U tokyo forum at usp 20131112

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  • 1. Department of Bioengineering School of Engineering, The University of Tokyo Nanomedicine for cancer diagnosis and treatment Horacio Cabral Department of Bioengineering The University of Tokyo
  • 2. Targeted Drug Delivery : Why is necessary? •Systemic distribution •Toxicity •Inactivation •Low accumulation at the target •Site specific targeting •Reduce toxicity •Protect drugs from inactivation •High accumulation in the target •Enhance efficiency Systemic Distribution Site Specific Targeting
  • 3. Polymeric nanodevices for drug delivery Hydrophilic Hydrophobic Polyamino acid PEG Drug Drug-loaded core: Biodegradable: Poly(aspartic acid), Poly(Glutamic acid), Poly(Lysine) PEG shell: Self assembly in aqueous condition Provides biocompatibility Tens of nanometer K. Kataoka, A. Harada, Y. Nagasaki, Adv Drug Delivery Rev. 43 (2001) 113-131 A. Harada, K. Kataoka, Science, 283 (1999) , pp. 65 - 67
  • 4. Targeting Cancer Cancer has a wide range of distinctive characteristics that are exploited for anticancer therapies Molecular, genetic and biological therapies can be used in combination to attack directly specific targets
  • 5. Tumor vasculature Healthy Structure of blood vessel Tumor
  • 6. Targeting solid tumors: Enhanced permeability and retention effect Lymphatic drainage Healthy tissue Small drugs Healthy High permeability of the blood vessel in the tumor allows the nanodevices to Tumor extravasate Blood vessel Tumor tissue Leaky vasculature Nanodevices are retained in the tumor tissue Internalization Nanodevices Cell targeting Impaired lymphatic drainage Y. Matsumura, H. Maeda. Cancer Res 46 (1986) 6387-6392
  • 7. Overcoming biological barriers during circulation Liver: Over 100 nm Hydrophobic Positively charged Kidney: <10 nm Lungs: >700 nm Hydrophobic Positively charged Spleen: >200 nm Hydrophobic Positively charged Stability and size of nanomedicines control their fate in the body
  • 8. Dual fluorescent nanodevices loaded with anticancer drug + Dual fluorescent block copolymer Anticancer Drug Self-assembly in water –Drug core conjugated dye is –The is released at low pH invisible –The fluorescence from the dye –Only the shell-conjugated core appears emits fluorescence
  • 9. In vivo confocal laser microscopy Nikon A1R CLSM with a high-speed resonant scanner; Ar laser; He-Ne laser; NIR laser The behavior of the nanomedicines can be trace in vivo in real time
  • 10. In vivo confocal laser microscopy Experimental setup (Nikon A1R CLSM with a high-speed resonant scanner; Ar laser; He-Ne laser)
  • 11. In vivo real-time intratumoral behavior Intravital imaging in subcutaneous tumors Injection point Intact nanodevice/Broken nanodevice 12 h Intact nanodevice/Broken nanodevice/Cell membrane -Nanodevices maintain their structure during blood circulation -Nanodevices penetrate in the tumor tissue
  • 12. In vivo real-time intratumoral distribution 2h 2h 4h 4h 12 h 12 h 24 h 24 h Nanodevice Shell Nanodevice decay Merged + Cell membrane M. Murakami, et al. Sc. Transl. Med 2011 -Nanodevices selectively break inside the cancer cells
  • 13. Targeting solid tumors: Enhanced permeability and retention effect Lymphatic drainage Healthy tissue Small drugs Blood vessel High permeability of the blood vessel in the tumor allows the nanodevices to extravasate Tumor tissue Leaky vasculature Penetration of nanodevices may be affected by size Nanodevices are retained in the tumor tissue Internalization Nanodevices Cell targeting Impaired lymphatic drainage Y. Matsumura, H. Maeda. Cancer Res 46 (1986) 6387-6392
  • 14. Size-modulation of nanodevices 30-nm nanodevices 50-nm nanodevices 70-nm nanodevices 100-nm nanodevices 50 nm 700 100 500 100 500 400 50 300 200 25 100 0 0 1 31 61 91 121 151 SIze (nm) 1000 100 600 75 500 400 50 300 200 25 800 75 600 50 400 25 200 100 0 0 1 31 61 91 121 SIze (nm) 0 0 1 31 61 91 121 SIze (nm) 0 0 1 31 61 91 121 SIze (nm) The diameter of nanodevices can be precisely controlled Cummulative amount (%) 25 100 Cummulative amount (%) Number of particles x Diameter 200 75 Cummulative amount (%) 50 Number of particles x Diameter 300 Cummulative amount (%) Number of particles x Diameter 75 800 50 nm 700 600 400 50 nm Number of particles x Diameter 100 50 nm
  • 15. Real-time in vivo confocal laser microscopy Experimental setup (Nikon A1R CLSM with a high-speed resonant scanner; Ar laser; He-Ne laser) Co-injection of 30- and 70-nm nanodevices
  • 16. In vivo real-time microdistribution of sizemodulated nanodevices in pancreatic tumors Intratumoral microdistribution 1 h post-injection H.Cabral, et al. Nat Nanotech (2011) 30-nm nanodevices/70-nm nanodevices/Colocalization Size of nanodevices determined their tumor penetration
