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Tumor heterogeneity and nanoparticle-mediated tumor targeting: the importance of delivery system personalization

Drug Delivery and Translational Research volume 8, pages 1508–1526 (2018)Cite this article

Abstract

After the discovery of the enhanced permeability and retention effect in 1986, it was envisioned that nanoparticle-mediated tumor-targeted delivery of chemotherapeutics would make a radical change in cancer therapy. However, after three decades of extensive research, only a few nanotherapeutics have been approved for clinical use. Although significant advantages of nanomedicines have been demonstrated in pre-clinical studies, clinical outcome was found to be variable. Advanced research has revealed that significant biochemical and structural variations exist between (and among) different tumors. These variations can considerably affect the tumor delivery and efficacy of nanomedicines. Tumor penetration is an important determining factor for positive therapeutic outcome and same nanomedicine can show diverse efficacy against different tumors depending on the extent of tumor accumulation and penetration. Recent research has started shading light on how the tumor variations can influence nanoparticle tumor delivery. These findings indicate that there is no “ideal” design of nanoparticles for exhibiting equally high efficacy against a broad spectrum of tumors. For achieving maximum benefit of the nanotherapeutics, it is necessary to analyze the tumor microenvironment for understanding the biological and structural characteristics of the tumor. Designing of the nanomedicine should be done according to the tumor characteristics. In this comprehensive review, we have first given a brief overview of the design characteristics of nanomedicine which impact their tumor delivery. Then we discussed about the variability in the tumor architecture and how it influences nanomedicine delivery. Finally, we have discussed the possibility of delivery system personalization based on the tumor characteristics.

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References

  1. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46(12 Pt 1):6387–92.

    PubMed  CAS  Google Scholar 

  2. Singh R, Lillard JW Jr. Nanoparticle-based targeted drug delivery. Exp Mol Pathol. 2009;86(3):215–23. https://doi.org/10.1016/j.yexmp.2008.12.004.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  3. Greish K. Enhanced permeability and retention (EPR) effect for anticancer nanomedicine drug targeting. Methods Mol Biol. 2010;624:25–37. https://doi.org/10.1007/978-1-60761-609-2_3.

    PubMed  CAS  Article  Google Scholar 

  4. Fidler IJ. Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res. 1978;38(9):2651–60.

    PubMed  CAS  Google Scholar 

  5. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. https://doi.org/10.1038/nature11412.

    CAS  Article  Google Scholar 

  6. Li Y, Wang J, Wientjes MG, Au JL. Delivery of nanomedicines to extracellular and intracellular compartments of a solid tumor. Adv Drug Deliv Rev. 2012;64(1):29–39. https://doi.org/10.1016/j.addr.2011.04.006.

    PubMed  CAS  Article  Google Scholar 

  7. Nichols JW, Bae YH. EPR: evidence and fallacy. J Control Release. 2014;190:451–64. https://doi.org/10.1016/j.jconrel.2014.03.057.

    PubMed  CAS  Article  Google Scholar 

  8. McNeil SE, (2009) Nanoparticle therapeutics: a personal perspective. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 1 (3):264–271

  9. Petros RA, DeSimone JM. Strategies in the design of nanoparticles for therapeutic applications. Nat Rev Drug Discov. 2010;9(8):615–27. https://doi.org/10.1038/nrd2591.

    PubMed  CAS  Article  Google Scholar 

  10. Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev. 2001;53(2):283–318.

    PubMed  CAS  Google Scholar 

  11. Roy A, Ernsting MJ, Undzys E, Li SD. A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors. Biomaterials. 2015;52:335–46. https://doi.org/10.1016/j.biomaterials.2015.02.041.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  12. Yang Y, Roy A, Zhao Y, Undzys E, Li SD. Comparison of tumor penetration of podophyllotoxin-carboxymethylcellulose conjugates with various chemical compositions in tumor spheroid culture and in vivo solid tumor. Bioconjug Chem. 2017;28(5):1505–18. https://doi.org/10.1021/acs.bioconjchem.7b00165.

    PubMed  CAS  Article  Google Scholar 

  13. Ernsting MJ, Murakami M, Roy A, Li SD. Factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles. J Control Release. 2013;172(3):782–94. https://doi.org/10.1016/j.jconrel.2013.09.013.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  14. Rejman J, Oberle V, Zuhorn IS, Hoekstra D. Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J. 2004;377(Pt 1):159–69. https://doi.org/10.1042/BJ20031253.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  15. Tammam SN, Azzazy HME, Lamprecht A. The effect of nanoparticle size and NLS density on nuclear targeting in cancer and normal cells; impaired nuclear import and aberrant nanoparticle intracellular trafficking in glioma. J Control Release. 2017;253:30–6. https://doi.org/10.1016/j.jconrel.2017.02.029.

    PubMed  CAS  Article  Google Scholar 

  16. Tammam SN, Azzazy HM, Breitinger HG, Lamprecht A. Chitosan nanoparticles for nuclear targeting: the effect of nanoparticle size and nuclear localization sequence density. Mol Pharm. 2015;12(12):4277–89. https://doi.org/10.1021/acs.molpharmaceut.5b00478.

    PubMed  CAS  Article  Google Scholar 

  17. Champion JA, Mitragotri S. Shape induced inhibition of phagocytosis of polymer particles. Pharm Res. 2009;26(1):244–9. https://doi.org/10.1007/s11095-008-9626-z.

