Barriers to drug delivery in solid tumors

Over the last decade, significant progress has been made in the field of drug delivery. The advent of engineered nanoparticles has allowed us to circumvent the initial limitations to drug delivery such as pharmacokinetics and solubility. However, in spite of significant advances to tumor targeting, an effective treatment strategy for malignant tumors still remains elusive. Tumors possess distinct physiological features which allow them to resist traditional treatment approaches. This combined with the complexity of the biological system presents significant hurdles to the site-specific delivery of therapeutic drugs. One of the key features of engineered nanoparticles is that these can be tailored to execute specific functions. With this review, we hope to provide the reader with a clear understanding and knowledge of biological barriers and the methods to exploit these characteristics to design multifunctional nanocarriers, effect useful dosing regimens and subsequently improve therapeutic outcomes in the clinic.

[1]  Jan E Schnitzer,et al.  Overcoming in vivo barriers to targeted nanodelivery. , 2011, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[2]  Ezequiel Bernabeu,et al.  The transferrin receptor and the targeted delivery of therapeutic agents against cancer. , 2012, Biochimica et biophysica acta.

[3]  Q. Lu,et al.  Nanoparticle-mediated drug delivery to tumor neovasculature to combat P-gp expressing multidrug resistant cancer. , 2013, Biomaterials.

[4]  V. Torchilin,et al.  Phospholipid–polyethylenimine conjugate-based micelle-like nanoparticles for siRNA delivery , 2011, Drug Delivery and Translational Research.

[5]  R. Giavazzi,et al.  Matrix metalloproteinase inhibition: a review of anti-tumour activity. , 1995, Annals of oncology : official journal of the European Society for Medical Oncology.

[6]  Olga Kovalchuk,et al.  Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin , 2008, Molecular Cancer Therapeutics.

[7]  K. Brew,et al.  Reactive Site Mutations in Tissue Inhibitor of Metalloproteinase-3 Disrupt Inhibition of Matrix Metalloproteinases but Not Tumor Necrosis Factor-α-converting Enzyme* , 2005, Journal of Biological Chemistry.

[8]  G. Wood,et al.  Targeted nanoparticulate drug-delivery systems for treatment of solid tumors: a review. , 2010, Therapeutic delivery.

[9]  S. Hanada,et al.  Expression of the multidrug transporter, P‐glycoprotein, in acute leukemia cells and correlation to clinical drug resistance , 1990, Cancer.

[10]  W. Kuebler,et al.  Co‐regulation of Transcellular and Paracellular Leak Across Microvascular Endothelium By Dynamin and Rac , 2012, The American journal of pathology.

[11]  Marianne Fillet,et al.  NF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells , 2003, Oncogene.

[12]  P. Sutphin,et al.  Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy , 2007, Proceedings of the National Academy of Sciences.

[13]  C. Hopkins,et al.  Signal-dependent membrane protein trafficking in the endocytic pathway. , 1993, Annual review of cell biology.

[14]  D. Talbot,et al.  Experimental and clinical studies on the use of matrix metalloproteinase inhibitors for the treatment of cancer. , 1996, European journal of cancer.

[15]  P. Low,et al.  Ligand Binding and Kinetics of Folate Receptor Recycling in Vivo: Impact on Receptor-Mediated Drug Delivery , 2004, Molecular Pharmacology.

[16]  M Ferrari,et al.  Size and shape effects in the biodistribution of intravascularly injected particles. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[17]  Cui Tang,et al.  Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. , 2010, Biomaterials.

[18]  M. Papisov,et al.  Why do Polyethylene Glycol-Coated Liposomes Circulate So Long?: Molecular Mechanism of Liposome Steric Protection with Polyethylene Glycol: Role of Polymer Chain Flexibility , 1994 .

[19]  R M Heethaar,et al.  Blood platelets are concentrated near the wall and red blood cells, in the center in flowing blood. , 1988, Arteriosclerosis.

[20]  Pallavi Sethi,et al.  Tumor microenvironment and nanotherapeutics. , 2013, Translational cancer research.

