Exploring the tumor microenvironment with nanoparticles.

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

[1]  T. Ogawa,et al.  Role of stromal myofibroblasts in invasive breast cancer: stromal expression of alpha-smooth muscle actin correlates with worse clinical outcome , 2012, Breast Cancer.

[2]  Mauro Ferrari,et al.  Capillary-wall collagen as a biophysical marker of nanotherapeutic permeability into the tumor microenvironment. , 2014, Cancer research.

[3]  T. Sjöblom,et al.  Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate. , 2004, Cancer research.

[4]  R. Jain,et al.  TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma , 2012, Proceedings of the National Academy of Sciences.

[5]  R. Mahato,et al.  Extravasation of polymeric nanomedicines across tumor vasculature. , 2011, Advanced drug delivery reviews.

[6]  Triantafyllos Stylianopoulos,et al.  Diffusion anisotropy in collagen gels and tumors: the effect of fiber network orientation. , 2010, Biophysical journal.

[7]  R K Jain,et al.  Barriers to drug delivery in solid tumors. , 1994, Scientific American.

[8]  Zhiyuan Zhong,et al.  pH-Sensitive degradable polymersomes for triggered release of anticancer drugs: a comparative study with micelles. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[9]  Pradeep Tyagi,et al.  Anisamide‐targeted stealth liposomes: A potent carrier for targeting doxorubicin to human prostate cancer cells , 2004, International journal of cancer.

[10]  Eun-Kyung Lim,et al.  pH‐Triggered Drug‐Releasing Magnetic Nanoparticles for Cancer Therapy Guided by Molecular Imaging by MRI , 2011, Advanced materials.

[11]  Y. Ouchi,et al.  Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor‐β receptor inhibitor on extravasation of nanoparticles from neovasculature , 2009, Cancer science.

[12]  M. Yeh,et al.  Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy , 2011, International journal of nanomedicine.

[13]  Jun Du,et al.  Evaluation of the tumor targeting of a FAPα-based doxorubicin prodrug , 2011, Journal of drug targeting.

[14]  D. McDonald,et al.  Rapid vascular regrowth in tumors after reversal of VEGF inhibition. , 2006, The Journal of clinical investigation.

[15]  Liangfang Zhang,et al.  Polymeric nanoparticles with precise ratiometric control over drug loading for combination therapy. , 2011, Molecular pharmaceutics.

[16]  R K Jain,et al.  Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. , 1990, Cancer research.

[17]  E. Ruoslahti,et al.  Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma , 2011, Proceedings of the National Academy of Sciences.

[18]  Wilson Mok,et al.  Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. , 2006, Cancer research.

[19]  Z. Cui,et al.  Targeting of tumor-associated macrophages made possible by PEG-sheddable, mannose-modified nanoparticles. , 2013, Molecular pharmaceutics.

[20]  Véronique Préat,et al.  To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[21]  Vladimir P Torchilin,et al.  Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors. , 2002, Cancer research.

[22]  Gemma K. Alderton.  Microenvironment: An exercise in restraint , 2014, Nature Reviews Cancer.

[23]  Ming-Zher Poh,et al.  Diffusion of particles in the extracellular matrix: the effect of repulsive electrostatic interactions. , 2010, Biophysical journal.

[24]  G. De Rosa,et al.  Peptide-modified liposomes for selective targeting of bombesin receptors overexpressed by cancer cells: a potential theranostic agent , 2012, International journal of nanomedicine.

[25]  S. Inoue.  Ultrastructure of basement membranes. , 1989, International review of cytology.

[26]  C. Betsholtz,et al.  Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. , 2003, The Journal of clinical investigation.

[27]  T. Sugino,et al.  Increase in tumour permeability following TGF-β type I receptor-inhibitor treatment observed by dynamic contrast-enhanced MRI , 2009, British Journal of Cancer.

[28]  K. Smalley,et al.  Fibroblast-mediated drug resistance in cancer. , 2013, Biochemical pharmacology.

[29]  Nicholas A Peppas,et al.  A review of current nanoparticle and targeting moieties for the delivery of cancer therapeutics. , 2013, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[30]  M. Swartz,et al.  Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity , 2012, Nature Reviews Cancer.

