Skip to main content

The Tumor Microenvironment as a Barrier to Cancer Nanotherapy

  • Chapter
  • First Online:
Systems Biology of Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 936))

Abstract

Although extensive research effort and resources have been dedicated to the development of nanotherapeutics to treat cancer, few formulations have reached clinical application. A major reason is that the large number of parameters available to tune nanotherapy characteristics coupled with the variability in tumor tissue precludes evaluation of complex interactions through experimentation alone. In order to optimize the nanotechnology design and gain further insight into these phenomena, mathematical modeling and computational simulation have been applied to complement empirical work. In this chapter, we discuss modeling work related to nanotherapy and the tumor microenvironment. We first summarize the biology underlying the dysregulated tumor microenvironment, followed by a description of major nano-scale parameters. We then present an overview of the mathematical modeling of cancer nanotherapy, including evaluation of nanotherapy in multi-dimensional tumor tissue, coupling of nanotherapy with vascular flow, modeling of nanotherapy in combination with in vivo imaging, modeling of nanoparticle transport based on in vitro data, modeling of vasculature-bound nanoparticles, evaluation of nanotherapy using pharmacokinetic modeling, and modeling of nano-based hyperthermia. We conclude that an even tighter interdisciplinary effort between biological, material, and physical scientists is needed in order to eventually overcome the tumor microenvironment barrier to successful nanotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Allen JD, Brinkhuis RF, van Deemter L, Wijnholds J, Schinkel AH (2000) Extensive contribution of the multidrug transporters P-glycoprotein and Mrp1 to basal drug resistance. Cancer Res 60(20):5761–5766

    CAS  PubMed  Google Scholar 

  2. Andasari V, Gerisch A, Lolas G, South AP, Chaplain MA (2011) Mathematical modeling of cancer cell invasion of tissue: biological insight from mathematical analysis and computational simulation. J Math Biol 63(1):141–171. doi:10.1007/s00285-010-0369-1

    Article  PubMed  Google Scholar 

  3. Anderson AR, Chaplain MA (1998) Continuous and discrete mathematical models of tumor-induced angiogenesis. Bull Math Biol 60(5):857–899. doi:10.1006/bulm.1998.0042

    Article  CAS  PubMed  Google Scholar 

  4. Aschoff L, Kiyono K (1913) Zur frage der grossen Mononuclearen. Folia Haematol 15:383–390

    Google Scholar 

  5. Bachmann J, Raue A, Schilling M, Becker V, Timmer J, Klingmuller U (2012) Predictive mathematical models of cancer signalling pathways. J Intern Med 271(2):155–165. doi:10.1111/j.1365-2796.2011.02492.x

    Article  CAS  PubMed  Google Scholar 

  6. Beh CW, Seow WY, Wang Y, Zhang Y, Ong ZY, Ee PLR, Yang YY (2009) Efficient delivery of Bcl-2-targeted siRNA using cationic polymer nanoparticles: downregulating mRNA expression level and sensitizing cancer cells to anticancer drug. Biomacromolecules 10(1):41–48. doi:10.1021/Bm801109g

    Article  CAS  PubMed  Google Scholar 

  7. Byrne HM (2010) Dissecting cancer through mathematics: from the cell to the animal model. Nat Rev Cancer 10(3):221–230. doi:10.1038/Nrc2808

    Article  CAS  PubMed  Google Scholar 

  8. Cairns R, Papandreou I, Denko N (2006) Overcoming physiologic barriers to cancer treatment by molecularly targeting the tumor microenvironment. Mol Cancer Res 4(2):61–70. doi:10.1158/1541-7786.mcr-06-0002

    Article  CAS  PubMed  Google Scholar 

  9. Chaplain MAJ (2011) Multiscale mathematical modelling in biology and medicine. IMA J Appl Math 76(3):371–388. doi:10.1093/imamat/hxr025

    Article  Google Scholar 

  10. Chauhan VP, Jain RK (2013) Strategies for advancing cancer nanomedicine. Nat Mater 12(11):958–962. doi:10.1038/nmat3792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen AM, Zhang M, Wei DG, Stueber D, Taratula O, Minko T, He HX (2009) Co-delivery of doxorubicin and Bcl-2 siRNA by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug-resistant cancer cells. Small 5(23):2673–2677. doi:10.1002/smll.200900621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cheng D, Cao N, Chen JF, Yu XS, Shuai XT (2012) Multifunctional nanocarrier mediated co-delivery of doxorubicin and siRNA for synergistic enhancement of glioma apoptosis in rat. Biomaterials 33(4):1170–1179. doi:10.1016/j.biomaterials.2011.10.057