[21]  J. Cooper,et al.  Endothelial barrier function. , 1989, The Journal of investigative dermatology.

[22]  Masahiro Hiraoka,et al.  Optical Imaging of Tumor Hypoxia and Evaluation of Efficacy of a Hypoxia-Targeting Drug in Living Animals , 2005, Molecular imaging.

[23]  R. Gillies,et al.  pH and drug resistance in tumors. , 2000, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[24]  Giulio Caracciolo,et al.  Effect of DOPE and cholesterol on the protein adsorption onto lipid nanoparticles , 2013, Journal of Nanoparticle Research.

[25]  Hideyoshi Harashima,et al.  Enhanced Hepatic Uptake of Liposomes Through Complement Activation Depending on the Size of Liposomes , 1994, Pharmaceutical Research.

[26]  Xìao-chun Xu,et al.  Prognostic significance of MMP‐9 and TIMP‐1 serum and tissue expression in breast cancer , 2008, International journal of cancer.

[27]  Lin Zhang,et al.  Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells , 2011, Nature.

[28]  Vladimir P Torchilin,et al.  Enhanced transfection of tumor cells in vivo using “Smart” pH-sensitive TAT-modified pegylated liposomes , 2007, Journal of drug targeting.

[29]  D. Hanahan,et al.  Induction of angiogenesis during the transition from hyperplasia to neoplasia , 1989, Nature.

[30]  W. Stetler-Stevenson,et al.  Proteases in invasion: matrix metalloproteinases. , 2001, Seminars in cancer biology.

[31]  Wen-Qi Jiang,et al.  Reversal of MRP7 (ABCC10)-Mediated Multidrug Resistance by Tariquidar , 2013, PloS one.

[32]  Dai Fukumura,et al.  Tumor microenvironment abnormalities: Causes, consequences, and strategies to normalize , 2007, Journal of cellular biochemistry.

[33]  Y. Maitani,et al.  Cationic liposome (DC-Chol/DOPE=1:2) and a modified ethanol injection method to prepare liposomes, increased gene expression. , 2007, International journal of pharmaceutics.

[34]  Ning Gu,et al.  Preparation, characterization and evaluation of breviscapine lipid emulsions coated with monooleate-PEG-COOH. , 2011, International journal of pharmaceutics.

[35]  Vladimir P Torchilin,et al.  Multifunctional nanocarriers. , 2006, Advanced drug delivery reviews.

[36]  Nicholas Denko,et al.  Overcoming Physiologic Barriers to Cancer Treatment by Molecularly Targeting the Tumor Microenvironment , 2006, Molecular Cancer Research.

[37]  Vladimir P Torchilin,et al.  pH-sensitive poly(histidine)-PEG/DSPE-PEG co-polymer micelles for cytosolic drug delivery. , 2013, Biomaterials.

[38]  J. Garcia,et al.  Lung endothelial heparan sulfates mediate cationic peptide-induced barrier dysfunction: a new role for the glycocalyx. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[39]  J. Benoit,et al.  Evaluation of pegylated lipid nanocapsules versus complement system activation and macrophage uptake. , 2006, Journal of biomedical materials research. Part A.

[40]  Francesco Stellacci,et al.  Effect of surface properties on nanoparticle-cell interactions. , 2010, Small.

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

[42]  Rakesh K. Jain,et al.  Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors , 2004, Cancer Research.

[43]  Umesh Kumar,et al.  Cellular Binding of Anionic Nanoparticles is Inhibited by Serum Proteins Independent of Nanoparticle Composition. , 2013, Biomaterials science.

[44]  S. Zahler,et al.  Endothelial Glycocalyx as an Additional Barrier Determining Extravasation of 6% Hydroxyethyl Starch or 5% Albumin Solutions in the Coronary Vascular Bed , 2004, Anesthesiology.

[45]  Vladimir P Torchilin,et al.  Increased apoptosis in cancer cells in vitro and in vivo by ceramides in transferrin-modified liposomes , 2012, Cancer biology & therapy.

[46]  Chi-Hwa Wang,et al.  Transferrin-conjugated magnetic silica PLGA nanoparticles loaded with doxorubicin and paclitaxel for brain glioma treatment. , 2013, Biomaterials.

