Leukocytes as carriers for targeted cancer drug delivery

Introduction: Metastasis contributes to over 90% of cancer-related deaths. Numerous nanoparticle platforms have been developed to target and treat cancer, yet efficient delivery of these systems to the appropriate site remains challenging. Leukocytes, which share similarities to tumor cells in terms of their transport and migration through the body, are well suited to serve as carriers of drug delivery systems to target cancer sites. Areas covered: This review focuses on the use and functionalization of leukocytes for therapeutic targeting of metastatic cancer. Tumor cell and leukocyte extravasation, margination in the bloodstream, and migration into soft tissue are discussed, along with the potential to exploit these functional similarities to effectively deliver drugs. Current nanoparticle-based drug formulations for the treatment of cancer are reviewed, along with methods to functionalize delivery vehicles to leukocytes, either on the surface and/or within the cell. Recent progress in this area, both in vitro and in vivo, is also discussed, with a particular emphasis on targeting cancer cells in the bloodstream as a means to interrupt the metastatic process. Expert opinion: Leukocytes interact with cancer cells both in the bloodstream and at the site of solid tumors. These interactions can be utilized to effectively deliver drugs to targeted areas, which can reduce both the amount of drug required and various nonspecific cytotoxic effects within the body. If drug delivery vehicle functionalization does not interfere with leukocyte function, this approach may be utilized to neutralize tumor cells in the bloodstream to prevent the formation of new metastases, and also to deliver drugs to metastatic sites within tissues.

[1]  M. King,et al.  Fluid Shear Stress Increases Neutrophil Activation via Platelet-Activating Factor , 2014, Biophysical journal.

[2]  L. Brannon-Peppas,et al.  Nanoparticle and targeted systems for cancer therapy. , 2004, Advanced drug delivery reviews.

[3]  M. King,et al.  Fluid shear stress sensitizes cancer cells to receptor-mediated apoptosis via trimeric death receptors , 2013, New journal of physics.

[4]  R. McEver,et al.  Leukocyte trafficking mediated by selectin-carbohydrate interactions , 1995, The Journal of Biological Chemistry.

[5]  A. Richmond,et al.  Chemokines and chemokine receptors: new insights into cancer-related inflammation. , 2010, Trends in molecular medicine.

[6]  Y. Barenholz Doxil®--the first FDA-approved nano-drug: lessons learned. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[7]  Samir Mitragotri,et al.  Cell‐Based Drug Delivery Devices Using Phagocytosis‐Resistant Backpacks , 2011, Advanced materials.

[8]  K. Ley,et al.  Biomechanics of leukocyte rolling. , 2011, Biorheology.

[9]  W. Sterry,et al.  Stability of polylactic acid particles and release of fluorochromes upon topical application on human skin explants. , 2012, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[10]  Ji-Ho Park,et al.  Cooperative nanomaterial system to sensitize, target, and treat tumors , 2009, Proceedings of the National Academy of Sciences.

[11]  J. Kutok,et al.  Rolling of Human Bone-Metastatic Prostate Tumor Cells on Human Bone Marrow Endothelium under Shear Flow Is Mediated by E-Selectin , 2004, Cancer Research.

[12]  W. Pardridge The blood-brain barrier: Bottleneck in brain drug development , 2005, NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics.

[13]  Sherry X. Yang Bevacizumab and breast cancer: current therapeutic progress and future perspectives , 2009, Expert review of anticancer therapy.

[14]  P. Allavena,et al.  Cancer-related inflammation , 2008, Nature.

[15]  R. Muzzarelli,et al.  Biological activity of chitosan: ultrastructural study. , 1988, Biomaterials.

[16]  K. Ley,et al.  Neutrophil rolling at high shear: flattening, catch bond behavior, tethers and slings. , 2013, Molecular immunology.

[17]  J. A. Badwey,et al.  Active oxygen species and the functions of phagocytic leukocytes. , 1980, Annual review of biochemistry.

[18]  M. Diamond,et al.  ICAM-1 (CD54): a counter-receptor for Mac-1 (CD11b/CD18) , 1990, The Journal of cell biology.

[19]  M. Stevens,et al.  Engineering nanocomposite materials for cancer therapy. , 2010, Small.

[20]  M. Bally,et al.  Optimized procedures for the coupling of proteins to liposomes. , 1990, JIM - Journal of Immunological Methods.

[21]  G. Nicolson,et al.  Organ selectivity for implantation survival and growth of B16 melanoma variant tumor lines. , 1976, Journal of the National Cancer Institute.

[22]  Seth M Steinberg,et al.  A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. , 2003, The New England journal of medicine.