    Article  CAS  PubMed  Google Scholar 

  13. Systems CDD (1994) Drugs and the pharmaceutical sciences, 1st edn. CRC Press/Marcel-Dekker, Inc., New York/Basel/Hong Kong

    Google Scholar 

  14. Creixell M, Bohorquez AC, Torres-Lugo M, Rinaldi C (2011) EGFR-targeted magnetic nanoparticle heaters kill cancer cells without a perceptible temperature rise. ACS Nano 5(9):7124–7129. doi:10.1021/Nn201822b

    Article  CAS  PubMed  Google Scholar 

  15. Cristini V, Lowengrub J (2010) Multiscale modeling of cancer: an integrated experimental and mathematical modeling approach. Cambridge University Press, Cambridge

    Book  Google Scholar 

  16. Curti BD, Urba WJ, Alvord WG, Janik JE, Smith JW 2nd, Madara K, Longo DL (1993) Interstitial pressure of subcutaneous nodules in melanoma and lymphoma patients: changes during treatment. Cancer Res 53(10 Suppl):2204–2207

    CAS  PubMed  Google Scholar 

  17. Curtis LT, England CG, Wu M, Lowengrub J, Frieboes HB (2016) An interdisciplinary computational/experimental approach to evaluate drug-loaded gold nanoparticle tumor cytotoxicity. Nanomedicine (Lond) 11(3):197–216. doi:10.2217/nnm.15.195

    Article  CAS  Google Scholar 

  18. Curtis LT, Wu M, Lowengrub J, Decuzzi P, Frieboes HB (2015) Computational modeling of tumor response to drug release from vasculature-bound nanoparticles. PLoS One 10(12):e0144888. doi:10.1371/journal.pone.0144888, eCollection 2015

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Cuvier C, Roblot-Treupel L, Millot JM, Lizard G, Chevillard S, Manfait M, Couvreur P, Poupon MF (1992) Doxorubicin-loaded nanospheres bypass tumor cell multidrug resistance. Biochem Pharmacol 44(3):509–517. doi:10.1016/0006-2952(92)90443-M

    Article  CAS  PubMed  Google Scholar 

  20. Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5(4):275–284. doi:10.1038/nrc1590

    Article  CAS  PubMed  Google Scholar 

  21. Decuzzi P, Ferrari M (2006) The adhesive strength of non-spherical particles mediated by specific interactions. Biomaterials 27(30):5307–5314. doi:10.1016/j.biomaterials.2006.05.024

    Article  CAS  PubMed  Google Scholar 

  22. Decuzzi P, Pasqualini R, Arap W, Ferrari M (2009) Intravascular delivery of particulate systems: does geometry really matter? Pharm Res 26(1):235–243. doi:10.1007/s11095-008-9697-x

    Article  CAS  PubMed  Google Scholar 

  23. Deisboeck TS, Wang Z, Macklin P, Cristini V (2011) Multiscale cancer modeling. Annu Rev Biomed Eng 13:127–155. doi:10.1146/annurev-bioeng-071910-124729

    Article  CAS  PubMed  Google Scholar 

  24. Edelman LB, Eddy JA, Price ND (2010) In silico models of cancer. Wiley Interdiscip Rev Syst Biol Med 2(4):438–459. doi:10.1002/Wsbm.75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. England CG, Miller MC, Kuttan A, Trent JO, Frieboes HB (2015) Release kinetics of paclitaxel and cisplatin from two and three layered gold nanoparticles. Eur J Pharm Biopharm 92:120–129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Frieboes HB, Chaplain MA, Thompson AM, Bearer EL, Lowengrub JS, Cristini V (2011) Physical oncology: a bench-to-bedside quantitative and predictive approach. Cancer Res 71(2):298–302. doi:10.1158/0008-5472.CAN-10-2676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Frieboes HB, Sinek JP, Nalcioglu O, Fruehauf JP, Cristini V (2006) Nanotechnology in cancer drug therapy: a biocomputational approach. In: Lee AP, Lee LJ, Ferrari M (eds) BioMEMS and biomedical nanotechnology. Springer, New York, pp 435–460. doi:10.1007/978-0-387-25842-3_15

