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Imaging of Nanoparticle Distribution to Assess Treatments That Alter Delivery

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Abstract

Molecular imaging is a vital tool to non-invasively measure nanoparticle delivery to solid tumors. Despite the myriad of nanoparticles studied for cancer, successful applications of nanoparticles in humans is limited by inconsistent and ineffective delivery. Successful nanoparticle delivery in preclinical models is often attributed to enhanced permeability and retention (EPR)—a set of conditions that is heterogeneous and transient in patients. Thus, researchers are evaluating therapeutic strategies to modify nanoparticle delivery, particularly treatments which have demonstrated effects on EPR conditions. Imaging nanoparticle distribution provides a means to measure the effects of therapeutic intervention on nanoparticle delivery to solid tumors. This review focuses on the utility of imaging to measure treatment-induced changes in nanoparticle delivery to tumors and provides preclinical examples studying a broad range of therapeutic interventions.

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References

  1. Sagnella SM, McCarroll JA, Kavallaris M (2014) Drug delivery: beyond active tumour targeting. Nanomedicine 10:1131–1137

    Article  CAS  PubMed  Google Scholar 

  2. Jain RK, Stylianopoulos T (2010) Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 7:653–664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Toussaint M, Pinel S, Auger F et al (2017) Proton MR spectroscopy and diffusion MR imaging monitoring to predict tumor response to interstitial photodynamic therapy for glioblastoma. Theranostics 7:436–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Miller MA, Gadde S, Pfirschke C et al (2015) Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle. Sci Transl Med:7–314ra183

  5. Prabhakar U, Maeda H, Jain RK et al (2013) Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res 73:2412–2417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lee H, Shields AF, Siegel BA et al (2017) 64Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer. Clin Cancer Res 23:4190–4202

    Article  CAS  PubMed  Google Scholar 

  7. Ren L, Chen S, Li H et al (2016) MRI-guided liposomes for targeted tandem chemotherapy and therapeutic response prediction. Acta Biomater 35:260–268

    Article  CAS  PubMed  Google Scholar 

  8. Devaraj NK, Keliher EJ, Thurber GM et al (2009) 18F labeled nanoparticles for in vivo PET-CT imaging. Bioconjug Chem 20:397–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Funkhouser J (2002) Reinventing pharma: the Theranostic revolution. Curr Drug Discov 2:17–19

    Google Scholar 

  10. Lammers T, Aime S, Hennink WE et al (2011) Theranostic nanomedicine. Acc Chem Res 44:1029–1038

    Article  CAS  PubMed  Google Scholar 

  11. Zhou H, Qian W, Uckun FM et al (2015) IGF1 receptor targeted theranostic nanoparticles for targeted and image-guided therapy of pancreatic cancer. ACS Nano 9:7976–7991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Minowa T, Kawano K, Kuribayashi H et al (2009) Increase in tumour permeability following TGF-beta type I receptor-inhibitor treatment observed by dynamic contrast-enhanced MRI. Br J Cancer 101:1884–1890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Geretti E, Leonard SC, Dumont N et al (2015) Cyclophosphamide-mediated tumor priming for enhanced delivery and antitumor activity of HER2-targeted liposomal doxorubicin (MM-302). Mol Cancer Ther 14:2060–2071

    Article  CAS  PubMed  Google Scholar 

  14. Doi Y, Abu Lila AS, Matsumoto H et al (2016) Improvement of intratumor microdistribution of PEGylated liposome via tumor priming by metronomic S-1 dosing. Int J Nanomedicine 11:5573–5582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nakamura K, Abu Lila AS, Matsunaga M et al (2011) A double-modulation strategy in cancer treatment with a chemotherapeutic agent and siRNA. Mol Ther 19:2040–2047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Moding EJ, Clark DP, Qi Y et al (2013) Dual-energy micro-computed tomography imaging of radiation-induced vascular changes in primary mouse sarcomas. Int J Radiat Oncol Biol Phys 85:1353–1359