  • 17. In vivo real-time microdistribution of sizemodulated nanodevices in pancreatic tumors Intratumoral microdistribution 1 h post-injection 100 BxPC3 30-nm nanodevices 70-nm nanodevices Intensity (%Vmax) 80 60 40 0 -100 Vessel 20 -80 -60 -40 -20 0 Length (mm) 30-nm nanodevices/70-nm nanodevices/Colocalization H.Cabral, et al. Nat Nanotech (2011)
  • 18. In vivo real-time microdistribution of sizemodulated nanodevices in pancreatic tumors Intratumoral microdistribution 24 h post-injection 30-nm nanodevices/ 70-nm nanodevices/ Colocalization H.Cabral, et al. Nat Nanotech (2011)
  • 19. Treatment of spontaneous pancreatic cancer tumors by nanodevices Survival rate of pancreatic cancer spontaneous mouse Mice at day 60 30-nm Nanodevices 100 Overall survival (%) p<0.001 Nanodevices Control 80 80 60 60 Control (Saline) 40 40 20 20 dose: 2mg/kg every week 0 0 0 0 10 15 20 30 30 45 40 60 50 75 60 90 70 105 Nanodevices prevented ascites Time (day) Time (days) Nanodevices significantly extended the survival of mice, avoiding metastasis formation
  • 20. Clinical treatment of refractory pancreatic cancer Characteristics of pancreatic cancer ・Five-year survival rate is the lowest in the major organs cancer (less than 10%) ・Stromal barrier prevents the penetration of drugs. ・In many cases, invasion and metastasis is observed With nanodevice Pancreatic cancer After treatment Before treatment: patient(69 years Liver metastasis old) CTimage Metastasis disappeare Stage IV d after pancreatic treatment Nanodevice treatment cancer ○Low side effects Long life Pass barrier ・There are metastasis to liver. Thus, surgery and radiation are not enough to del with the tumor ・Only way is chemotherapy Find cancer Selective action ○No need of hospitalization ○Broad therapeutic range Extend survival for more than 3 years With traditional treatment: ○Drug is eliminated from the body However, for conventional chemotherapy Hospitalization for administration ○Drug can not reach the cancer cells Ineffective ○Drug also acts on normal cells Major problem Side effects Survival 3 -6months
  • 21. Nanodevices for therapy and diagnosis: Theranostic nanomedicine PET Several imaging functionalities can be combined into nanodevices X-ray MRI t u m o r Gadolinium in nanodevices for small metastasis diagnosis High sensitivity Manganese in nanodevices responding to tumor environment Real-time efficacy Nanodevices can enhance sensitivity to existing contrast agents Immediate visualization immediately therapeutic effect tumor Imaging tumor microenvironment MRI Hypoxia staining Tumor hypoxia imaging
  • 22. Nanodevice-enhanced 3D MRI of tumors Before administration of nanodevices After administration of nanodevices 50 µm -Nanodevices can provide microstructural information of tumors
  • 23. Nanodevices under clinical trials •Paclitaxel-loaded nanodevices Phase III clinical trials (Japan;Gastric cancer) •Cisplatin-loaded nanodevices Phase III clinical trial (Pancreatic cancer; Japan/Taiwan/USA) •SN-38-loaded nanodevices Phase II clinical trial (Japan; Colorectal cancer; USA: Breast cancer) •Doxorubicin-loaded nanodevices Phase II clinical trial (Japan; various tumors) •Oxaliplatin-loaded nanodevices Phase I clinical trial (USA; various tumors) •Epirubicin-loaded nanodevices Phase I clinical trial (Japan; various tumors)
  • 24. Acknowledgements Kataoka Lab., The University of Tokyo Prof. Kazunori Kataoka The Anticancer Group Dr. Yutaka Miura Dr. Yu Matsumoto, MD Dr. Stephanie Deshayes Dr. Sabina Quader Dr. Kazue Mizuno Dr.Mi Peng Miwako Kimura, MD Yuki Mochida Huailiang Wu Jooyeon Ahn Jun Makino HungChi Yen Masato Sasano Naoki Yamada Surasa Nagachinta Chida Tsukasa Kitikhun Hiangrat Surachet imlimthan http://www.bmw.t.u-tokyo.ac.jp Dr. Ichio Aoki Dr. Daisuke Kokuryo National institute of Radiological Sciences Prof. Mitsuru Uesaka Department of Nuclear Engineering, The University of Tokyo Prof. Kohei Miyazono Assoc. Prof. Mitsunobu Kano Dr. Caname Iwata Department of Molecular Pathology, The University of Tokyo Dr.Yasuko Terada SPring 8 Assoc. Prof. Hiroshi Nishihara Translational Pathology Graduate School of Medicine Hokkaido University
  • 25. Webpages For more info: Department of Bioengineering http://www.bioeng.t.u-tokyo.ac.jp/ Kataoka Laboratory http://www.bmw.t.u-tokyo.ac.jp/
  • 26. International Bioengineering Program Students who have •Good English communication skills •High qualifications •Wide vision and willing to take active roles in research can join the International Bioengineering Program http://www.global30.t.utokyo.ac.jp/g30_hp/internationalbioengineering.html