    Chapter  Google Scholar 

  28. Frieboes HB, Wu M, Lowengrub J, Decuzzi P, Cristini V (2013) A computational model for predicting nanoparticle accumulation in tumor vasculature. PLoS One 8(2):e56876. doi:10.1371/journal.pone.0056876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fung YC (1997) Biomechanics: Circulation. Springer, University of California, San Diego

    Google Scholar 

  30. Gao Y, Li M, Chen B, Shen Z, Guo P, Wientjes MG, Au JL (2013) Predictive models of diffusive nanoparticle transport in 3-dimensional tumor cell spheroids. AAPS J 15(3):816–831. doi:10.1208/s12248-013-9478-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Godin B, Driessen WH, Proneth B, Lee SY, Srinivasan S, Rumbaut R, Arap W, Pasqualini R, Ferrari M, Decuzzi P (2010) An integrated approach for the rational design of nanovectors for biomedical imaging and therapy. Adv Genet 69:31–64. doi:10.1016/S0065-2660(10)69009-8

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Gradishar WJ (2006) Albumin-bound paclitaxel: a next-generation taxane. Expert Opin Pharmacother 7(8):1041–1053. doi:10.1517/14656566.7.8.1041

    Article  CAS  PubMed  Google Scholar 

  33. Grant CE, Valdimarsson G, Hipfner DR, Almquist KC, Cole SPC, Deeley RG (1994) Overexpression of multidrug resistance-associated protein (Mrp) increases resistance to natural product drugs. Cancer Res 54(2):357–361

    CAS  PubMed  Google Scholar 

  34. Greenspan HP (1972) Models for the growth of a solid tumor by diffusion. Stud Appl Math 51:317–340

    Article  Google Scholar 

  35. Greenspan HP (1976) On the growth and stability of cell cultures and solid tumors. J Theor Biol 56:229–242

    Article  CAS  PubMed  Google Scholar 

  36. Greish K (2007) Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J Drug Target 15(7-8):457–464. doi:10.1080/10611860701539584

    Article  CAS  PubMed  Google Scholar 

  37. Heldin CH, Rubin K, Pietras K, Ostman A (2004) High interstitial fluid pressure – an obstacle in cancer therapy. Nat Rev Cancer 4(10):806–813. doi:10.1038/nrc1456

    Article  CAS  PubMed  Google Scholar 

  38. Hirst DG, Denekamp J (1979) Tumour cell proliferation in relation to the vasculature. Cell Tissue Kinet 12(1):31–42

    CAS  PubMed  Google Scholar 

  39. Hong MH, Zhu SJ, Jiang YY, Tang GT, Pei YY (2009) Efficient tumor targeting of hydroxycamptothecin loaded PEGylated niosomes modified with transferrin. J Control Release 133(2):96–102. doi:10.1016/j.jconrel.2008.09.005

    Article  CAS  PubMed  Google Scholar 

  40. Huang K, Ma H, Liu J, Huo S, Kumar A, Wei T, Zhang X, Jin S, Gan Y, Wang PC, He S, Zhang X, Liang XJ (2012) Size-dependent localization and penetration of ultrasmall gold nanoparticles in cancer cells, multicellular spheroids, and tumors in vivo. ACS Nano 6(5):4483–4493. doi:10.1021/nn301282m

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Izuishi K, Kato K, Ogura T, Kinoshita T, Esumi H (2000) Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy. Cancer Res 60(21):6201–6207

    CAS  PubMed  Google Scholar 

  42. Jain RK (2013) Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol 31(17):2205–2218. doi:10.1200/JCO.2012.46.3653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kaddi CD, Phan JH, Wang MD (2013) Computational nanomedicine: modeling of nanoparticle-mediated hyperthermal cancer therapy. Nanomedicine (Lond) 8(8):1323–1333. doi:10.2217/nnm.13.117

    Article  CAS  Google Scholar 

  44. Kao HW, Lin YY, Chen CC, Chi KH, Tien DC, Hsia CC, Lin MH, Wang HE (2013) Evaluation of EGFR-targeted radioimmuno-gold-nanoparticles as a theranostic agent in a tumor animal model. Bioorg Med Chem Lett 23(11):3180–3185. doi:10.1016/j.bmcl.2013.04.002