    Article  PubMed  Google Scholar 

  17. Matteucci ML, Anyarambhatla G, Rosner G et al (2000) Hyperthermia increases accumulation of technetium-99m-labeled liposomes in feline sarcomas. Clin Cancer Res 6:3748–3755

    CAS  PubMed  Google Scholar 

  18. Kleiter MM, Yu D, Mohammadian LA et al (2006) A tracer dose of technetium-99m-labeled liposomes can estimate the effect of hyperthermia on intratumoral doxil extravasation. Clin Cancer Res 12:6800–6807

    Article  CAS  PubMed  Google Scholar 

  19. Head HW, Dodd GD 3rd, Bao A et al (2010) Combination radiofrequency ablation and intravenous radiolabeled liposomal doxorubicin: imaging and quantification of increased drug delivery to tumors. Radiology 255:405–414

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zheng X, Goins BA, Cameron IL et al (2011) Ultrasound-guided intratumoral administration of collagenase-2 improved liposome drug accumulation in solid tumor xenografts. Cancer Chemother Pharmacol 67:173–182

    Article  CAS  PubMed  Google Scholar 

  21. Lammers T, Subr V, Peschke P et al (2008) Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy. Br J Cancer 99:900–910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kobayashi H, Reijnders K, English S et al (2004) Application of a macromolecular contrast agent for detection of alterations of tumor vessel permeability induced by radiation. Clin Cancer Res 10:7712–7720

    Article  CAS  PubMed  Google Scholar 

  23. Daldrup-Link HE, Mohanty S, Ansari C et al (2016) Alk5 inhibition increases delivery of macromolecular and protein-bound contrast agents to tumors. JCI Insight 1:e85608

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kumar V, Boucher Y, Liu H et al (2016) Noninvasive assessment of losartan-induced increase in functional microvasculature and drug delivery in pancreatic ductal adenocarcinoma. Transl Oncol 9:431–437

    Article  PubMed  PubMed Central  Google Scholar 

  25. Appelbe OK, Zhang Q, Pelizzari CA et al (2016) Image-guided radiotherapy targets macromolecules through altering the tumor microenvironment. Mol Pharm 13:3457–3467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wilmes LJ, Pallavicini MG, Fleming LM et al (2007) AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging. Magn Reson Imaging 25:319–327

    Article  CAS  PubMed  Google Scholar 

  27. Zhao Y, Houston ZH, Simpson JD et al (2017) Using peptide aptamer targeted polymers as a model nanomedicine for investigating drug distribution in cancer nanotheranostics. Mol Pharm

  28. 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 46:6387–6392

    CAS  PubMed  Google Scholar 

  29. Hobbs SK, Monsky WL, Yuan F et al (1998) Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A 95:4607–4612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bartlett DW, Su H, Hildebrandt IJ et al (2007) Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc Natl Acad Sci U S A 104:15549–15554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kirpotin DB, Drummond DC, Shao Y et al (2006) Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. Cancer Res 66:6732–6740

    Article  CAS  PubMed  Google Scholar 

  32. Jung B, Shim MK, Park MJ et al (2017) Hydrophobically modified polysaccharide-based on polysialic acid nanoparticles as carriers for anticancer drugs. Int J Pharm 520:111–118

    Article  CAS  PubMed  Google Scholar 

  33. Gao W, Wang Z, Lv L et al (2016) Photodynamic therapy induced enhancement of tumor vasculature permeability using an upconversion nanoconstruct for improved intratumoral nanoparticle delivery in deep tissues. Theranostics 6:1131–1144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li Y, Xiao K, Luo J et al (2010) A novel size-tunable nanocarrier system for targeted anticancer drug delivery. J Control Release 144:314–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lv S, Li M, Tang Z et al (2013) Doxorubicin-loaded amphiphilic polypeptide-based nanoparticles as an efficient drug delivery system for cancer therapy. Acta Biomater 9:9330–9342

    Article  CAS  PubMed  Google Scholar 

  36. Danhier F (2016) To exploit the tumor microenvironment: since the EPR effect fails in the clinic, what is the future of nanomedicine? J Control Release 244:108–121