[31]  Ahmed O Elzoghby,et al.  Albumin-based nanoparticles as potential controlled release drug delivery systems. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[32]  Mark B. Carter,et al.  The Targeted Delivery of Multicomponent Cargos to Cancer Cells via Nanoporous Particle-Supported Lipid Bilayers , 2011, Nature materials.

[33]  Shyh-Dar Li,et al.  Docetaxel conjugate nanoparticles that target α-smooth muscle actin-expressing stromal cells suppress breast cancer metastasis. , 2013, Cancer research.

[34]  T. Golub,et al.  Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion , 2012, Nature.

[35]  Huan Meng,et al.  Two-wave nanotherapy to target the stroma and optimize gemcitabine delivery to a human pancreatic cancer model in mice. , 2013, ACS nano.

[36]  Gerard A Ateshian,et al.  Direct measurement of osmotic pressure of glycosaminoglycan solutions by membrane osmometry at room temperature. , 2005, Biophysical journal.

[37]  Frances E. Lennon,et al.  High-molecular-weight hyaluronan is a novel inhibitor of pulmonary vascular leakiness. , 2010, American journal of physiology. Lung cellular and molecular physiology.

[38]  J. Campisi,et al.  Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[39]  D. Siemann.  Tumor Microenvironment: Siemann/Tumor Microenvironment , 2010 .

[40]  U. Landegren,et al.  Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. , 2003, Genes & development.

[41]  C. Betsholtz,et al.  Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. , 2011, Developmental cell.

[42]  H. Nishihara.  Human pathological basis of blood vessels and stromal tissue for nanotechnology. , 2014, Advanced drug delivery reviews.

[43]  Umar Mahmood,et al.  Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. , 2014, Cancer cell.

[44]  Jun Ge,et al.  Drug release from electric-field-responsive nanoparticles. , 2012, ACS nano.

[45]  M. Dewhirst,et al.  Hyperthermia enables tumor-specific nanoparticle delivery: effect of particle size. , 2000, Cancer research.

[46]  Leaf Huang,et al.  Calcium phosphate nanoparticles with an asymmetric lipid bilayer coating for siRNA delivery to the tumor. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[47]  Ricky T. Tong,et al.  Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer , 2004, Nature Medicine.

[48]  Stephen A. Sastra,et al.  Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. , 2014, Cancer cell.

[49]  Malte Buchholz,et al.  Stromal biology and therapy in pancreatic cancer , 2010, Gut.

[50]  L. Galluzzi,et al.  Molecular mechanisms of cisplatin resistance , 2012, Oncogene.

[51]  J. Berlin,et al.  Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  G. Besner,et al.  Heparin-binding EGF-like growth factor protects pericytes from injury. , 2012, The Journal of surgical research.

[53]  Zhengrong Cui,et al.  Physical Characterization and Macrophage Cell Uptake of Mannan-Coated Nanoparticles , 2003, Drug development and industrial pharmacy.

[54]  Yuhua Wang,et al.  Lipid-coated Cisplatin nanoparticles induce neighboring effect and exhibit enhanced anticancer efficacy. , 2013, ACS nano.

[55]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[56]  B. de Kruijff,et al.  High Cytotoxicity of Cisplatin Nanocapsules in Ovarian Carcinoma Cells Depends on Uptake by Caveolae-Mediated Endocytosis , 2009, Clinical Cancer Research.

[57]  Xiaohu Gao,et al.  Nanocomposites with spatially separated functionalities for combined imaging and magnetolytic therapy. , 2010, Journal of the American Chemical Society.

[58]  M. Steiert,et al.  Pharmacokinetics and biodistribution of RGD-targeted doxorubicin-loaded nanoparticles in tumor-bearing mice. , 2005, International journal of pharmaceutics.

[59]  Erkki Ruoslahti,et al.  Tissue-penetrating delivery of compounds and nanoparticles into tumors. , 2009, Cancer cell.

[60]  Yuhua Wang,et al.  Co-delivery of Cisplatin and Rapamycin for Enhanced Anticancer Therapy through Synergistic Effects and Microenvironment Modulation , 2014, ACS nano.

[61]  Kwangmeyung Kim,et al.  The tumor accumulation and therapeutic efficacy of doxorubicin carried in calcium phosphate-reinforced polymer nanoparticles. , 2012, Biomaterials.