    Article  CAS  PubMed  Google Scholar 

  45. Konno T, Maeda H, Iwai K, Tashiro S, Maki S, Morinaga T, Mochinaga M, Hiraoka T, Yokoyama I (1983) Effect of arterial administration of high-molecular-weight anti-cancer agent SMANCS with lipid lymphographic agent on hepatoma – a preliminary-report. Eur J Cancer Clin Oncol 19(8):1053–1065. doi:10.1016/0277-5379(83)90028-7

    Article  CAS  PubMed  Google Scholar 

  46. Krasnici S, Werner A, Eichhorn ME, Schmitt-Sody M, Pahernik SA, Sauer B, Schulze B, Teifel M, Michaelis U, Naujoks K, Dellian M (2003) Effect of the surface charge of liposomes on their uptake by angiogenic tumor vessels. Int J Cancer 105(4):561–567. doi:10.1002/Ijc.11108

    Article  CAS  PubMed  Google Scholar 

  47. Kreeger PK, Lauffenburger DA (2010) Cancer systems biology: a network modeling perspective. Carcinogenesis 31(1):2–8. doi:10.1093/carcin/bgp261

    Article  CAS  PubMed  Google Scholar 

  48. Lankelma J, Dekker H, Luque FR, Luykx S, Hoekman K, van der Valk P, van Diest PJ, Pinedo HM (1999) Doxorubicin gradients in human breast cancer. Clin Cancer Res 5(7):1703–1707

    CAS  PubMed  Google Scholar 

  49. Li M, Al-Jamal KT, Kostarelos K, Reineke J (2010) Physiologically based pharmacokinetic modeling of nanoparticles. ACS Nano 4(11):6303–6317. doi:10.1021/nn1018818

    Article  CAS  PubMed  Google Scholar 

  50. Li M, Czyszczon EA, Reineke JJ (2013) Delineating intracellular pharmacokinetics of paclitaxel delivered by PLGA nanoparticles. Drug Deliv Transl Res 3(6):551–561. doi:10.1007/s13346-013-0162-y

    Article  CAS  PubMed  Google Scholar 

  51. Li M, Panagi Z, Avgoustakis K, Reineke J (2012) Physiologically based pharmacokinetic modeling of PLGA nanoparticles with varied mPEG content. Int J Nanomedicine 7:1345–1356

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Li M, Reineke J (2011) Mathematical modelling of nanoparticle biodistribution: extrapolation among intravenous, oral and pulmonary administration routes. Int J Nano Biomater 3(3):222–238

    Article  CAS  Google Scholar 

  53. Lieleg O, Baumgartel RM, Bausch AR (2009) Selective filtering of particles by the extracellular matrix: an electrostatic bandpass. Biophys J 97(6):1569–1577. doi:10.1016/j.bpj.2009.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Litzinger DC, Buiting AMJ, Vanrooijen N, Huang L (1994) Effect of liposome size on the circulation time and intraorgan distribution of amphipathic poly(ethylene glycol)-containing liposomes. Biochim Et Biophys Acta-Biomembranes 1190(1):99–107. doi:10.1016/0005-2736(94)90038-8

    Article  CAS  Google Scholar 

  55. Liu Q, Zhang J, Sun W, Xie QR, Xia W, Gu H (2012) Delivering hydrophilic and hydrophobic chemotherapeutics simultaneously by magnetic mesoporous silica nanoparticles to inhibit cancer cells. Int J Nanomedicine 7:999–1013. doi:10.2147/ijn.s28088

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Lowengrub JS, Frieboes HB, Jin F, Chuang YL, Li X, Macklin P, Wise SM, Cristini V (2010) Nonlinear modelling of cancer: bridging the gap between cells and tumours. Nonlinearity 23(1):R1–R9

    Article  PubMed  PubMed Central  Google Scholar 

  57. Ma P, Mumper RJ (2013) Paclitaxel nano-delivery systems: a comprehensive review. J Nanomed Nanotechnol 4(2):1000164. doi:10.4172/2157-7439.1000164

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Ma R, Taruttis A, Ntziachristos V, Razansky D (2009) Multispectral optoacoustic tomography (MSOT) scanner for whole-body small animal imaging. Opt Express 17(24):21414–21426

    Article  CAS  PubMed  Google Scholar 

  59. Macklin P, Lowengrub J (2007) Nonlinear simulation of the effect of microenvironment on tumor growth. J Theor Biol 245(4):677–704. doi:10.1016/j.jtbi.2006.12.004