[47]  R. Jain,et al.  Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. , 2013, Cancer research.

[48]  L. Matrisian,et al.  Changing views of the role of matrix metalloproteinases in metastasis. , 1997, Journal of the National Cancer Institute.

[49]  Brenda Baggett,et al.  Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro. , 2003, Biochemical pharmacology.

[50]  Krishnamurthy V. Nemani,et al.  The diaphragms of fenestrated endothelia: gatekeepers of vascular permeability and blood composition. , 2012, Developmental cell.

[51]  E. Rofstad,et al.  High Interstitial Fluid Pressure Is Associated with Tumor-Line Specific Vascular Abnormalities in Human Melanoma Xenografts , 2012, PloS one.

[52]  Gaurav Sahay,et al.  Endocytosis of nanomedicines. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[53]  Y. Boucher,et al.  Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  Katharina Landfester,et al.  Differential uptake of functionalized polystyrene nanoparticles by human macrophages and a monocytic cell line. , 2011, ACS nano.

[55]  R. Brock,et al.  Cell surface clustering of heparan sulfate proteoglycans by amphipathic cell-penetrating peptides does not contribute to uptake. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[56]  I. Zuhorn,et al.  Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. , 2004, The Biochemical journal.

[57]  D. Pinsky,et al.  Targeting therapeutics to the vascular wall in atherosclerosis--carrier size matters. , 2011, Atherosclerosis.

[58]  L. Liotta,et al.  Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. , 1974, Cancer research.

[59]  Carlos López-Otín,et al.  Strategies for MMP inhibition in cancer: innovations for the post-trial era , 2002, Nature Reviews Cancer.

[60]  Palmitoyl Ascorbate Liposomes and Free Ascorbic Acid: Comparison of Anticancer Therapeutic Effects Upon Parenteral Administration , 2012, Pharmaceutical Research.

[61]  Phapanin Charoenphol,et al.  Potential role of size and hemodynamics in the efficacy of vascular-targeted spherical drug carriers. , 2010, Biomaterials.

[62]  R. van Furth The mononuclear phagocyte system. , 1980, Verhandlungen der Deutschen Gesellschaft fur Pathologie.

[63]  I. Elkin,et al.  Drug-loaded nanocarriers: passive targeting and crossing of biological barriers. , 2012, Current medicinal chemistry.

[64]  Dieter Haemmerich,et al.  Improved intratumoral nanoparticle extravasation and penetration by mild hyperthermia. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

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

[66]  Angelo Corti,et al.  Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. , 2002, The Journal of clinical investigation.

[67]  Vladimir P Torchilin,et al.  Tumor-specific antibody-mediated targeted delivery of Doxil reduces the manifestation of auricular erythema side effect in mice. , 2008, International journal of pharmaceutics.

[68]  A. Hilgeroth,et al.  Development of small-molecule P-gp inhibitors of the N-benzyl 1,4-dihydropyridine type: novel aspects in SAR and bioanalytical evaluation of multidrug resistance (MDR) reversal properties. , 2013, Bioorganic & medicinal chemistry.

[69]  Long Yu,et al.  Reversal of P-gp and MRP1-mediated multidrug resistance by H6, a gypenoside aglycon from Gynostemma pentaphyllum, in vincristine-resistant human oral cancer (KB/VCR) cells. , 2012, European journal of pharmacology.

[70]  P. Charoenphol,et al.  Particle-cell dynamics in human blood flow: implications for vascular-targeted drug delivery. , 2012, Journal of biomechanics.

[71]  H. Kim,et al.  An efficient liposomal gene delivery vehicle using Sendai F/HN proteins and protamine , 2008, Cancer Gene Therapy.

[72]  Lin Zhu,et al.  Stimulus-responsive nanopreparations for tumor targeting. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[73]  Parag Aggarwal,et al.  Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. , 2009, Advanced drug delivery reviews.

[74]  Daniel G. Anderson,et al.  Knocking down barriers: advances in siRNA delivery , 2009, Nature Reviews Drug Discovery.