[62]  Hua Ai,et al.  cRGD-functionalized polymer micelles for targeted doxorubicin delivery. , 2004, Angewandte Chemie.

[63]  D. McDonald,et al.  Endothelial Gaps as Sites for Plasma Leakage in Inflammation , 1999, Microcirculation.

[64]  M. Dewhirst,et al.  Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. , 2006, Journal of the National Cancer Institute.

[65]  G. Bernhardt,et al.  Hyaluronidase enhances the activity of Adriamycin in breast cancer models in vitro and in vivo , 2005, Journal of Cancer Research and Clinical Oncology.

[66]  Sébastien Lecommandoux,et al.  Magnetic field triggered drug release from polymersomes for cancer therapeutics. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[67]  Douglas B. Evans,et al.  Cancer-associated stromal fibroblasts promote pancreatic tumor progression. , 2008, Cancer research.

[68]  R. Jain.  Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy , 2005, Science.

[69]  Mikala Egeblad,et al.  Dynamic interplay between the collagen scaffold and tumor evolution. , 2010, Current opinion in cell biology.

[70]  M Ancukiewicz,et al.  Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. , 2000, Cancer research.

[71]  Liangfang Zhang,et al.  Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. , 2012, Biochemical pharmacology.

[72]  T. Kole,et al.  Fibroblast activation protein peptide substrates identified from human collagen I derived gelatin cleavage sites. , 2008, Biochemistry.

[73]  Yuan Zhang,et al.  Combinational delivery of c-myc siRNA and nucleoside analogs in a single, synthetic nanocarrier for targeted cancer therapy. , 2013, Biomaterials.

[74]  David Allard,et al.  Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer , 2009, Science.

[75]  Elena M De-Juan-Pardo,et al.  In vitro modeling of the prostate cancer microenvironment. , 2014, Advanced drug delivery reviews.

[76]  Philip S Low,et al.  Folate-mediated delivery of macromolecular anticancer therapeutic agents. , 2002, Advanced drug delivery reviews.

[77]  Amy Brock,et al.  Nanoparticle targeting of anti-cancer drugs that alter intracellular signaling or influence the tumor microenvironment. , 2014, Advanced drug delivery reviews.

[78]  S. Veintemillas-Verdaguer,et al.  Biodistribution and pharmacokinetics of uniform magnetite nanoparticles chemically modified with polyethylene glycol. , 2013, Nanoscale.

[79]  Weili Lin,et al.  Multifunctional mesoporous silica nanospheres with cleavable Gd(III) chelates as MRI contrast agents: synthesis, characterization, target-specificity, and renal clearance. , 2011, Small.

[80]  Hua Ai,et al.  Multifunctional polymeric micelles as cancer-targeted, MRI-ultrasensitive drug delivery systems. , 2006, Nano letters.

[81]  C. Yun,et al.  Relaxin-expressing, fiber chimeric oncolytic adenovirus prolongs survival of tumor-bearing mice. , 2007, Cancer research.

[82]  Jun Fang,et al.  The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. , 2011, Advanced drug delivery reviews.

[83]  J. Isaacs,et al.  Rationale Behind Targeting Fibroblast Activation Protein–Expressing Carcinoma-Associated Fibroblasts as a Novel Chemotherapeutic Strategy , 2012, Molecular Cancer Therapeutics.

[84]  D. McDonald,et al.  Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. , 2003, The American journal of pathology.

[85]  L. Zhang,et al.  Nanoparticles in Medicine: Therapeutic Applications and Developments , 2008, Clinical pharmacology and therapeutics.

[86]  R. Jain,et al.  Studying primary tumor–associated fibroblast involvement in cancer metastasis in mice , 2012, Nature Protocols.

[87]  Jonathan M. Yingling,et al.  Development of TGF-β signalling inhibitors for cancer therapy , 2004, Nature Reviews Drug Discovery.

[88]  Tianjiao Ji,et al.  Using Functional Nanomaterials to Target and Regulate the Tumor Microenvironment: Diagnostic and Therapeutic Applications , 2013, Advanced materials.

[89]  R. Weissleder,et al.  Imaging macrophages with nanoparticles. , 2014, Nature materials.

