009. doi: 10.1021/nn5010815 PubMedCentralPubMedCrossRefGoogle Scholar
  147. 147.
    Mao Y, Keller ET, Garfield DH, Shen K, Wang J (2013) Stromal cells in tumor microenvironment and breast cancer. Cancer metastasis rev 32(1–2):303–315. doi: 10.1007/s10555-012-9415-3 PubMedCentralPubMedCrossRefGoogle Scholar
  148. 148.
    Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, Ji B, Evans DB, Logsdon CD (2008) Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 68(3):918–926. doi: 10.1158/0008-5472.CAN-07-5714 PubMedCentralPubMedCrossRefGoogle Scholar
  149. 149.
    Brennen WN, Isaacs JT, Denmeade SR (2012) Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol Cancer Ther 11(2):257–266. doi: 10.1158/1535-7163.MCT-11-0340 PubMedCentralPubMedCrossRefGoogle Scholar
  150. 150.
    Xu Z, Wang Y, Zhang L, Huang L (2014) Nanoparticle-delivered transforming growth factor-beta siRNA enhances vaccination against advanced melanoma by modifying tumor microenvironment. ACS Nano 8(4):3636–3645. doi: 10.1021/nn500216y PubMedCentralPubMedCrossRefGoogle Scholar
  151. 151.
    Gore J, Korc M (2014) Pancreatic cancer stroma: friend or foe? Cancer Cell 25(6):711–712. doi: 10.1016/j.ccr.2014.05.026 PubMedCrossRefGoogle Scholar
  152. 152.
    Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersall IW, Westphalen CB, Kitajewski J, Fernandez-Barrena MG, Fernandez-Zapico ME, Iacobuzio-Donahue C, Olive KP, Stanger BZ (2014) Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25(6):735–747. doi: 10.1016/j.ccr.2014.04.021 PubMedCentralPubMedCrossRefGoogle Scholar
  153. 153.
    Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 98(21):12072–12077. doi: 10.1073/pnas.211053698 PubMedCentralPubMedCrossRefGoogle Scholar
  154. 154.
    Swami A, Reagan MR, Basto P, Mishima Y, Kamaly N, Glavey S, Zhang S, Moschetta M, Seevaratnam D, Zhang Y, Liu J, Memarzadeh M, Wu J, Manier S, Shi J, Bertrand N, Lu ZN, Nagano K, Baron R, Sacco A, Roccaro AM, Farokhzad OC, Ghobrial IM (2014) Engineered nanomedicine for myeloma and bone microenvironment targeting. Proc Natl Acad Sci USA 111(28):10287–10292. doi: 10.1073/pnas.1401337111 PubMedCentralPubMedCrossRefGoogle Scholar
  155. 155.
    Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar C, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18(6):883–891. doi: 10.1038/nm.2753 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations