Multifunctional nanoemulsion platform for imaging guided therapy evaluated in experimental cancer.

Nanoparticle applications in medicine have seen a tremendous growth in the past decade. In addition to their drug targeting application and their ability to improve bioavailability of drugs, nanoparticles can be designed to allow their detection with a variety of imaging methodologies. In the current study, we developed a multimodal nanoparticle platform to enable imaging guided therapy, which was evaluated in a colon cancer mouse model. This "theranostic" platform is based on oil-in-water nanoemulsions and carries iron oxide nanocrystals for MRI, the fluorescent dye Cy7 for NIRF imaging, and the hydrophobic glucocorticoid prednisolone acetate valerate (PAV) for therapeutic purposes. Angiogenesis-targeted nanoemulsions functionalized with αvβ(3)-specific RGD peptides were evaluated, as well. When subcutaneous tumors were palpable, the nanoemulsions were administered at a dose of 30 mg of FeO/kg and 10 mg of PAV/kg. MRI and NIRF imaging showed significant nanoparticle accumulation in the tumors, while tumor growth profiles revealed a potent inhibitory effect in all of the PAV nanoemulsion-treated animals as compared to the ones treated with control nanoemulsions, the free drug, or saline. This study demonstrated that our nanoemulsions, when loaded with PAV, iron oxide nanocrystals, and Cy7, represent a flexible and unique theranostic nanoparticle platform that can be applied for imaging guided therapy of cancer.

[1]  R. Schiffelers,et al.  Liposomal glucocorticoids as tumor-targeted anti-angiogenic nanomedicine in B16 melanoma-bearing mice , 2008, The Journal of Steroid Biochemistry and Molecular Biology.

[2]  A. Griffioen,et al.  Monocyte/macrophage infiltration in tumors: modulators of angiogenesis , 2006, Journal of leukocyte biology.

[3]  Klaas Nicolay,et al.  MR molecular imaging and fluorescence microscopy for identification of activated tumor endothelium using a bimodal lipidic nanoparticle , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  R K Jain,et al.  Openings between defective endothelial cells explain tumor vessel leakiness. , 2000, The American journal of pathology.

[5]  A. Pathak,et al.  Antiangiogenic effects of dexamethasone in 9L gliosarcoma assessed by MRI cerebral blood volume maps. , 2003, Neuro-oncology.

[6]  D. Cheresh,et al.  Requirement of vascular integrin alpha v beta 3 for angiogenesis. , 1994, Science.

[7]  L. Calvo,et al.  Phase I clinical trial of liposomal-encapsulated doxorubicin citrate and docetaxel, associated with trastuzumab, as neo-adjuvant treatment in stages II and IIIA, HER2-overexpressing breast cancer patients. GEICAM 2003-03 study. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[8]  R. Schiffelers,et al.  Antitumor activity and tumor localization of liposomal glucocorticoids in B16 melanoma-bearing mice. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[9]  J. Fendler,et al.  Liposomes as drug carriers. , 1977, Life sciences.

[10]  Gaurav Kumar Jain,et al.  Metallic nanoparticles: technology overview & drug delivery applications in oncology , 2010, Expert opinion on drug delivery.

[11]  Y. Iwakura,et al.  IL-1 is required for tumor invasiveness and angiogenesis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Immobilized platelets support human colon carcinoma cell tethering, rolling, and firm adhesion under dynamic flow conditions , 2000 .

[13]  T. Wheeler,et al.  Reduced infiltration of tumor-associated macrophages in human prostate cancer: association with cancer progression. , 2000, Cancer research.

[14]  T. Allen Long-circulating (sterically stabilized) liposomes for targeted drug delivery. , 1994, Trends in pharmacological sciences.

[15]  H. Ghandehari,et al.  Nanocarriers for nuclear imaging and radiotherapy of cancer. , 2006, Current pharmaceutical design.

[16]  Klaas Nicolay,et al.  Improved magnetic resonance molecular imaging of tumor angiogenesis by avidin-induced clearance of nonbound bimodal liposomes. , 2008, Neoplasia.

[17]  G. Goldstein,et al.  Dexamethasone reduces vascular density and plasminogen activator activity in 9L rat brain tumors , 1993, Brain Research.

[18]  E. Ruoslahti,et al.  Arg-Gly-Asp: A versatile cell recognition signal , 1986, Cell.

[19]  R. Schiffelers,et al.  Therapeutic Application of Long-Circulating Liposomal Glucocorticoids in Auto-Immune Diseases and Cancer , 2006, Journal of liposome research.

[20]  Klaas Nicolay,et al.  MRI contrast agents: current status and future perspectives. , 2007, Anti-cancer agents in medicinal chemistry.