    Article  CAS  PubMed  Google Scholar 

  37. Zhang L, Nishihara H, Kano MR (2012) Pericyte-coverage of human tumor vasculature and nanoparticle permeability. Biol Pharm Bull 35:761–766

    Article  CAS  PubMed  Google Scholar 

  38. Kano MR, Bae Y, Iwata C et al (2007) Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling. Proc Natl Acad Sci U S A 104:3460–3465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yokoi K, Kojic M, Milosevic M et al (2014) Capillary-wall collagen as a biophysical marker of nanotherapeutic permeability into the tumor microenvironment. Cancer Res 74:4239–4246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yokoi K, Chan D, Kojic M et al (2015) Liposomal doxorubicin extravasation controlled by phenotype-specific transport properties of tumor microenvironment and vascular barrier. J Control Release 217:293–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Durymanov MO, Rosenkranz AA, Sobolev AS (2015) Current approaches for improving intratumoral accumulation and distribution of nanomedicines. Theranostics 5:1007–1020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kjellman P, in ‘t Zandt R, Fredriksson S et al (2014) Optimizing retention of multimodal imaging nanostructures in sentinel lymph nodes by nanoscale size tailoring. Nanomedicine 10:1089–1095

    Article  CAS  PubMed  Google Scholar 

  43. Song J, Yang X, Yang Z et al (2017) Rational design of branched nanoporous gold nanoshells with enhanced physico-optical properties for optical imaging and cancer therapy. ACS Nano

  44. Ramishetti S, Huang L (2012) Intelligent design of multifunctional lipid-coated nanoparticle platforms for cancer therapy. Ther Deliv 3:1429–1445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chung AS, Lee J, Ferrara N (2010) Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer 10:505–514

    Article  CAS  PubMed  Google Scholar 

  46. Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  CAS  PubMed  Google Scholar 

  47. Miller KD, Chap LI, Holmes FA et al (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792–799

    Article  CAS  PubMed  Google Scholar 

  48. Reck M, von Pawel J, Zatloukal P et al (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 27:1227–1234

    Article  CAS  PubMed  Google Scholar 

  49. Zalcman G, Mazieres J, Margery J et al (2016) Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 387:1405–1414

    Article  CAS  PubMed  Google Scholar 

  50. Miller K, Wang M, Gralow J et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676

    Article  CAS  PubMed  Google Scholar 

  51. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989

    Article  CAS  PubMed  Google Scholar 

  52. Dickson PV, Hamner JB, Sims TL et al (2007) Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res 13:3942–3950

    Article  CAS  PubMed  Google Scholar 

  53. Curnis F, Sacchi A, Corti A (2002) Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. J Clin Invest 110:475–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Dreher MR, Liu W, Michelich CR et al (2006) Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst 98:335–344

    Article  CAS  PubMed  Google Scholar 

  55. Sounni NE, Dehne K, van Kempen L et al (2010) Stromal regulation of vessel stability by MMP14 and TGFbeta. Dis Model Mech 3:317–332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nichols JW, Bae YH (2014) EPR: evidence and fallacy. J Control Release 190:451–464

    Article  CAS  PubMed  Google Scholar 

  57. Ait-Oudhia S, Straubinger RM, Mager DE (2013) Systems pharmacological analysis of paclitaxel-mediated tumor priming that enhances nanocarrier deposition and efficacy. J Pharmacol Exp Ther 344:103–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hylander BL, Sen A, Beachy SH et al (2015) Tumor priming by Apo2L/TRAIL reduces interstitial fluid pressure and enhances efficacy of liposomal gemcitabine in a patient derived xenograft tumor model. J Control Release 217:160–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lu D, Wientjes MG, Lu Z et al (2007) Tumor priming enhances delivery and efficacy of nanomedicines. J Pharmacol Exp Ther 322:80–88

    Article  CAS  PubMed  Google Scholar 

  60. Wang J, Lu Z, Wang J et al (2015) Paclitaxel tumor priming promotes delivery and transfection of intravenous lipid-siRNA in pancreatic tumors. J Control Release 216:103–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Violette S, Poulain L, Dussaulx E et al (2002) Resistance of colon cancer cells to long-term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-X(L) in addition to Bax and p53 status. Int J Cancer 98:498–504

    Article  CAS  PubMed  Google Scholar 

  62. Stapleton S, Jaffray D, Milosevic M (2016) Radiation effects on the tumor microenvironment: implications for nanomedicine delivery. Adv Drug Deliv Rev.