[23]  Wan-Wan Lin,et al.  Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis , 2009, Nature.

[24]  Soong Ho Um,et al.  Surface functionalization of living cells with multilayer patches. , 2008, Nano letters.

[25]  T. Reimer,et al.  Simultaneous immunohistochemical detection of tumor cells in lymph nodes and bone marrow aspirates in breast cancer and its correlation with other prognostic factors. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  Unnatural killer cells to prevent bloodborne metastasis: inspiration from biology and engineering , 2014, Expert review of anticancer therapy.

[27]  Daniel A. Heller,et al.  Treating metastatic cancer with nanotechnology , 2011, Nature Reviews Cancer.

[28]  Haixiong Ge,et al.  Synthesis and characterization of chitosan-poly(acrylic acid) nanoparticles. , 2002, Biomaterials.

[29]  M. Prato,et al.  Functionalized carbon nanotubes are non-cytotoxic and preserve the functionality of primary immune cells. , 2006, Nano letters.

[30]  Stefano Papa,et al.  NK Cells and Cancer1 , 2007, The Journal of Immunology.

[31]  K. Ley,et al.  Molecular mechanisms of leukocyte recruitment in the inflammatory process. , 1996, Cardiovascular research.

[32]  A. Mantovani,et al.  Cancer: Inflaming metastasis , 2008, Nature.

[33]  G. Murphy,et al.  Metalloproteinase-mediated Regulation of L-selectin Levels on Leucocytes (*) , 1996, The Journal of Biological Chemistry.

[34]  H. Kleinman,et al.  E‐selectin‐mediated dynamic interactions of breast‐and colon‐cancer cells with endothelial‐cell monolayers , 2006, International journal of cancer.

[35]  Zhuang Liu,et al.  Selective probing and imaging of cells with single walled carbon nanotubes as near-infrared fluorescent molecules. , 2008, Nano letters.

[36]  M. King,et al.  Nanostructured Surfaces to Target and Kill Circulating Tumor Cells While Repelling Leukocytes. , 2012, Journal of nanomaterials.

[37]  Robert Langer,et al.  Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers , 2008, Proceedings of the National Academy of Sciences.

[38]  M. King,et al.  Computational and Experimental Models of Cancer Cell Response to Fluid Shear Stress , 2013, Front. Oncol..

[39]  J. James,et al.  Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

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

[41]  Pnina Brodt,et al.  Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms , 2009, International journal of cancer.

[42]  Z. Ding,et al.  Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration. , 1999, Journal of immunology.

[43]  E. Butcher Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversity , 1991, Cell.

[44]  R. Weinberg,et al.  A Perspective on Cancer Cell Metastasis , 2011, Science.

[45]  Ann Richmond,et al.  Chemokines in health and disease. , 2011, Experimental cell research.

[46]  M. King,et al.  Mechanical Shedding of L-selectin from the Neutrophil Surface during Rolling on Sialyl Lewis x under Flow* , 2007, Journal of Biological Chemistry.

[47]  K. Gollahon,et al.  Macrophages in experimental and human brain tumors. Part 2: studies of the macrophage content of human brain tumors. , 1979, Journal of neurosurgery.

[48]  H. Pircher,et al.  CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset. , 2010, Blood.

[49]  J. Ijzermans,et al.  Preoperative dietary restriction reduces hepatic tumor load by reduced E‐selectin‐mediated adhesion in mice , 2010, Journal of surgical oncology.

[50]  George Coukos,et al.  Cancer immunotherapy comes of age , 2011, Nature.

[51]  Huajian Gao,et al.  Effect of single wall carbon nanotubes on human HEK293 cells. , 2005, Toxicology letters.

[52]  J. Izbicki,et al.  Disseminated tumor cells in lymph nodes as a determinant for survival in surgically resected non-small-cell lung cancer. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  A. Ashkenazi,et al.  Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/Tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  D. Vestweber,et al.  Mechanisms that regulate the function of the selectins and their ligands. , 1999, Physiological reviews.

[55]  Jennifer Sturgis,et al.  A cellular Trojan Horse for delivery of therapeutic nanoparticles into tumors. , 2007, Nano letters.

[56]  Robert Langer,et al.  Nanoparticle delivery of cancer drugs. , 2012, Annual review of medicine.

[57]  Timothy A. Springer,et al.  Adhesion receptors of the immune system , 1990, Nature.

[58]  Lawrence Tamarkin,et al.  Phase I and Pharmacokinetic Studies of CYT-6091, a Novel PEGylated Colloidal Gold-rhTNF Nanomedicine , 2010, Clinical Cancer Research.