    PubMed  CAS  Article  Google Scholar 

  18. Champion JA, Mitragotri S. Role of target geometry in phagocytosis. Proc Natl Acad Sci U S A. 2006;103(13):4930–4. https://doi.org/10.1073/pnas.0600997103.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  19. Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015;33(9):941–51. https://doi.org/10.1038/nbt.3330.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  20. Xie X, Liao J, Shao X, Li Q, Lin Y. The effect of shape on cellular uptake of gold nanoparticles in the forms of stars, rods, and triangles. Sci Rep. 2017;7(1):3827. https://doi.org/10.1038/s41598-017-04229-z.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  21. Levchenko TS, Rammohan R, Lukyanov AN, Whiteman KR, Torchilin VP. Liposome clearance in mice: the effect of a separate and combined presence of surface charge and polymer coating. Int J Pharm. 2002;240(1–2):95–102.

    PubMed  CAS  Article  Google Scholar 

  22. Xiao K, Li Y, Luo J, Lee JS, Xiao W, Gonik AM, et al. The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials. 2011;32(13):3435–46. https://doi.org/10.1016/j.biomaterials.2011.01.021.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  23. Stylianopoulos T, Poh MZ, Insin N, Bawendi MG, Fukumura D, Munn LL, et al. Diffusion of particles in the extracellular matrix: the effect of repulsive electrostatic interactions. Biophys J. 2010;99(5):1342–9. https://doi.org/10.1016/j.bpj.2010.06.016.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  24. Lieleg O, Baumgartel RM, Bausch AR. Selective filtering of particles by the extracellular matrix: an electrostatic bandpass. Biophys J. 2009;97(6):1569–77. https://doi.org/10.1016/j.bpj.2009.07.009.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  25. Bannunah AM, Vllasaliu D, Lord J, Stolnik S. Mechanisms of nanoparticle internalization and transport across an intestinal epithelial cell model: effect of size and surface charge. Mol Pharm. 2014;11(12):4363–73. https://doi.org/10.1021/mp500439c.

    PubMed  CAS  Article  Google Scholar 

  26. Rao L, Meng QF, Bu LL, Cai B, Huang Q, Sun ZJ, et al. Erythrocyte membrane-coated upconversion nanoparticles with minimal protein adsorption for enhanced tumor imaging. ACS Appl Mater Interfaces. 2017;9(3):2159–68. https://doi.org/10.1021/acsami.6b14450.

    PubMed  CAS  Article  Google Scholar 

  27. Hu CM, Zhang L, Aryal S, Cheung C, Fang RH, Zhang L. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc Natl Acad Sci U S A. 2011;108(27):10980–5. https://doi.org/10.1073/pnas.1106634108.

    PubMed  PubMed Central  Article  Google Scholar 

  28. Yokoe J, Sakuragi S, Yamamoto K, Teragaki T, Ogawara K, Higaki K, et al. Albumin-conjugated PEG liposome enhances tumor distribution of liposomal doxorubicin in rats. Int J Pharm. 2008;353(1–2):28–34. https://doi.org/10.1016/j.ijpharm.2007.11.008.

    PubMed  CAS  Article  Google Scholar 

  29. Wilhelm S, Tavares AJ, Dai Q, Ohta S, Audet J, Dvorak HF, et al. Analysis of nanoparticle delivery to tumours. Nature Reviews Materials. 2016;1:16014. https://doi.org/10.1038/natrevmats.2016.14. https://www.nature.com/articles/natrevmats201614#supplementary-information

    CAS  Article  Google Scholar 

  30. Walkey CD, Olsen JB, Guo H, Emili A, Chan WC. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J Am Chem Soc. 2012;134(4):2139–47. https://doi.org/10.1021/ja2084338.

    PubMed  CAS  Article  Google Scholar 

  31. Dos Santos N, Allen C, Doppen AM, Anantha M, Cox KA, Gallagher RC, et al. Influence of poly (ethylene glycol) grafting density and polymer length on liposomes: relating plasma circulation lifetimes to protein binding. Biochim Biophys Acta. 2007;1768(6):1367–77. https://doi.org/10.1016/j.bbamem.2006.12.013.

    PubMed  CAS  Article  Google Scholar 

  32. Sengupta S. Cancer nanomedicine: lessons for immuno-oncology. Trends in cancer. 2017;3(8):551–60. https://doi.org/10.1016/j.trecan.2017.06.006.

    PubMed  Article  Google Scholar 

  33. Li SD, Huang L. Stealth nanoparticles: high density but sheddable PEG is a key for tumor targeting. J Control Release. 2010;145(3):178–81. https://doi.org/10.1016/j.jconrel.2010.03.016.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  34. Tagami T, Nakamura K, Shimizu T, Yamazaki N, Ishida T, Kiwada H. CpG motifs in pDNA-sequences increase anti-PEG IgM production induced by PEG-coated pDNA-lipoplexes. J Control Release. 2010;142(2):160–6. https://doi.org/10.1016/j.jconrel.2009.10.017.

    PubMed  CAS  Article  Google Scholar 

  35. Hak S, Helgesen E, Hektoen HH, Huuse EM, Jarzyna PA, Mulder WJ, et al. The effect of nanoparticle polyethylene glycol surface density on ligand-directed tumor targeting studied in vivo by dual modality imaging. ACS Nano. 2012;6(6):5648–58. https://doi.org/10.1021/nn301630n.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  36. Zhu X, Tao W, Liu D, Wu J, Guo Z, Ji X, et al. Surface de-PEGylation controls nanoparticle-mediated siRNA delivery in vitro and in vivo. Theranostics. 2017;7(7):1990–2002. https://doi.org/10.7150/thno.18136.