[21]  Robert Langer,et al.  Nanoparticle technologies for cancer therapy. , 2010, Handbook of experimental pharmacology.

[22]  Shuang Liu Radiolabeled Multimeric Cyclic RGD Peptides as Integrin αvβ3 Targeted Radiotracers for Tumor Imaging , 2006 .

[23]  T. Forte,et al.  Electron microscopy of negatively stained lipoproteins. , 1986, Methods in enzymology.

[24]  J Verweij,et al.  Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. , 2001, European journal of cancer.

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

[26]  A. Harris,et al.  Tumor-Associated Macrophages in Breast Cancer , 2002, Journal of Mammary Gland Biology and Neoplasia.

[27]  Z. Fayad,et al.  RGD peptide functionalized and reconstituted high‐density lipoprotein nanoparticles as a versatile and multimodal tumor targeting molecular imaging probe , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[28]  Klaas Nicolay,et al.  Lipid‐based nanoparticles for contrast‐enhanced MRI and molecular imaging , 2006, NMR in biomedicine.

[29]  Jeremy J. W. Chen,et al.  Up-regulation of tumor interleukin-8 expression by infiltrating macrophages: its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[30]  M. Rosenblum,et al.  Detecting and Treating Cancer with Nanotechnology , 2012, Molecular Diagnosis & Therapy.

[31]  B. Ross,et al.  Targeted imaging and therapy of brain cancer using theranostic nanoparticles. , 2010, Molecular pharmaceutics.

[32]  David A. Cheresh,et al.  Detection of tumor angiogenesis in vivo by αvβ3-targeted magnetic resonance imaging , 1998, Nature Medicine.

[33]  A. Griffioen,et al.  Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. , 2000, Pharmacological reviews.

[34]  Zahi A Fayad,et al.  Multifunctional imaging nanoprobes. , 2010, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[35]  Grietje Molema,et al.  Preparation and functional evaluation of RGD-modified proteins as alpha(v)beta(3) integrin directed therapeutics. , 2002, Bioconjugate chemistry.

[36]  R. Pierce,et al.  Matrix metalloproteinases generate angiostatin: effects on neovascularization. , 1998, Journal of immunology.

[37]  Zahi A Fayad,et al.  Nanotechnology in Medical Imaging: Probe Design and Applications , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[38]  A. Pardakhty,et al.  Role of nanocarrier systems in cancer nanotherapy , 2009, Journal of liposome research.

[39]  Anna Moore,et al.  In vivo imaging of siRNA delivery and silencing in tumors , 2007, Nature Medicine.

[40]  E. Carrasco,et al.  Phase II clinical trial of liposomal-encapsulated doxorubicin citrate and docetaxel, associated with trastuzumab, as neoadjuvant treatment in stages II and IIIA HER2-overexpressing breast cancer patients. GEICAM 2003-03 study. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[41]  A. Griffioen,et al.  Rocking the foundations of solid tumor growth by attacking the tumor's blood supply. , 1998, Immunology today.

[42]  Zahi A Fayad,et al.  Iron oxide core oil-in-water emulsions as a multifunctional nanoparticle platform for tumor targeting and imaging. , 2009, Biomaterials.

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

[44]  Dipanjan Pan,et al.  Nanomedicine: perspective and promises with ligand-directed molecular imaging. , 2009, European journal of radiology.

[45]  Klaas Nicolay,et al.  Cellular compartmentalization of internalized paramagnetic liposomes strongly influences both T1 and T2 relaxivity , 2009, Magnetic resonance in medicine.

[46]  O. Goulet,et al.  A new intravenous fat emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil: a single-center, double-blind randomized study on efficacy and safety in pediatric patients receiving home parenteral nutrition. , 2010, JPEN. Journal of parenteral and enteral nutrition.

[47]  R. Jain,et al.  During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. , 1996, Nature medicine.

[48]  G. Trinchieri,et al.  Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis. , 1998, The Journal of clinical investigation.

[49]  K. Saito,et al.  Differing expression of MMPs‐1 and ‐9 and urokinase receptor between diffuse‐ and intestinal‐type gastric carcinoma , 1999, International journal of cancer.

[50]  Z. Fayad,et al.  Molecular imaging of tumor angiogenesis using αvβ3-integrin targeted multimodal quantum dots , 2008, Angiogenesis.

[51]  T. Forte,et al.  [26] Electron microscopy of negatively stained lipoproteins , 1986 .

[52]  G. Groenewegen,et al.  Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. , 1996, Blood.

[53]  H. Maeda,et al.  Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. , 2000, Journal of controlled release : official journal of the Controlled Release Society.