[75]  D. Tzemach,et al.  Nuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance efflux pump. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[76]  A. Davidoff,et al.  Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model. , 2002, Blood.

[77]  M Beth McCarville,et al.  Bevacizumab-Induced Transient Remodeling of the Vasculature in Neuroblastoma Xenografts Results in Improved Delivery and Efficacy of Systemically Administered Chemotherapy , 2007, Clinical Cancer Research.

[78]  Vladimir P Torchilin,et al.  Efficient intracellular drug-targeting of macrophages using stealth liposomes directed to the hemoglobin scavenger receptor CD163. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[79]  S. Parveen,et al.  Long circulating chitosan/PEG blended PLGA nanoparticle for tumor drug delivery. , 2011, European journal of pharmacology.

[80]  K. Chen,et al.  Nanoparticles meet cell membranes: probing nonspecific interactions using model membranes. , 2014, Environmental science & technology.

[81]  A. Dufour,et al.  Inhibition of Matrix Metalloproteinase 14 (MMP-14)-mediated Cancer Cell Migration* , 2011, The Journal of Biological Chemistry.

[82]  L. Gerweck,et al.  The pH partition theory predicts the accumulation and toxicity of doxorubicin in normal and low-pH-adapted cells , 1999, British Journal of Cancer.

[83]  S. Leung,et al.  Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. , 2011, Cancer research.

[84]  V. Torchilin,et al.  Polyethyleneimine-lipid conjugate-based pH-sensitive micellar carrier for gene delivery. , 2012, Biomaterials.

[85]  C. Overall,et al.  Towards third generation matrix metalloproteinase inhibitors for cancer therapy , 2006, British Journal of Cancer.

[86]  Christina L. Ting,et al.  Interactions of a charged nanoparticle with a lipid membrane: implications for gene delivery. , 2011, Biophysical journal.

[87]  Vladimir P Torchilin,et al.  Multifunctional PEGylated 2C5-immunoliposomes containing pH-sensitive bonds and TAT peptide for enhanced tumor cell internalization and cytotoxicity. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[88]  D. Hallahan,et al.  Proteolytic surface functionalization enhances in vitro magnetic nanoparticle mobility through extracellular matrix. , 2006, Nano letters.

[89]  Stephen Gould,et al.  Canonical hedgehog signaling augments tumor angiogenesis by induction of VEGF-A in stromal perivascular cells , 2011, Proceedings of the National Academy of Sciences.

[90]  H. Maeda,et al.  A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. , 1986, Cancer research.

[91]  B. Zhang,et al.  LDLR-mediated peptide-22-conjugated nanoparticles for dual-targeting therapy of brain glioma. , 2013, Biomaterials.

[92]  A. Degterev,et al.  Micellar formulations of pro-apoptotic DM-PIT-1 analogs and TRAIL in vitro and in vivo , 2013, Drug delivery.

[93]  R. Athawale,et al.  Studies on stabilization mechanism and stealth effect of poloxamer 188 onto PLGA nanoparticles. , 2013, Colloids and surfaces. B, Biointerfaces.

[94]  Jun Qian,et al.  Up-regulating Blood Brain Barrier Permeability of Nanoparticles via Multivalent Effect , 2013, Pharmaceutical Research.

[95]  V. Torchilin,et al.  Lipid modified triblock PAMAM-based nanocarriers for siRNA drug co-delivery. , 2013, Biomaterials.

[96]  T. Xia,et al.  Understanding biophysicochemical interactions at the nano-bio interface. , 2009, Nature materials.

[97]  M. Junttila,et al.  Influence of tumour micro-environment heterogeneity on therapeutic response , 2013, Nature.

[98]  Sara Linse,et al.  Understanding the nanoparticle–protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles , 2007, Proceedings of the National Academy of Sciences.

[99]  A. Corti,et al.  Tumor Vascular Targeting with Tumor Necrosis Factor α and Chemotherapeutic Drugs , 2004 .

[100]  M. Dewhirst,et al.  Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-β and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation , 2006, British Journal of Cancer.