[59]  A. Pries,et al.  Radial distribution of white cells during blood flow in small tubes. , 1985, Microvascular research.

[60]  H. H. Lipowsky,et al.  Leukocyte margination and deformation in mesenteric venules of rat. , 1989, The American journal of physiology.

[61]  A. Levine,et al.  Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer , 2012, Proceedings of the National Academy of Sciences.

[62]  Soong Ho Um,et al.  Therapeutic cell engineering using surface-conjugated synthetic nanoparticles , 2010, Nature Medicine.

[63]  Y. Zheng,et al.  In-vitro Strain and Modulus Measurements in Porcine Cervical Lymph Nodes , 2011, The open biomedical engineering journal.

[64]  K. Gollahon,et al.  Macrophages in experimental and human brain tumors. Part 1: Studies of the macrophage content of experimental rat brain tumors of varying immunogenicity. , 1979, Journal of neurosurgery.

[65]  Denis Wirtz,et al.  The physics of cancer: the role of physical interactions and mechanical forces in metastasis , 2011, Nature Reviews Cancer.

[66]  P. Hersey,et al.  Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types , 2000, FEBS letters.

[67]  I. Fidler Inhibition of pulmonary metastasis by intravenous injection of specifically activated macrophages. , 1974, Cancer research.

[68]  Daniel Day,et al.  Cancer cell imaging and photothermal therapy using gold nanorods , 2008 .

[69]  Yoon-Koo Kang,et al.  Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial , 2010, The Lancet.

[70]  G S Kansas,et al.  Selectins and their ligands: current concepts and controversies. , 1996, Blood.

[71]  R. Stafford,et al.  Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[72]  C. L. Graff,et al.  Drug transport at the blood-brain barrier and the choroid plexus. , 2004, Current drug metabolism.

[73]  Jennifer A. Prescher,et al.  Selective uptake of single walled carbon nanotubes by circulating monocytes for enhanced tumour delivery , 2014, Nature nanotechnology.

[74]  Y. Jou,et al.  Somatic LMCD1 mutations promoted cell migration and tumor metastasis in hepatocellular carcinoma , 2012, Oncogene.

[75]  S Chien,et al.  The interaction of leukocytes and erythrocytes in capillary and postcapillary vessels. , 1980, Microvascular research.

[76]  M. King,et al.  Physical Biology in Cancer. 3. The role of cell glycocalyx in vascular transport of circulating tumor cells , 2013, American journal of physiology. Cell physiology.

[77]  W. Liles,et al.  The phagocytes: neutrophils and monocytes. , 2008, Blood.

[78]  U. Schumacher,et al.  E-/P-selectins and colon carcinoma metastasis: first in vivo evidence for their crucial role in a clinically relevant model of spontaneous metastasis formation in the lung , 2009, British Journal of Cancer.

[79]  S. Wise Nanocarriers as an emerging platform for cancer therapy , 2007 .

[80]  Tae Gwan Park,et al.  Target-specific cellular uptake of PLGA nanoparticles coated with poly(L-lysine)-poly(ethylene glycol)-folate conjugate. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[81]  D. Lawrence,et al.  Surface thiols of human lymphocytes and their changes after in vitro and in vivo activation , 1996, Journal of leukocyte biology.

[82]  Robert Gurny,et al.  Current methods for attaching targeting ligands to liposomes and nanoparticles. , 2004, Journal of pharmaceutical sciences.

[83]  M. Rubner,et al.  Bioactive polyelectrolyte multilayers: hyaluronic acid mediated B lymphocyte adhesion. , 2010, Biomacromolecules.

[84]  Michael R. King,et al.  Unnatural killer cells: TRAIL-coated leukocytes that kill cancer cells in the circulation , 2014, NEBEC 2014.

[85]  Omid C. Farokhzad,et al.  Nanoparticle-Aptamer Bioconjugates , 2004, Cancer Research.

[86]  H. Gendelman,et al.  A macrophage-nanozyme delivery system for Parkinson's disease. , 2007, Bioconjugate chemistry.

[87]  F. Balkwill The chemokine system and cancer , 2012, The Journal of pathology.

[88]  C. Smith,et al.  Recruitment of CD11b/CD18 to the neutrophil surface and adherence-dependent cell locomotion. , 1992, The Journal of clinical investigation.

[89]  Jaspal Kaeda,et al.  Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[90]  D. Irvine,et al.  Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles. , 2012, Biomaterials.

[91]  Zhuang Liu,et al.  Drug delivery with carbon nanotubes for in vivo cancer treatment. , 2008, Cancer research.