    PubMed  PubMed Central  Article  Google Scholar 

  37. Kim HK, Van den Bossche J, Hyun SH, Thompson DH. Acid-triggered release via dePEGylation of fusogenic liposomes mediated by heterobifunctional phenyl-substituted vinyl ethers with tunable pH-sensitivity. Bioconjug Chem. 2012;23(10):2071–7. https://doi.org/10.1021/bc300266y.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  38. Xu H, Deng Y, Chen D, Hong W, Lu Y, Dong X. Esterase-catalyzed dePEGylation of pH-sensitive vesicles modified with cleavable PEG-lipid derivatives. J Control Release. 2008;130(3):238–45. https://doi.org/10.1016/j.jconrel.2008.05.009.

    PubMed  CAS  Article  Google Scholar 

  39. LoPresti C, Massignani M, Fernyhough C, Blanazs A, Ryan AJ, Madsen J, et al. Controlling polymersome surface topology at the nanoscale by membrane confined polymer/polymer phase separation. ACS Nano. 2011;5(3):1775–84. https://doi.org/10.1021/nn102455z.

    PubMed  CAS  Article  Google Scholar 

  40. Niu Y, Yu M, Hartono SB, Yang J, Xu H, Zhang H, et al. Nanoparticles mimicking viral surface topography for enhanced cellular delivery. Adv Mater. 2013;25(43):6233–7. https://doi.org/10.1002/adma.201302737.

    PubMed  CAS  Article  Google Scholar 

  41. Wurster EC, Liebl R, Michaelis S, Robelek R, Wastl DS, Giessibl FJ, et al. Oligolayer-coated nanoparticles: impact of surface topography at the nanobio interface. ACS Appl Mater Interfaces. 2015;7(15):7891–900. https://doi.org/10.1021/am508435j.

    PubMed  CAS  Article  Google Scholar 

  42. Bazak R, Houri M, El Achy S, Kamel S, Refaat T. Cancer active targeting by nanoparticles: a comprehensive review of literature. J Cancer Res Clin Oncol. 2015;141(5):769–84. https://doi.org/10.1007/s00432-014-1767-3.

    PubMed  CAS  Article  Google Scholar 

  43. Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol. 2006;3(5):269–80. https://doi.org/10.1038/ncponc0509.

    PubMed  CAS  Article  Google Scholar 

  44. Harding J, Burtness B. Cetuximab: an epidermal growth factor receptor chemeric human-murine monoclonal antibody. Drugs Today. 2005;41(2):107–27. https://doi.org/10.1358/dot.2005.41.2.882662.

    PubMed  CAS  Article  Google Scholar 

  45. Hogemann-Savellano D, Bos E, Blondet C, Sato F, Abe T, Josephson L, et al. The transferrin receptor: a potential molecular imaging marker for human cancer. Neoplasia. 2003;5(6):495–506.

    PubMed  PubMed Central  Article  Google Scholar 

  46. Schmidt LH, Heitkotter B, Schulze AB, Schliemann C, Steinestel K, Trautmann M, et al. Prostate specific membrane antigen (PSMA) expression in non-small cell lung cancer. PLoS One. 2017;12(10):e0186280. https://doi.org/10.1371/journal.pone.0186280.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  47. Cirstoiu-Hapca A, Bossy-Nobs L, Buchegger F, Gurny R, Delie F. Differential tumor cell targeting of anti-HER2 (Herceptin) and anti-CD20 (Mabthera) coupled nanoparticles. Int J Pharm. 2007;331(2):190–6. https://doi.org/10.1016/j.ijpharm.2006.12.002.

    PubMed  CAS  Article  Google Scholar 

  48. Ni X, Castanares M, Mukherjee A, Lupold SE. Nucleic acid aptamers: clinical applications and promising new horizons. Curr Med Chem. 2011;18(27):4206–14.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  49. Farokhzad OC, Cheng J, Teply BA, Sherifi I, Jon S, Kantoff PW, et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci U S A. 2006;103(16):6315–20. https://doi.org/10.1073/pnas.0601755103.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  50. Parashar A. Aptamers in therapeutics. J Clin Diagn Res. 2016;10(6):BE01–6. https://doi.org/10.7860/JCDR/2016/18712.7922.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  51. Sahoo SK, Ma W, Labhasetwar V. Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. Int J Cancer. 2004;112(2):335–40. https://doi.org/10.1002/ijc.20405.

    PubMed  CAS  Article  Google Scholar 

  52. Zhang J, Wang L, Fai Chan H, Xie W, Chen S, He C, et al. Co-delivery of paclitaxel and tetrandrine via iRGD peptide conjugated lipid-polymer hybrid nanoparticles overcome multidrug resistance in cancer cells. Sci Rep. 2017;7:46057. https://doi.org/10.1038/srep46057.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  53. Hilgenbrink AR, Low PS. Folate receptor-mediated drug targeting: from therapeutics to diagnostics. J Pharm Sci. 2005;94(10):2135–46. https://doi.org/10.1002/jps.20457.

    PubMed  CAS  Article  Google Scholar 

  54. Better nanoparticle targeting with P-selectin. Cancer Discov. 2016;6(9):936. https://doi.org/10.1158/2159-8290.CD-NB2016-093.