    Article  CAS  PubMed  Google Scholar 

  60. Macklin P, McDougall S, Anderson AR, Chaplain MA, Cristini V, Lowengrub J (2009) Multiscale modelling and nonlinear simulation of vascular tumour growth. J Math Biol 58(4–5):765–798. doi:10.1007/s00285-008-0216-9

    Article  PubMed  Google Scholar 

  61. Maeda H, Ueda M, Morinaga T, Matsumoto T (1985) Conjugation of poly(styrene-co-maleic acid) derivatives to the antitumor protein neocarzinostatin - pronounced improvements in pharmacological properties. J Med Chem 28(4):455–461. doi:10.1021/Jm00382a012

    Article  CAS  PubMed  Google Scholar 

  62. Mahoney BP, Raghunand N, Baggett B, Gillies RJ (2003) Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro. Biochem Pharmacol 66(7):1207–1218

    Article  CAS  PubMed  Google Scholar 

  63. Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer-chemotherapy - mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46(12):6387–6392

    CAS  PubMed  Google Scholar 

  64. McDougall SR, Anderson AR, Chaplain MA (2006) Mathematical modelling of dynamic adaptive tumour-induced angiogenesis: clinical implications and therapeutic targeting strategies. J Theor Biol 241(3):564–589. doi:10.1016/j.jtbi.2005.12.022

    Article  PubMed  Google Scholar 

  65. McDougall SR, Anderson AR, Chaplain MA, Sherratt JA (2002) Mathematical modelling of flow through vascular networks: implications for tumour-induced angiogenesis and chemotherapy strategies. Bull Math Biol 64(4):673–702. doi:10.1006/bulm.2002.0293

    Article  CAS  PubMed  Google Scholar 

  66. Merisko-Liversidge EM, Liversidge GG (2008) Drug nanoparticles: formulating poorly water-soluble compounds. Toxicol Pathol 36(1):43–48. doi:10.1177/0192623307310946

    Article  CAS  PubMed  Google Scholar 

  67. Michor F, Liphardt J, Ferrari M, Widom J (2011) What does physics have to do with cancer? Nat Rev Cancer 11(9):657–670. doi:10.1038/Nrc3092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Milane L, Duan ZF, Amiji M (2011) Pharmacokinetics and biodistribution of lonidamine/paclitaxel loaded, EGFR-targeted nanoparticles in an orthotopic animal model of multi-drug resistant breast cancer. Nanomedicine 7(4):435–444. doi:10.1016/j.nano.2010.12.009

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6(8):583–592. doi:10.1038/nrc1893

    Article  CAS  PubMed  Google Scholar 

  70. Moulder JE, Rockwell S (1987) Tumor hypoxia: its impact on cancer therapy. Cancer Metastasis Rev 5(4):313–341

    Article  CAS  PubMed  Google Scholar 

  71. Ntziachristos V, Razansky D (2010) Molecular imaging by means of multispectral optoacoustic tomography (MSOT). Chem Rev 110(5):2783–2794. doi:10.1021/cr9002566

    Article  CAS  PubMed  Google Scholar 

  72. Osborne JM, Walter A, Kershaw SK, Mirams GR, Fletcher AG, Pathmanathan P, Gavaghan D, Jensen OE, Maini PK, Byrne HM (2010) A hybrid approach to multi-scale modelling of cancer. Philos Trans R Soc A-Math Phys Eng Sci 368(1930):5013–5028. doi:10.1098/rsta.2010.0173

    Article  CAS  Google Scholar 

  73. Palladini A, Nicoletti G, Pappalardo F, Murgo A, Grosso V, Stivani V, Ianzano ML, Antognoli A, Croci S, Landuzzi L, De Giovanni C, Nanni P, Motta S, Lollini PL (2010) In silico modeling and in vivo efficacy of cancer-preventive vaccinations. Cancer Res 70(20):7755–7763. doi:10.1158/0008-5472.Can-10-0701

    Article  CAS  PubMed  Google Scholar 

  74. Patel AR, Chougule MB, Lim E, Francis KP, Safe S, Sachdeva M (2013) Theranostic tumor homing nanocarriers for the treatment of lung cancer. Nanomedicine. doi:10.1016/j.nano.2013.12.002