  63. Davies Cde L, Lundstrom LM, Frengen J et al (2004) Radiation improves the distribution and uptake of liposomal doxorubicin (caelyx) in human osteosarcoma xenografts. Cancer Res 64:547–553

    Article  PubMed  Google Scholar 

  64. Giustini AJ, Petryk AA, Hoopes PJ (2012) Ionizing radiation increases systemic nanoparticle tumor accumulation. Nanomedicine 8:818–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Vernon CC, Hand JW, Field SB et al (1996) Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group. Int J Radiat Oncol Biol Phys 35:731–744

    Article  CAS  PubMed  Google Scholar 

  66. Ware MJ, Krzykawska-Serda M, Chak-Shing Ho J et al (2017) Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model. Sci Rep 7:43961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. McGahan JP, Brock JM, Tesluk H et al (1992) Hepatic ablation with use of radio-frequency electrocautery in the animal model. J Vasc Interv Radiol 3:291–297

    Article  CAS  PubMed  Google Scholar 

  68. Kirui DK, Mai J, Palange AL et al (2014) Transient mild hyperthermia induces E-selectin mediated localization of mesoporous silicon vectors in solid tumors. PLoS One 9:e86489

    Article  PubMed  PubMed Central  Google Scholar 

  69. Kirui DK, Koay EJ, Guo X et al (2014) Tumor vascular permeabilization using localized mild hyperthermia to improve macromolecule transport. Nanomedicine 10:1487–1496

    Article  CAS  PubMed  Google Scholar 

  70. Kong G, Braun RD, Dewhirst MW (2001) Characterization of the effect of hyperthermia on nanoparticle extravasation from tumor vasculature. Cancer Res 61:3027–3032

    CAS  PubMed  Google Scholar 

  71. Huang SK, Stauffer PR, Hong K et al (1994) Liposomes and hyperthermia in mice: increased tumor uptake and therapeutic efficacy of doxorubicin in sterically stabilized liposomes. Cancer Res 54:2186–2191

    CAS  PubMed  Google Scholar 

  72. Li L, ten Hagen TL, Bolkestein M et al (2013) Improved intratumoral nanoparticle extravasation and penetration by mild hyperthermia. J Control Release 167:130–137

    Article  CAS  PubMed  Google Scholar 

  73. Maeda H, Nakamura H, Fang J (2013) The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliv Rev 65:71–79

    Article  CAS  PubMed  Google Scholar 

  74. Diop-Frimpong B, Chauhan VP, Krane S et al (2011) Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci U S A 108:2909–2914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Provenzano PP, Cuevas C, Chang AE et al (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21:418–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology, Wayne State University, Detroit, MI, USA

    Stephanie J. Blocker & Anthony F. Shields

  2. Karmanos Cancer Institute, 4100 John R., HW04HO, Detroit, MI, 48201, USA

    Anthony F. Shields

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  1. Stephanie J. Blocker
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  2. Anthony F. Shields
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Correspondence to Anthony F. Shields.

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Conflict of Interest

The investigators have received research support from Merrimack Pharmaceuticals, Cambridge, MA, and Ipsen Biopharmaceuticals, Cambridge, MA.

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Blocker, S.J., Shields, A.F. Imaging of Nanoparticle Distribution to Assess Treatments That Alter Delivery. Mol Imaging Biol 20, 340–351 (2018). https://doi.org/10.1007/s11307-017-1142-2

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