  55. Mizrachi A, Shamay Y, Shah J, Brook S, Soong J, Rajasekhar VK, et al. Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma. Nat Commun. 2017;8:14292. https://doi.org/10.1038/ncomms14292.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  56. Doolittle E, Peiris PM, Doron G, Goldberg A, Tucci S, Rao S, et al. Spatiotemporal targeting of a dual-ligand nanoparticle to cancer metastasis. ACS Nano. 2015;9(8):8012–21. https://doi.org/10.1021/acsnano.5b01552.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  57. Cheng H, Zhu JY, Xu XD, Qiu WX, Lei Q, Han K, et al. Activable cell-penetrating peptide conjugated prodrug for tumor targeted drug delivery. ACS Appl Mater Interfaces. 2015;7(29):16061–9. https://doi.org/10.1021/acsami.5b04517.

    PubMed  CAS  Article  Google Scholar 

  58. Cesbron Y, Shaheen U, Free P, Levy R. TAT and HA2 facilitate cellular uptake of gold nanoparticles but do not lead to cytosolic localisation. PLoS One. 2015;10(4):e0121683. https://doi.org/10.1371/journal.pone.0121683.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  59. Trabulo S, Cardoso AL, Mano M, De Lima MC. Cell-penetrating peptides-mechanisms of cellular uptake and generation of delivery systems. Pharmaceuticals. 2010;3(4):961–93. https://doi.org/10.3390/ph3040961.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  60. Juweid M, Neumann R, Paik C, Perez-Bacete MJ, Sato J, van Osdol W, et al. Micropharmacology of monoclonal antibodies in solid tumors: direct experimental evidence for a binding site barrier. Cancer Res. 1992;52(19):5144–53.

    PubMed  CAS  Google Scholar 

  61. Lee H, Fonge H, Hoang B, Reilly RM, Allen C. The effects of particle size and molecular targeting on the intratumoral and subcellular distribution of polymeric nanoparticles. Mol Pharm. 2010;7(4):1195–208. https://doi.org/10.1021/mp100038h.

    PubMed  CAS  Article  Google Scholar 

  62. Ibrahim SA, Katara GK, Kulshrestha A, Jaiswal MK, Amin MA, Beaman KD. Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression. Oncotarget. 2015;6(32):33033–45. https://doi.org/10.18632/oncotarget.5439.

    PubMed  PubMed Central  Article  Google Scholar 

  63. Marchiq I, Pouyssegur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H(+) symporters. J Mol Med. 2016;94(2):155–71. https://doi.org/10.1007/s00109-015-1307-x.

    PubMed  CAS  Article  Google Scholar 

  64. Tan S, Wang G. Redox-responsive and pH-sensitive nanoparticles enhanced stability and anticancer ability of erlotinib to treat lung cancer in vivo. Drug Des Devel Ther. 2017;11:3519–29. https://doi.org/10.2147/DDDT.S151422.

    PubMed  PubMed Central  Article  Google Scholar 

  65. Lv Y, Hao L, Hu W, Ran Y, Bai Y, Zhang L. Novel multifunctional pH-sensitive nanoparticles loaded into microbubbles as drug delivery vehicles for enhanced tumor targeting. Sci Rep. 2016;6:29321. https://doi.org/10.1038/srep29321.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  66. Li M, Tang Z, Lv S, Song W, Hong H, Jing X, et al. Cisplatin crosslinked pH-sensitive nanoparticles for efficient delivery of doxorubicin. Biomaterials. 2014;35(12):3851–64. https://doi.org/10.1016/j.biomaterials.2014.01.018.

    PubMed  CAS  Article  Google Scholar 

  67. Zhu L, Torchilin VP. Stimulus-responsive nanopreparations for tumor targeting. Integr Biol. 2013;5(1):96–107. https://doi.org/10.1039/c2ib20135f.

    CAS  Article  Google Scholar 

  68. Xu R, Wang XL, Lu ZR. New amphiphilic carriers forming pH-sensitive nanoparticles for nucleic acid delivery. Langmuir. 2010;26(17):13874–82. https://doi.org/10.1021/la1024185.

    PubMed  CAS  Article  Google Scholar 

  69. Marusyk A, Almendro V, Polyak K. Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer. 2012;12(5):323–34. https://doi.org/10.1038/nrc3261.

    PubMed  CAS  Article  PubMed Central  Google Scholar 

  70. Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010;1805(1):105–17. https://doi.org/10.1016/j.bbcan.2009.11.002.

    PubMed  CAS  Article  Google Scholar 

  71. Sun XX, Yu Q. Intra-tumor heterogeneity of cancer cells and its implications for cancer treatment. Acta Pharmacol Sin. 2015;36(10):1219–27. https://doi.org/10.1038/aps.2015.92.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  72. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31(1):27–36. https://doi.org/10.1093/carcin/bgp220.

    PubMed  CAS  Article  Google Scholar 

  73. Shah M, Allegrucci C. Keeping an open mind: highlights and controversies of the breast cancer stem cell theory. Breast Cancer. 2012;4:155–66. https://doi.org/10.2147/BCTT.S26434.

    PubMed  Article  Google Scholar 

  74. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683–92. https://doi.org/10.1016/j.cell.2007.01.029.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  75. Illmensee K, Mintz B. Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. Proc Natl Acad Sci U S A. 1976;73(2):549–53.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  76. Mahdipour-Shirayeh A, Kaveh K, Kohandel M, Sivaloganathan S. Phenotypic heterogeneity in modeling cancer evolution. PLoS One. 2017;12(10):e0187000. https://doi.org/10.1371/journal.pone.0187000.