    PubMed Central  Google Scholar 

  75. Patel NR, Pattni BS, Abouzeid AH, Torchilin VP (2013) Nanopreparations to overcome multidrug resistance in cancer. Adv Drug Deliv Rev 65(13–14):1748–1762. doi:10.1016/j.addr.2013.08.004

    Article  CAS  PubMed  Google Scholar 

  76. Peng XH, Wang YQ, Huang DH, Wang YX, Shin HJ, Chen ZJ, Spewak MB, Mao H, Wang X, Wang Y, Chen Z, Nie SM, Shin DM (2011) Targeted delivery of cisplatin to lung cancer using ScFvEGFR-heparin-cisplatin nanoparticles. ACS Nano 5(12):9480–9493. doi:10.1021/Nn202410f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Persidis A (1999) Cancer multidrug resistance. Nat Biotechnol 17(1):94–95. doi:10.1038/5289

    Article  CAS  PubMed  Google Scholar 

  78. Primeau AJ, Rendon A, Hedley D, Lilge L, Tannock IF (2005) The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumors. Clin Cancer Res 11(24 Pt 1):8782–8788. doi:10.1158/1078-0432.CCR-05-1664

    Article  CAS  PubMed  Google Scholar 

  79. Rangger C, Helbok A, Sosabowski J, Kremser C, Koehler G, Prassl R, Andreae F, Virgolini IJ, von Guggenberg E, Decristoforo C (2013) Tumor targeting and imaging with dual-peptide conjugated multifunctional liposomal nanoparticles. Int J Nanomedicine 8:4659–4670. doi:10.2147/Ijn.S51927

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Rejniak KA, Anderson ARA (2011) Hybrid models of tumor growth. Wiley Interdisciplinary Reviews-Systems Biology and Medicine 3(1):115–125. doi:10.1002/Wsbm.102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rejniak KA, McCawley LJ (2010) Current trends in mathematical modeling of tumor-microenvironment interactions: a survey of tools and applications. Exp Biol Med 235(4):411–423. doi:10.1258/ebm.2009.009230

    Article  CAS  Google Scholar 

  82. Saad M, Garbuzenko OB, Minko T (2008) Co-delivery of siRNA and an anticancer drug for treatment of multidrug-resistant cancer. Nanomedicine (Lond) 3(6):761–776. doi:10.2217/17435889.3.6.761

    Article  CAS  Google Scholar 

  83. Siepmann J, Göpferich A (2001) Mathematical modeling of bioerodible, polymeric drug delivery systems. Adv Drug Deliv Rev 48:229–247

    Article  CAS  PubMed  Google Scholar 

  84. Sinek J, Frieboes H, Zheng X, Cristini V (2004) Two-dimensional chemotherapy simulations demonstrate fundamental transport and tumor response limitations involving nanoparticles. Biomed Microdevices 6(4):297–309. doi:10.1023/B:BMMD.0000048562.29657.64

    Article  CAS  PubMed  Google Scholar 

  85. Sinek JP, Sanga S, Zheng X, Frieboes HB, Ferrari M, Cristini V (2009) Predicting drug pharmacokinetics and effect in vascularized tumors using computer simulation. J Math Biol 58(4–5):485–510. doi:10.1007/s00285-008-0214-y

    Article  PubMed  Google Scholar 

  86. Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE (2001) Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release 70(1–2):1–20

    Article  CAS  PubMed  Google Scholar 

  87. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sumner DD, Stevens JT (1994) Pharmacokinetic factors influencing risk assessment: saturation of biochemical processes and cofactor depletion. Environ Health Perspect 102(Suppl 11):13–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Swanson KR, Rockne RC, Claridge J, Chaplain MA, Alvord EC, Anderson ARA (2011) Quantifying the role of angiogenesis in malignant progression of gliomas: in silico modeling integrates imaging and histology. Cancer Res 71(24):7366–7375. doi:10.1158/0008-5472.Can-11-1399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Szala S, Jarosz M (2011) Tumor blood vessels. Postepy Hig Med Dosw (Online) 65:437–446

    Article  Google Scholar 

  91. Taratula O, Garbuzenko OB, Chen AM, Minko T (2011) Innovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNA. J Drug Target 19(10):900–914. doi:10.3109/1061186x.2011.622404