[92]  E. Perez,et al.  Adjuvant trastuzumab: a milestone in the treatment of HER-2-positive early breast cancer. , 2006, The oncologist.

[93]  T. Fehm,et al.  Bone marrow versus sentinel lymph node involvement in breast cancer: a comparison of early hematogenous and early lymphatic tumor spread , 2011, Breast Cancer Research and Treatment.

[94]  Naomi J Halas,et al.  Theranostic nanoshells: from probe design to imaging and treatment of cancer. , 2011, Accounts of chemical research.

[95]  Austin D. Swafford,et al.  Thermal ablation of tumor cells with antibody-functionalized single-walled carbon nanotubes , 2008, Proceedings of the National Academy of Sciences.

[96]  Mehmet Toner,et al.  Circulating tumor cells: approaches to isolation and characterization , 2011, The Journal of cell biology.

[97]  Stephanie Alexander,et al.  Cancer Invasion and the Microenvironment: Plasticity and Reciprocity , 2011, Cell.

[98]  Filip Braet,et al.  Carbon nanotubes for biological and biomedical applications , 2007 .

[99]  R. Germain,et al.  Natural killer cell behavior in lymph nodes revealed by static and real-time imaging , 2006, The Journal of experimental medicine.

[100]  K. Konstantopoulos,et al.  Biophysics of selectin–ligand interactions in inflammation and cancer , 2011, Physical biology.

[101]  Robert Langer,et al.  Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling , 2013, Nature Biotechnology.

[102]  Robert E. Brown,et al.  Targeting the Apoptotic Pathway in Chondrosarcoma Using Recombinant Human Apo2L/TRAIL (Dulanermin), a Dual Proapoptotic Receptor (DR4/DR5) Agonist , 2012, Molecular Cancer Therapeutics.

[103]  B. Echtenacher,et al.  Lysis of tumor cells by natural killer cells in mice is impeded by platelets. , 1999, Cancer research.

[104]  T. Springer Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm , 1994, Cell.

[105]  A. Maitra,et al.  Tumour targeted delivery of encapsulated dextran-doxorubicin conjugate using chitosan nanoparticles as carrier. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[106]  T. Xia,et al.  Toxic Potential of Materials at the Nanolevel , 2006, Science.

[107]  P Buri,et al.  Chitosan: a unique polysaccharide for drug delivery. , 1998, Drug development and industrial pharmacy.

[108]  Jonathan W. Uhr,et al.  Tumor Cells Circulate in the Peripheral Blood of All Major Carcinomas but not in Healthy Subjects or Patients With Nonmalignant Diseases , 2004, Clinical Cancer Research.

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

[110]  D. Hume,et al.  Macrophage infiltration into experimental brain metastases: occurrence through an intact blood-brain barrier. , 1988, Journal of the National Cancer Institute.

[111]  E. Berg,et al.  Neutrophil Mac-1 and MEL-14 adhesion proteins inversely regulated by chemotactic factors. , 1989, Science.

[112]  Michael R. King,et al.  Stem Cell Enrichment with Selectin Receptors: Mimicking the pH Environment of Trauma , 2013, Sensors.

[113]  A. Bangham Liposomes: the Babraham connection. , 1993, Chemistry and physics of lipids.

[114]  E. Choi,et al.  Use of macrophages to deliver therapeutic and imaging contrast agents to tumors. , 2012, Biomaterials.

[115]  R. Herbst,et al.  Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[116]  H. Gendelman,et al.  Macrophage delivery of therapeutic nanozymes in a murine model of Parkinson's disease. , 2010, Nanomedicine.

[117]  J. Chow,et al.  MUC1 Mediates Transendothelial Migration in vitro by Ligating Endothelial Cell ICAM-1 , 2005, Clinical & Experimental Metastasis.

[118]  H. Goldsmith,et al.  Margination of leukocytes in blood flow through small tubes. , 1984, Microvascular research.

[119]  R. Vessella,et al.  Cancer micrometastasis and tumour dormancy   , 2008, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[120]  Nastassja A. Lewinski,et al.  Cytotoxicity of nanoparticles. , 2008, Small.

[121]  R. Schreiber,et al.  Cancer immunoediting: from immunosurveillance to tumor escape , 2002, Nature Immunology.

[122]  Janice M. Y. Brown,et al.  The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture. , 1999, Cancer research.

[123]  R. Bresalier,et al.  Liver endothelial E‐selectin mediates carcinoma cell adhesion and promotes liver metastasis , 1997, International journal of cancer.

[124]  Timothy A. Springer,et al.  Adhesion through L-selectin requires a threshold hydrodynamic shear , 1996, Nature.