    PubMed  PubMed Central  Article  Google Scholar 

  77. Roy A, Li SD. Modifying the tumor microenvironment using nanoparticle therapeutics. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2016;8(6):891–908. https://doi.org/10.1002/wnan.1406.

    PubMed  PubMed Central  Article  Google Scholar 

  78. Mikhail AS, Allen C. Block copolymer micelles for delivery of cancer therapy: transport at the whole body, tissue and cellular levels. J Control Release. 2009;138(3):214–23. https://doi.org/10.1016/j.jconrel.2009.04.010.

    PubMed  CAS  Article  Google Scholar 

  79. Li L, Sun J, He Z. Deep penetration of nanoparticulate drug delivery systems into tumors: challenges and solutions. Curr Med Chem. 2013;20(23):2881–91.

    PubMed  CAS  Article  Google Scholar 

  80. Cabral H, Matsumoto Y, Mizuno K, Chen Q, Murakami M, Kimura M, et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat Nanotechnol. 2011;6(12):815–23. https://doi.org/10.1038/nnano.2011.166.

    PubMed  CAS  Article  Google Scholar 

  81. Yuan F, Dellian M, Fukumura D, Leunig M, Berk DA, Torchilin VP, et al. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 1995;55(17):3752–6.

    PubMed  CAS  Google Scholar 

  82. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29(6 Suppl 16):15–8. https://doi.org/10.1053/sonc.2002.37263.

    PubMed  CAS  Article  Google Scholar 

  83. Lammers T, Kiessling F, Hennink WE, Storm G. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress. J Control Release. 2012;161(2):175–87. https://doi.org/10.1016/j.jconrel.2011.09.063.

    PubMed  CAS  Article  Google Scholar 

  84. Siemann DW. The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents. Cancer Treat Rev. 2011;37(1):63–74. https://doi.org/10.1016/j.ctrv.2010.05.001.

    PubMed  CAS  Article  Google Scholar 

  85. de Jong M, Maina T. Of mice and humans: are they the same?—implications in cancer translational research. J Nucl Med. 2010;51(4):501–4. https://doi.org/10.2967/jnumed.109.065706.

    PubMed  Article  Google Scholar 

  86. Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res. 2000;60(5):1388–93.

    PubMed  CAS  Google Scholar 

  87. Lammers T, Peschke P, Kuhnlein R, Subr V, Ulbrich K, Debus J, et al. Effect of radiotherapy and hyperthermia on the tumor accumulation of HPMA copolymer-based drug delivery systems. J Control Release. 2007;117(3):333–41. https://doi.org/10.1016/j.jconrel.2006.10.032.

    PubMed  CAS  Article  Google Scholar 

  88. Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncology. 2005;7(4):452–64. https://doi.org/10.1215/S1152851705000232.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  89. Zhang L, Nishihara H, Kano MR. Pericyte-coverage of human tumor vasculature and nanoparticle permeability. Biol Pharm Bull. 2012;35(5):761–6.

    PubMed  CAS  Article  Google Scholar 

  90. Kano MR, Komuta Y, Iwata C, Oka M, Shirai YT, Morishita Y, et al. 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. 2009;100(1):173–80. https://doi.org/10.1111/j.1349-7006.2008.01003.x.

    PubMed  CAS  Article  Google Scholar 

  91. Kano MR. Nanotechnology and tumor microcirculation. Adv Drug Deliv Rev. 2014;74:2–11. https://doi.org/10.1016/j.addr.2013.08.010.

    PubMed  CAS  Article  Google Scholar 

  92. Danhier F. To exploit the tumor microenvironment: since the EPR effect fails in the clinic, what is the future of nanomedicine? J Control Rel. 2016;244(Pt A):108–21. https://doi.org/10.1016/j.jconrel.2016.11.015.

    CAS  Article  Google Scholar 

  93. Achilles EG, Fernandez A, Allred EN, Kisker O, Udagawa T, Beecken WD, et al. Heterogeneity of angiogenic activity in a human liposarcoma: a proposed mechanism for “no take” of human tumors in mice. J Natl Cancer Inst. 2001;93(14):1075–81.

    PubMed  CAS  Article  Google Scholar 

  94. Yu JL, Rak JW, Carmeliet P, Nagy A, Kerbel RS, Coomber BL. Heterogeneous vascular dependence of tumor cell populations. Am J Pathol. 2001;158(4):1325–34. https://doi.org/10.1016/S0002-9440(10)64083-7.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  95. Choi M, Choi K, Ryu SW, Lee J, Choi C. Dynamic fluorescence imaging for multiparametric measurement of tumor vasculature. J Biomed Opt. 2011;16(4):046008. https://doi.org/10.1117/1.3562956.

    PubMed  Article  Google Scholar 

  96. Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol. 2010;7(11):653–64. https://doi.org/10.1038/nrclinonc.2010.139.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  97. Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia. 2015;3:83–92. https://doi.org/10.2147/HP.S93413.

    PubMed  PubMed Central  Article  Google Scholar 

  98. Lee H, Hoang B, Fonge H, Reilly RM, Allen C. In vivo distribution of polymeric nanoparticles at the whole-body, tumor, and cellular levels. Pharm Res. 2010;27(11):2343–55. https://doi.org/10.1007/s11095-010-0068-z.

    PubMed  CAS  Article  Google Scholar 

  99. Casazza A, Di Conza G, Wenes M, Finisguerra V, Deschoemaeker S, Mazzone M. Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene. 2014;33(14):1743–54. https://doi.org/10.1038/onc.2013.121.