[101]  P. Kristjansen,et al.  Early effects of combretastatin-A4 disodium phosphate on tumor perfusion and interstitial fluid pressure. , 2007, Neoplasia.

[102]  V. Torchilin,et al.  Doxorubicin in TAT peptide-modified multifunctional immunoliposomes demonstrates increased activity against both drug-sensitive and drug-resistant ovarian cancer models , 2014, Cancer biology & therapy.

[103]  J. Panyam,et al.  Nanoparticle-mediated simultaneous and targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[104]  P. Jones,et al.  Destruction of extracellular matrices containing glycoproteins, elastin, and collagen by metastatic human tumor cells. , 1980, Cancer research.

[105]  J. Kamps,et al.  The role of apolipoprotein E in the elimination of liposomes from blood by hepatocytes in the mouse. , 2005, Biochemical and biophysical research communications.

[106]  Lin Zhu,et al.  Matrix metalloprotease 2-responsive multifunctional liposomal nanocarrier for enhanced tumor targeting. , 2012, ACS nano.

[107]  G. Fleuren,et al.  Tumor structure and extracellular matrix as a possible barrier for therapeutic approaches using immune cells or adenoviruses in colorectal cancer , 2001, Histochemistry and Cell Biology.

[108]  Gert Storm,et al.  Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system , 1995 .

[109]  A. Corti,et al.  Tumor vascular targeting with tumor necrosis factor alpha and chemotherapeutic drugs. , 2004, Annals of the New York Academy of Sciences.

[110]  V. Yang,et al.  Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours , 2008, BMC Cancer.

[111]  A. Zhang,et al.  Study of non-uniform nanoparticle liposome extravasation in tumour , 2005, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[112]  W. Mark Saltzman,et al.  Dilation and degradation of the brain extracellular matrix enhances penetration of infused polymer nanoparticles , 2007, Brain Research.

[113]  V. Torchilin,et al.  P-glycoprotein silencing with siRNA delivered by DOPE-modified PEI overcomes doxorubicin resistance in breast cancer cells. , 2012, Nanomedicine.

[114]  Vladimir P Torchilin,et al.  Reversal of multidrug resistance by co-delivery of tariquidar (XR9576) and paclitaxel using long-circulating liposomes. , 2011, International journal of pharmaceutics.

[115]  Jian Ding,et al.  PEGylated polycyanoacrylate nanoparticles as tumor necrosis factor-α carriers , 2001 .

[116]  L. Liotta,et al.  Extracellular matrix 6: Role of matrix metalloproteinases in tumor invasion and metastasis , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[117]  I. Zuhorn,et al.  Gene delivery by cationic lipid vectors: overcoming cellular barriers , 2007, European Biophysics Journal.

[118]  Kit S Lam,et al.  The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. , 2011, Biomaterials.

[119]  A. Bikfalvi,et al.  Tumor angiogenesis , 2020, Advances in cancer research.

[120]  E. Rofstad,et al.  Quantitative assessment of uptake and distribution of iron oxide particles (NC100150) in human melanoma xenografts by contrast‐enhanced MRI , 2004, Magnetic resonance in medicine.

[121]  Rakesh K. Jain,et al.  Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy , 2001, Nature Medicine.

[122]  Vladimir P Torchilin,et al.  The effect of dual ligand-targeted micelles on the delivery and efficacy of poorly soluble drug for cancer therapy , 2013, Journal of drug targeting.

[123]  A Ciechanover,et al.  Kinetics of internalization and recycling of transferrin and the transferrin receptor in a human hepatoma cell line. Effect of lysosomotropic agents. , 1983, The Journal of biological chemistry.

[124]  V. Torchilin,et al.  Octa-arginine-modified pegylated liposomal doxorubicin: an effective treatment strategy for non-small cell lung cancer. , 2013, Cancer letters.

[125]  Yan Zhang,et al.  Dual-targeting daunorubicin liposomes improve the therapeutic efficacy of brain glioma in animals. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[126]  Chen Jiang,et al.  T7 peptide-functionalized nanoparticles utilizing RNA interference for glioma dual targeting. , 2013, International journal of pharmaceutics.