    Article  CAS  PubMed  Google Scholar 

  92. Taruttis A, Herzog E, Razansky D, Ntziachristos V (2010) Real-time imaging of cardiovascular dynamics and circulating gold nanorods with multispectral optoacoustic tomography. Opt Express 18(19):19592–19602. doi:10.1364/oe.18.019592

    Article  CAS  PubMed  Google Scholar 

  93. Thurston G, McLean JW, Rizen M, Baluk P, Haskell A, Murphy TJ, Hanahan D, McDonald DM (1998) Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice. J Clin Invest 101(7):1401–1413. doi:10.1172/Jci965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Truskey G, Yuan F, Katz D (2004) Transport phenomena in biological systems. Pearson Prentice Hall, Upper Saddle River

    Google Scholar 

  95. Unezaki S, Maruyama K, Hosoda J, Nagae I, Koyanagi Y, Nakata M, Ishida O, Iwatsuru M, Tsuchiya S (1996) Direct measurement of the extravasation of polyethyleneglycol-coated liposomes into solid tumor tissue by in vivo fluorescence microscopy. Int J Pharm 144(1):11–17. doi:10.1016/S0378-5173(96)04674-1

    Article  CAS  Google Scholar 

  96. van de Ven AL, Abdollahi B, Martinez CJ, Burey LA, Landis MD, Chang JC, Ferrari M, Frieboes HB (2013) Modeling of nanotherapeutics delivery based on tumor perfusion. New J Phys 15:55004. doi:10.1088/1367-2630/15/5/055004

    Article  PubMed  CAS  Google Scholar 

  97. van de Ven AL, Wu M, Lowengrub J, McDougall SR, Chaplain MA, Cristini V, Ferrari M, Frieboes HB (2012) Integrated intravital microscopy and mathematical modeling to optimize nanotherapeutics delivery to tumors. AIP Adv 2(1):11208. doi:10.1063/1.3699060

    Article  PubMed  CAS  Google Scholar 

  98. Vandenberg AP, Wikehooley JL, Vandenbergblok AE, Vanderzee J, Reinhold HS (1982) Tumor pH in human mammary-carcinoma. Eur J Cancer Clin Oncol 18(5):457–462. doi:10.1016/0277-5379(82)90114-6

    Article  CAS  Google Scholar 

  99. Vineis P, Schatzkin A, Potter JD (2010) Models of carcinogenesis: an overview. Carcinogenesis 31(10):1703–1709. doi:10.1093/carcin/bgq087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Waite CL, Roth CM (2012) Nanoscale drug delivery systems for enhanced drug penetration into solid tumors: current progress and opportunities. Crit Rev Biomed Eng 40(1):21–41

    Article  PubMed  PubMed Central  Google Scholar 

  101. Wang Z, Butner JD, Cristini V, Deisboeck TS (2015) Integrated PK-PD and agent-based modeling in oncology. J Pharmacokinet Pharmacodyn 42(2):179–189. doi:10.1007/s10928-015-9403-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wang Z, Deisboeck TS (2014) Mathematical modeling in cancer drug discovery. Drug Discov Today 19(2):145–150. doi:10.1016/j.drudis.2013.06.015

    Article  PubMed  Google Scholar 

  103. Wu M, Frieboes HB, Chaplain MA, McDougall SR, Cristini V, Lowengrub J (2014) The effect of interstitial pressure on therapeutic agent transport: coupling with the tumor blood and lymphatic vascular systems. J Theor Biol 355:194–207. doi:10.1016/j.jtbi.2014.04.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhang Z, Feng SS (2006) Nanoparticles of poly(lactide)/vitamin E TPGS copolymer for cancer chemotherapy: synthesis, formulation, characterization and in vitro drug release. Biomaterials 27(2):262–270. doi:10.1016/j.biomaterials.2005.05.104

    Article  PubMed  CAS  Google Scholar 

  105. Zheng X, Wise SM, Cristini V (2005) Nonlinear simulation of tumor necrosis, neo-vascularization and tissue invasion via an adaptive finite-element/level-set method. Bull Math Biol 67(2):211–259. doi:10.1016/j.bulm.2004.08.001

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hermann B. Frieboes .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Curtis, L.T., Frieboes, H.B. (2016). The Tumor Microenvironment as a Barrier to Cancer Nanotherapy. In: Rejniak, K. (eds) Systems Biology of Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 936. Springer, Cham. https://doi.org/10.1007/978-3-319-42023-3_9

Download citation

Publish with us

Policies and ethics