[90]  R. Jain,et al.  Matrix metalloproteinases-1 and -8 improve the distribution and efficacy of an oncolytic virus. , 2007, Cancer research.

[91]  R. Jain,et al.  Delivering nanomedicine to solid tumors , 2010, Nature Reviews Clinical Oncology.

[92]  Liangfang Zhang,et al.  Therapeutic nanoparticles to combat cancer drug resistance. , 2009, Current drug metabolism.

[93]  C. de Lange Davies,et al.  Hyaluronidase reduces the interstitial fluid pressure in solid tumours in a non-linear concentration-dependent manner. , 1998, Cancer letters.

[94]  P. Couvreur,et al.  Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells , 2007, Cellular and Molecular Life Sciences.

[95]  M. Uesaka,et al.  Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. , 2011, Nature nanotechnology.

[96]  B. Berghuis,et al.  Pericyte coverage of differentiated vessels inside tumor vasculature is an independent unfavorable prognostic factor for patients with clear cell renal cell carcinoma , 2013, Cancer.

[97]  R K Jain,et al.  Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. , 1992, Cancer research.

[98]  M. Loeffler,et al.  Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. , 2006, The Journal of clinical investigation.

[99]  Mina J Bissell,et al.  The tumor microenvironment is a dominant force in multidrug resistance. , 2012, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[100]  Yuhua Wang,et al.  Incorporation of histone derived recombinant protein for enhanced disassembly of core-membrane structured liposomal nanoparticles for efficient siRNA delivery. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[101]  Jianhua Huang,et al.  A Role for VEGF as a Negative Regulator of Pericyte Function and Vessel Maturation , 2008, Nature.

[102]  R. Jain.  Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[103]  I. Kaur,et al.  Exploring solid lipid nanoparticles to enhance the oral bioavailability of curcumin. , 2011, Molecular nutrition & food research.

[104]  Yuan Zhang,et al.  Synergistic anti-tumor effects of combined gemcitabine and cisplatin nanoparticles in a stroma-rich bladder carcinoma model. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[105]  Kazuo Maruyama,et al.  Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes , 1990, FEBS letters.

[106]  Hideyoshi Harashima,et al.  A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: a strategy for overcoming the PEG dilemma. , 2011, Advanced drug delivery reviews.

[107]  T. Minko,et al.  Tumor targeted quantum dot-mucin 1 aptamer-doxorubicin conjugate for imaging and treatment of cancer. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[108]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[109]  M. Kano.  Nanotechnology and tumor microcirculation. , 2014, Advanced drug delivery reviews.

[110]  C. Engh,et al.  Five year results of the first US FDA-approved hip resurfacing device. , 2014, The Journal of arthroplasty.

[111]  R. Jain,et al.  Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors , 2011, Proceedings of the National Academy of Sciences.

[112]  B. Bauvois,et al.  New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. , 2012, Biochimica et biophysica acta.

[113]  Yuhua Wang,et al.  Multifunctional nanoparticles co-delivering Trp2 peptide and CpG adjuvant induce potent cytotoxic T-lymphocyte response against melanoma and its lung metastasis. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[114]  M. Dewhirst,et al.  Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors. , 2012, Cancer research.

[115]  Paolo P. Provenzano,et al.  Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer , 2013, British Journal of Cancer.

[116]  Rakesh K. Jain,et al.  Pathology: Cancer cells compress intratumour vessels , 2004, Nature.

[117]  R. Jain,et al.  Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner , 2012, Nature nanotechnology.

[118]  R. Baron,et al.  Engineered nanomedicine for myeloma and bone microenvironment targeting , 2014, Proceedings of the National Academy of Sciences.

[119]  Mark E. Davis,et al.  Nanoparticle therapeutics: an emerging treatment modality for cancer , 2008, Nature Reviews Drug Discovery.

[120]  Derek S. Chan,et al.  Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer , 2013, Proceedings of the National Academy of Sciences.

[121]  S. Denmeade,et al.  Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin , 2009, Molecular Cancer Therapeutics.

[122]  Dai Fukumura,et al.  Multistage nanoparticle delivery system for deep penetration into tumor tissue , 2011, Proceedings of the National Academy of Sciences.

[123]  Kunwei Shen,et al.  Stromal cells in tumor microenvironment and breast cancer , 2012, Cancer and Metastasis Reviews.