[125]  D. Haber,et al.  Circulating tumor cells: a window into cancer biology and metastasis. , 2010, Current opinion in genetics & development.

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

[127]  A microfluidic device to select for cells based on chemotactic phenotype. , 2014, Technology.

[128]  I. Fidler Biological behavior of malignant melanoma cells correlated to their survival in vivo. , 1975, Cancer research.

[129]  V. Torchilin Recent advances with liposomes as pharmaceutical carriers , 2005, Nature Reviews Drug Discovery.

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

[131]  D. Irvine,et al.  Freely Suspended Cellular “Backpacks” Lead to Cell Aggregate Self-Assembly , 2010, Biomacromolecules.

[132]  M. King,et al.  Sweeping lymph node micrometastases off their feet: an engineered model to evaluate natural killer cell mediated therapeutic intervention of circulating tumor cells that disseminate to the lymph nodes. , 2014, Lab on a chip.

[133]  R. Guo,et al.  Synthesis of alginic acid-poly[2-(diethylamino)ethyl methacrylate] monodispersed nanoparticles by a polymer-monomer pair reaction system. , 2007, Biomacromolecules.

[134]  R. Langer,et al.  Nanotechnology for biomaterials engineering: structural characterization of amphiphilic polymeric nanoparticles by 1H NMR spectroscopy. , 1997, Biomaterials.

[135]  K. Pienta,et al.  Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking , 2009, Proceedings of the National Academy of Sciences.

[136]  Nabil Ahmed,et al.  Crosstalk between Medulloblastoma Cells and Endothelium Triggers a Strong Chemotactic Signal Recruiting T Lymphocytes to the Tumor Microenvironment , 2011, PloS one.

[137]  P. Hogg,et al.  Presence of closely spaced protein thiols on the surface of mammalian cells , 2000, Protein science : a publication of the Protein Society.

[138]  A. Tulpule,et al.  Improving the therapeutic index of anthracycline chemotherapy: focus on liposomal doxorubicin (Myocet). , 2009, Breast.

[139]  M. King,et al.  E-selectin liposomal and nanotube-targeted delivery of doxorubicin to circulating tumor cells. , 2012, Journal of Controlled Release.

[140]  Indu Bala,et al.  PLGA nanoparticles in drug delivery: the state of the art. , 2004, Critical reviews in therapeutic drug carrier systems.

[141]  Eric Pridgen,et al.  Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles , 2008, Molecular pharmaceutics.

[142]  Julia T. Chu,et al.  HCELL Is the Major E- and L-selectin Ligand Expressed on LS174T Colon Carcinoma Cells* , 2006, Journal of Biological Chemistry.

[143]  M. Alonso,et al.  Chitosan and Chitosan/Ethylene Oxide-Propylene Oxide Block Copolymer Nanoparticles as Novel Carriers for Proteins and Vaccines , 1997, Pharmaceutical Research.

[144]  G. Christofori New signals from the invasive front , 2006, Nature.

[145]  G. Borisy,et al.  Cell Migration: Integrating Signals from Front to Back , 2003, Science.

[146]  Seungpyo Hong,et al.  Direct measurements on CD24-mediated rolling of human breast cancer MCF-7 cells on E-selectin. , 2011, Analytical chemistry.

[147]  R. Hynes,et al.  Lymphatic or Hematogenous Dissemination: How Does a Metastatic Tumor Cell Decide? , 2006, Cell cycle.

[148]  M. King,et al.  Shear-induced resistance to neutrophil activation via the formyl peptide receptor. , 2011, Biophysical journal.

[149]  I. Stamenkovic,et al.  Redirection of tumor metastasis by expression of E-selectin in vivo , 1996, The Journal of experimental medicine.

[150]  Keith M. Stantz,et al.  Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse , 2012, Cancer Nanotechnology.

[151]  Naomi J Halas,et al.  Nanoshell-enabled photothermal cancer therapy: impending clinical impact. , 2008, Accounts of chemical research.

[152]  Yan Xu,et al.  The Ubiquitin–CXCR4 Axis Plays an Important Role in Acute Lung Infection–Enhanced Lung Tumor Metastasis , 2013, Clinical Cancer Research.

[153]  S. Groshen,et al.  Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. , 2000, Annals of oncology : official journal of the European Society for Medical Oncology.

[154]  C. Rauch,et al.  Tumoricidal activity of tumor necrosis factor–related apoptosis–inducing ligand in vivo , 1999, Nature Medicine.

[155]  E. Butcher,et al.  Identification of a human peripheral lymph node homing receptor: a rapidly down-regulated adhesion molecule. , 1990, Proceedings of the National Academy of Sciences of the United States of America.