[127]  Si-Shen Feng,et al.  Effects of Particle Size and Surface Modification on Cellular Uptake and Biodistribution of Polymeric Nanoparticles for Drug Delivery , 2013, Pharmaceutical Research.

[128]  V. Torchilin,et al.  Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety , 2013, Proceedings of the National Academy of Sciences.

[129]  I. Tannock,et al.  Influence of low pH on cytotoxicity of paclitaxel, mitoxantrone and topotecan. , 1997, British Journal of Cancer.

[130]  M. Hiraoka,et al.  Tumor hypoxia: A target for selective cancer therapy , 2003, Cancer science.

[131]  Vladimir P. Torchilin,et al.  Liposomes as ‘smart’ pharmaceutical nanocarriers , 2010 .

[132]  Ajit Varki,et al.  Molecular basis of metastasis. , 2009, The New England journal of medicine.

[133]  Charles R. Martin Nanomedicine: a great first year and, with your help, a bright future ahead , 2007 .

[134]  Jianjun Cheng,et al.  Targeted delivery of RNA-cleaving DNA enzyme (DNAzyme) to tumor tissue by transferrin-modified, cyclodextrin-based particles , 2004, Cancer biology & therapy.

[135]  Jiuhong Kang,et al.  Histone Deacetylase (HDAC) 10 Suppresses Cervical Cancer Metastasis through Inhibition of Matrix Metalloproteinase (MMP) 2 and 9 Expression* , 2013, The Journal of Biological Chemistry.

[136]  Vladimir P Torchilin,et al.  Bleomycin in octaarginine-modified fusogenic liposomes results in improved tumor growth inhibition. , 2013, Cancer letters.

[137]  J. S. Rao,et al.  Tissue inhibitor of metalloproteinase 3 suppresses tumor angiogenesis in matrix metalloproteinase 2-down-regulated lung cancer. , 2008, Cancer research.

[138]  Quanyin Hu,et al.  Co-administration of dual-targeting nanoparticles with penetration enhancement peptide for antiglioblastoma therapy. , 2014, Molecular pharmaceutics.

[139]  Jianqing Gao,et al.  Characteristics of sequential targeting of brain glioma for transferrin-modified cisplatin liposome. , 2013, International journal of pharmaceutics.

[140]  R. Jain,et al.  Role of extracellular matrix assembly in interstitial transport in solid tumors. , 2000, Cancer research.

[141]  W. Stetler-Stevenson,et al.  Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. , 1999, The Journal of clinical investigation.

[142]  Bert Vogelstein,et al.  Overcoming the hypoxic barrier to radiation therapy with anaerobic bacteria , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[143]  Tao Zhang,et al.  Pigment epithelium-derived factor inhibits glioma cell growth in vitro and in vivo. , 2007, Life sciences.

[144]  R K Jain,et al.  Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. , 1999, Cancer research.

[145]  Ulo Langel,et al.  Cell-penetrating peptides: mechanism and kinetics of cargo delivery. , 2005, Advanced drug delivery reviews.

[146]  Yu-Lan Hu,et al.  Glioma targeting and blood-brain barrier penetration by dual-targeting doxorubincin liposomes. , 2013, Biomaterials.

[147]  S. Biswas,et al.  Hypoxia-targeted siRNA delivery. , 2014, Angewandte Chemie.

[148]  A. Corti,et al.  Synergistic Antitumor Activity of Cisplatin, Paclitaxel, and Gemcitabine with Tumor Vasculature-Targeted Tumor Necrosis Factor-α , 2006, Clinical Cancer Research.

[149]  Vladimir P Torchilin,et al.  Enhanced cytotoxicity of TATp-bearing paclitaxel-loaded micelles in vitro and in vivo. , 2009, International journal of pharmaceutics.

[150]  Alex Vitkin,et al.  Effects of the vascular disrupting agent ZD6126 on interstitial fluid pressure and cell survival in tumors. , 2006, Cancer research.

[151]  S. Pun,et al.  Increased nanoparticle penetration in collagenase-treated multicellular spheroids , 2007, International journal of nanomedicine.