[124]  G. Ruben,et al.  Basement membrane structure in situ: evidence for lateral associations in the type IV collagen network , 1987, The Journal of cell biology.

[125]  J. Houghton,et al.  Tumor microenvironment: The role of the tumor stroma in cancer , 2007, Journal of cellular biochemistry.

[126]  Joo H. Kang,et al.  Inhibition of mammary tumor growth using lysyl oxidase-targeting nanoparticles to modify extracellular matrix. , 2012, Nano letters.

[127]  J. Hainfeld,et al.  Radiotherapy enhancement with gold nanoparticles , 2008, The Journal of pharmacy and pharmacology.

[128]  M. Ferrari,et al.  Porous silicon nanocarriers for dual targeting tumor associated endothelial cells and macrophages in stroma of orthotopic human pancreatic cancers. , 2013, Cancer letters.

[129]  Judith Campisi,et al.  Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B , 2012, Nature Medicine.

[130]  Shoogo Ueno,et al.  Enhanced magnetic resonance imaging of experimental pancreatic tumor in vivo by block copolymer-coated magnetite nanoparticles with TGF-beta inhibitor. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[131]  Gema Moreno-Bueno,et al.  Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET , 2012, Nature Medicine.

[132]  Dai Fukumura,et al.  InAs(ZnCdS) quantum dots optimized for biological imaging in the near-infrared. , 2009, Journal of the American Chemical Society.

[133]  Hubing Shi,et al.  Overexpression of platelet-derived growth factor-BB increases tumor pericyte content via stromal-derived factor-1alpha/CXCR4 axis. , 2009, Cancer research.

[134]  Yihai Cao,et al.  Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis , 2013, Nature Communications.

[135]  Milan Makale,et al.  Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis , 2008, Proceedings of the National Academy of Sciences.

[136]  R K Jain,et al.  Diffusion of macromolecules in agarose gels: comparison of linear and globular configurations. , 1999, Biophysical journal.

[137]  J. Blay,et al.  Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. , 2014, Cancer cell.

[138]  Victor S-Y Lin,et al.  Functionalized mesoporous silica nanoparticle-based visible light responsive controlled release delivery system. , 2011, Chemical communications.

[139]  Chenjie Xu,et al.  PET/MRI Dual-Modality Tumor Imaging Using Arginine-Glycine-Aspartic (RGD)–Conjugated Radiolabeled Iron Oxide Nanoparticles , 2008, Journal of Nuclear Medicine.

[140]  Kazunori Kataoka,et al.  Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling , 2007, Proceedings of the National Academy of Sciences.

[141]  A. Mammoto,et al.  Role of collagen matrix in tumor angiogenesis and glioblastoma multiforme progression. , 2013, The American journal of pathology.

[142]  C. Thaxton,et al.  Update on current and potential nanoparticle cancer therapies , 2013, Current opinion in oncology.

[143]  C. Nicholson,et al.  In vivo diffusion of lactoferrin in brain extracellular space is regulated by interactions with heparan sulfate , 2008, Proceedings of the National Academy of Sciences.

[144]  Derek S. Chan,et al.  Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer , 2012, Gut.

[145]  Yuhua Wang,et al.  Unmodified drug used as a material to construct nanoparticles: delivery of cisplatin for enhanced anti-cancer therapy. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[146]  Robert Langer,et al.  Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy , 2010, Proceedings of the National Academy of Sciences.

[147]  D. Sims,et al.  The pericyte--a review. , 1986, Tissue & cell.

[148]  M. Kano,et al.  Pericyte-coverage of human tumor vasculature and nanoparticle permeability. , 2012, Biological & pharmaceutical bulletin.

[149]  Yuhua Wang,et al.  Nanoparticle-Delivered Transforming Growth Factor-β siRNA Enhances Vaccination against Advanced Melanoma by Modifying Tumor Microenvironment , 2014, ACS nano.

[150]  Rakesh K. Jain,et al.  Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases , 2011, Nature Reviews Drug Discovery.

[151]  Peter Nordlander,et al.  Light-induced release of DNA from gold nanoparticles: nanoshells and nanorods. , 2011, Journal of the American Chemical Society.

[152]  M. Korc,et al.  Pancreatic cancer stroma: friend or foe? , 2014, Cancer cell.