    PubMed  CAS  Article  Google Scholar 

  100. Miao L, Huang L. Exploring the tumor microenvironment with nanoparticles. Cancer Treat Res. 2015;166:193–226. https://doi.org/10.1007/978-3-319-16555-4_9.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  101. Brown EB, Boucher Y, Nasser S, Jain RK. Measurement of macromolecular diffusion coefficients in human tumors. Microvasc Res. 2004;67(3):231–6. https://doi.org/10.1016/j.mvr.2004.02.001.

    PubMed  CAS  Article  Google Scholar 

  102. Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 2000;60(9):2497–503.

    PubMed  CAS  Google Scholar 

  103. Sykes EA, Dai Q, Sarsons CD, Chen J, Rocheleau JV, Hwang DM, et al. Tailoring nanoparticle designs to target cancer based on tumor pathophysiology. Proc Natl Acad Sci U S A. 2016;113(9):E1142–51. https://doi.org/10.1073/pnas.1521265113.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  104. Yokoi K, Kojic M, Milosevic M, Tanei T, Ferrari M, Ziemys A. Capillary-wall collagen as a biophysical marker of nanotherapeutic permeability into the tumor microenvironment. Cancer Res. 2014;74(16):4239–46. https://doi.org/10.1158/0008-5472.CAN-13-3494.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  105. Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer. 2003;3(6):422–33. https://doi.org/10.1038/nrc1094.

    PubMed  CAS  Article  Google Scholar 

  106. Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2003;163(5):1801–15. https://doi.org/10.1016/S0002-9440(10)63540-7.

    PubMed  PubMed Central  Article  Google Scholar 

  107. Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science. 2002;296(5574):1883–6. https://doi.org/10.1126/science.1071420.

    PubMed  CAS  Article  Google Scholar 

  108. Heldin CH, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer. 2004;4(10):806–13. https://doi.org/10.1038/nrc1456.

    PubMed  CAS  Article  Google Scholar 

  109. Hompland T, Ellingsen C, Ovrebo KM, Rofstad EK. Interstitial fluid pressure and associated lymph node metastasis revealed in tumors by dynamic contrast-enhanced MRI. Cancer Res. 2012;72(19):4899–908. https://doi.org/10.1158/0008-5472.CAN-12-0903.

    PubMed  CAS  Article  Google Scholar 

  110. Liu Y, Cao X. The origin and function of tumor-associated macrophages. Cellular & molecular immunology. 2015;12(1):1–4. https://doi.org/10.1038/cmi.2014.83.

    CAS  Article  Google Scholar 

  111. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39–51. https://doi.org/10.1016/j.cell.2010.03.014.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  112. Kubota K, Moriyama M, Furukawa S, Rafiul H, Maruse Y, Jinno T, et al. CD163(+)CD204(+) tumor-associated macrophages contribute to T cell regulation via interleukin-10 and PD-L1 production in oral squamous cell carcinoma. Sci Rep. 2017;7(1):1755. https://doi.org/10.1038/s41598-017-01661-z.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  113. Cuccarese MF, Dubach JM, Pfirschke C, Engblom C, Garris C, Miller MA, et al. Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging. Nat Commun. 2017;8:14293. https://doi.org/10.1038/ncomms14293.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  114. Yin S, Huang J, Li Z, Zhang J, Luo J, Lu C, et al. The prognostic and clinicopathological significance of tumor-associated macrophages in patients with gastric cancer: a meta-analysis. PLoS One. 2017;12(1):e0170042. https://doi.org/10.1371/journal.pone.0170042.

    PubMed  PubMed Central  Article  Google Scholar 

  115. Williams CB, Yeh ES, Soloff AC. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy. NPJ Breast Cancer. 2016;2. https://doi.org/10.1038/npjbcancer.2015.25.

  116. Jung KY, Cho SW, Kim YA, Kim D, Oh BC, Park DJ, et al. Cancers with higher density of tumor-associated macrophages were associated with poor survival rates. Journal of pathology and translational medicine. 2015;49(4):318–24. https://doi.org/10.4132/jptm.2015.06.01.

    PubMed  PubMed Central  Article  Google Scholar 

  117. Galdiero MR, Garlanda C, Jaillon S, Marone G, Mantovani A. Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol. 2013;228(7):1404–12. https://doi.org/10.1002/jcp.24260.

    PubMed  CAS  Article  Google Scholar 

  118. Chen XW, Yu TJ, Zhang J, Li Y, Chen HL, Yang GF, et al. CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis. Oncogene. 2017;36(35):5045–57. https://doi.org/10.1038/onc.2017.118.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  119. Qing W, Fang WY, Ye L, Shen LY, Zhang XF, Fei XC, et al. Density of tumor-associated macrophages correlates with lymph node metastasis in papillary thyroid carcinoma. Thyroid. 2012;22(9):905–10. https://doi.org/10.1089/thy.2011.0452.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  120. Komohara Y, Jinushi M, Takeya M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 2014;105(1):1–8. https://doi.org/10.1111/cas.12314.

    PubMed  CAS  Article  Google Scholar 

  121. Shaffer SA, Baker-Lee C, Kennedy J, Lai MS, de Vries P, Buhler K, et al. In vitro and in vivo metabolism of paclitaxel poliglumex: identification of metabolites and active proteases. Cancer Chemother Pharmacol. 2007;59(4):537–48. https://doi.org/10.1007/s00280-006-0296-4.

    PubMed  CAS  Article  Google Scholar 

  122. Jackson EF, Esparza-Coss E, Wen X, Ng CS, Daniel SL, Price RE, et al. Magnetic resonance imaging of therapy-induced necrosis using gadolinium-chelated polyglutamic acids. Int J Radiat Oncol Biol Phys. 2007;68(3):830–8. https://doi.org/10.1016/j.ijrobp.2007.01.011.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  123. Alizadeh D, Zhang L, Hwang J, Schluep T, Badie B. Tumor-associated macrophages are predominant carriers of cyclodextrin-based nanoparticles into gliomas. Nanomedicine. 2010;6(2):382–90. https://doi.org/10.1016/j.nano.2009.10.001.

    PubMed  CAS  Article  Google Scholar 

  124. Penn CA, Yang K, Zong H, Lim JY, Cole A, Yang D, et al. Therapeutic impact of nanoparticle therapy targeting tumor-associated macrophages. Mol Cancer Ther. 2018;17(1):96–106. https://doi.org/10.1158/1535-7163.MCT-17-0688.

    PubMed  CAS  Article  Google Scholar 

  125. Zamboni WC, Eiseman JL, Strychor S, Rice PM, Joseph E, Zamboni BA, et al. Tumor disposition of pegylated liposomal CKD-602 and the reticuloendothelial system in preclinical tumor models. J Liposome Res. 2011;21(1):70–80. https://doi.org/10.3109/08982101003754385.

    PubMed  CAS  Article  Google Scholar 

  126. Zhu S, Niu M, O'Mary H, Cui Z. Targeting of tumor-associated macrophages made possible by PEG-sheddable, mannose-modified nanoparticles. Mol Pharm. 2013;10(9):3525–30. https://doi.org/10.1021/mp400216r.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  127. Qiu W, Su GH. Development of orthotopic pancreatic tumor mouse models. Methods Mol Biol. 2013;980:215–23. https://doi.org/10.1007/978-1-62703-287-2_11.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  128. Morton JJ, Bird G, Keysar SB, Astling DP, Lyons TR, Anderson RT, et al. XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer. Oncogene. 2016;35(3):290–300. https://doi.org/10.1038/onc.2015.94.

    PubMed  CAS  Article  Google Scholar 

  129. Pompili L, Porru M, Caruso C, Biroccio A, Leonetti C. Patient-derived xenografts: a relevant preclinical model for drug development. J Exp Clin Cancer Res. 2016;35(1):189. https://doi.org/10.1186/s13046-016-0462-4.

    PubMed  PubMed Central  Article  Google Scholar 

  130. DeRose YS, Wang G, Lin YC, Bernard PS, Buys SS, Ebbert MT, et al. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med. 2011;17(11):1514–20. https://doi.org/10.1038/nm.2454.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  131. Rangarajan A, Weinberg RA. Opinion: comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer. 2003;3(12):952–9. https://doi.org/10.1038/nrc1235.

    PubMed  CAS  Article  Google Scholar 

  132. Politi K, Pao W. How genetically engineered mouse tumor models provide insights into human cancers. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(16):2273–81. https://doi.org/10.1200/JCO.2010.30.8304.

    CAS  Article  Google Scholar 

  133. Cekanova M, Rathore K. Animal models and therapeutic molecular targets of cancer: utility and limitations. Drug Des Devel Ther. 2014;8:1911–21. https://doi.org/10.2147/DDDT.S49584.

    PubMed  PubMed Central  Article  Google Scholar 

  134. Garralda E, Paz K, Lopez-Casas PP, Jones S, Katz A, Kann LM, et al. Integrated next-generation sequencing and avatar mouse models for personalized cancer treatment. Clin Cancer Res. 2014;20(9):2476–84. https://doi.org/10.1158/1078-0432.CCR-13-3047.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  135. Song G, Suzuki OT, Santos CM, Lucas AT, Wiltshire T, Zamboni WC. Gulp1 is associated with the pharmacokinetics of PEGylated liposomal doxorubicin (PLD) in inbred mouse strains. Nanomedicine. 2016;12(7):2007–17. https://doi.org/10.1016/j.nano.2016.05.019.

    PubMed  CAS  Article  Google Scholar 

  136. Miller MA, Chandra R, Cuccarese MF, Pfirschke C, Engblom C, Stapleton S, et al. Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts. Sci Transl Med. 2017;9(392):eaal0225. https://doi.org/10.1126/scitranslmed.aal0225.

    PubMed  Article  Google Scholar 

  137. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell. 2004;6(6):553–63. https://doi.org/10.1016/j.ccr.2004.10.011.

    PubMed  CAS  Article  Google Scholar 

  138. Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004;64(11):3731–6. https://doi.org/10.1158/0008-5472.CAN-04-0074.

    PubMed  CAS  Article  Google Scholar 

  139. Shenoi MM, Iltis I, Choi J, Koonce NA, Metzger GJ, Griffin RJ, et al. Nanoparticle delivered vascular disrupting agents (VDAs): use of TNF-alpha conjugated gold nanoparticles for multimodal cancer therapy. Mol Pharm. 2013;10(5):1683–94. https://doi.org/10.1021/mp300505w.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  140. Langer CJ, O'Byrne KJ, Socinski MA, Mikhailov SM, Lesniewski-Kmak K, Smakal M, et al. Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naive advanced non-small cell lung cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2008;3(6):623–30. https://doi.org/10.1097/JTO.0b013e3181753b4b.

    Article  Google Scholar 

  141. Melancon MP, Wang W, Wang Y, Shao R, Ji X, Gelovani JG, et al. A novel method for imaging in vivo degradation of poly (L-glutamic acid), a biodegradable drug carrier. Pharm Res. 2007;24(6):1217–24. https://doi.org/10.1007/s11095-007-9253-0.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  142. Hare JI, Lammers T, Ashford MB, Puri S, Storm G, Barry ST. Challenges and strategies in anti-cancer nanomedicine development: an industry perspective. Adv Drug Deliv Rev. 2017;108:25–38. https://doi.org/10.1016/j.addr.2016.04.025.

    PubMed  CAS  Article  Google Scholar 

  143. Stapleton S, Allen C, Pintilie M, Jaffray DA. Tumor perfusion imaging predicts the intra-tumoral accumulation of liposomes. J Control Release. 2013;172(1):351–7. https://doi.org/10.1016/j.jconrel.2013.08.296.

    PubMed  CAS  Article  Google Scholar 

  144. Karathanasis E, Suryanarayanan S, Balusu SR, McNeeley K, Sechopoulos I, Karellas A, et al. Imaging nanoprobe for prediction of outcome of nanoparticle chemotherapy by using mammography. Radiology. 2009;250(2):398–406. https://doi.org/10.1148/radiol.2502080801.

    PubMed  Article  Google Scholar 

  145. Yokoi K, Tanei T, Godin B, van de Ven AL, Hanibuchi M, Matsunoki A, et al. Serum biomarkers for personalization of nanotherapeutics-based therapy in different tumor and organ microenvironments. Cancer Lett. 2014;345(1):48–55. https://doi.org/10.1016/j.canlet.2013.11.015.

    PubMed  CAS  Article  Google Scholar 

  146. Wu J, Akaike T, Hayashida K, Okamoto T, Okuyama A, Maeda H. Enhanced vascular permeability in solid tumor involving peroxynitrite and matrix metalloproteinases. Jpn J Cancer Res. 2001;92(4):439–51.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  147. Maeda H. Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity. Adv Drug Deliv Rev. 2015;91:3–6. https://doi.org/10.1016/j.addr.2015.01.002.

    PubMed  CAS  Article  Google Scholar 

  148. Murakami M, Ernsting MJ, Undzys E, Holwell N, Foltz WD, Li SD. Docetaxel conjugate nanoparticles that target alpha-smooth muscle actin-expressing stromal cells suppress breast cancer metastasis. Cancer Res. 2013;73(15):4862–71. https://doi.org/10.1158/0008-5472.CAN-13-0062.

    PubMed  CAS  Article  Google Scholar 

  149. Hoang B, Ernsting MJ, Roy A, Murakami M, Undzys E, Li SD. Docetaxel-carboxymethylcellulose nanoparticles target cells via a SPARC and albumin dependent mechanism. Biomaterials. 2015;59:66–76. https://doi.org/10.1016/j.biomaterials.2015.04.032.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  150. Madar S, Goldstein I, Rotter V. ‘Cancer associated fibroblasts’—more than meets the eye. Trends Mol Med. 2013;19(8):447–53. https://doi.org/10.1016/j.molmed.2013.05.004.

    PubMed  CAS  Article  Google Scholar 

  151. Ernsting MJ, Hoang B, Lohse I, Undzys E, Cao P, Do T, et al. Targeting of metastasis-promoting tumor-associated fibroblasts and modulation of pancreatic tumor-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle. J Control Release. 2015;206:122–30. https://doi.org/10.1016/j.jconrel.2015.03.023.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  152. Park K. The drug delivery field at the inflection point: time to fight its way out of the egg. Journal of controlled release: official journal of the Controlled Release Society. 2017;267:2–14. https://doi.org/10.1016/j.jconrel.2017.07.030.

    CAS  Article  Google Scholar 

  153. Rosenblum D, Joshi N, Tao W, Karp JM, Peer D. Progress and challenges towards targeted delivery of cancer therapeutics. Nat Commun. 2018;9(1):1410. https://doi.org/10.1038/s41467-018-03705-y.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  154. Autio KA, Dreicer R, Anderson J, Garcia JA, Alva A, Hart LL, et al. Safety and efficacy of BIND-014, a docetaxel nanoparticle targeting prostate-specific membrane antigen for patients with metastatic castration-resistant prostate cancer: a phase 2 clinical trial. JAMA Oncol. 2018; https://doi.org/10.1001/jamaoncol.2018.2168.

  155. Raemdonck K, De Smedt SC. Lessons in simplicity that should shape the future of drug delivery. Nat Biotechnol. 2015;33(10):1026–7. https://doi.org/10.1038/nbt.3366.

    PubMed  CAS  Article  Google Scholar 

  156. Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018:JCO2017776112. https://doi.org/10.1200/JCO.2017.77.6112.

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Funding

Both the authors thank the “Department of Science and Technology (DST), Govt. of India” for the financial support under the project ECR/2016/000566/LS.

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  1. Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Vidya Vihar, Pilani, Rajasthan, 333031, India

    K. Laxmi Swetha & Aniruddha Roy

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  1. K. Laxmi Swetha
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Swetha, K.L., Roy, A. Tumor heterogeneity and nanoparticle-mediated tumor targeting: the importance of delivery system personalization. Drug Deliv. and Transl. Res. 8, 1508–1526 (2018). https://doi.org/10.1007/s13346-018-0578-5

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Keywords

  • Nanoparticle
  • Pharmacokinetics
  • Tumor penetration
  • Tumor heterogeneity
  • Personalized therapy