u tokyo forum at usp 20131112

Nanomedicine for cancer diagnosis and treatment

Department of Bioengineering

School of Engineering, The University of Tokyo

Horacio CabralDepartment of Bioengineering

The University of Tokyo

Targeted Drug Delivery :

Why is necessary?

Site Specific

Targeting

•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

Polymeric nanodevices

for drug delivery

PEG

Polyamino acid

Tens of nanometer

Drug

PEG shell:Provides

biocompatibility

Drug-loaded core:Biodegradable: Poly(aspartic acid),

Poly(Glutamic acid), Poly(Lysine)

HydrophobicHydrophilic

Self assembly in aqueous

condition

K. Kataoka, A. Harada, Y. Nagasaki, Adv Drug Delivery Rev. 43 (2001) 113-131

A. Harada, K. Kataoka, Science, 283 (1999) , pp. 65 - 67

Targeting CancerCancer 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

Tumor vasculatureHealthy Tumor

Structure of blood vessel

Lymphatic drainage

Healthy tissue

Tumor tissue

Nanodevices

Small

drugs

Blood

vessel

Leaky

vasculature

Cell targeting

Internalization

Impaired lymphatic drainage

Y. Matsumura, H. Maeda. Cancer Res 46 (1986) 6387-6392

High permeability of the

blood vessel in the tumor

allows the nanodevices to

extravasate

Nanodevices are retained in

the tumor tissue

Targeting solid tumors:Enhanced permeability and retention effect

Healthy Tumor

Overcoming biological barriers

during circulation

Stability and size of nanomedicines

control their fate in the body

Liver:

Over 100 nm

Hydrophobic

Positively charged

Kidney:

<10 nm

Spleen:

>200 nm

Hydrophobic

Positively charged

Lungs:

>700 nm

Hydrophobic

Positively charged

–The core conjugated dye is

invisible

–Only the shell-conjugated dye

emits fluorescence

Self-assembly in water

+

Anticancer DrugDual fluorescent block copolymer

–Drug is released at low pH

–The fluorescence from the

core appears

Dual fluorescent nanodevices

loaded with anticancer drug

Nikon A1R CLSM with a high-speed resonant scanner; Ar laser; He-Ne laser; NIR laser

In vivo confocal laser microscopy

The behavior of the nanomedicines can be trace in vivo in real time

In vivo confocal laser microscopy Experimental setup

(Nikon A1R CLSM with a high-speed resonant scanner; Ar laser; He-Ne laser)

In vivo real-time intratumoral behavior

Intact nanodevice/Broken nanodevice

-Nanodevices maintain their structure during blood circulation

-Nanodevices penetrate in the tumor tissue

Intravital imaging in subcutaneous tumors

Injection point

Intact nanodevice/Broken nanodevice/Cell membrane

12 h

Nanodevice

Shell

Nanodevice

decay

Merged

+

Cell

membrane

2 h 4 h 12 h 24 h

2 h 4 h 12 h 24 h

In vivo real-time intratumoral distribution

M. Murakami, et al. Sc. Transl. Med 2011

-Nanodevices selectively break inside the cancer cells

Lymphatic drainage

Healthy tissue

Tumor tissue

Nanodevices

Small

drugs

Blood

vessel

Leaky

vasculature

Cell targeting

Internalization

Impaired lymphatic drainage

Y. Matsumura, H. Maeda. Cancer Res 46 (1986) 6387-6392

High permeability of the

blood vessel in the tumor

allows the nanodevices to

extravasate

Nanodevices are retained in

the tumor tissue

Targeting solid tumors:Enhanced permeability and retention effect

Penetration of nanodevices

may be affected by size

50 nm50 nm

30-nm nanodevices

50 nm

50-nm nanodevices 70-nm nanodevices 100-nm nanodevices

50 nm

0

200

400

600

800

1000

1 31 61 91 121

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mm

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tive a

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Size-modulation of nanodevices

The diameter of nanodevices can be precisely controlled

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

In vivo real-time microdistribution of size-

modulated nanodevices in pancreatic tumors

30-nm nanodevices/70-nm nanodevices/Colocalization

H.Cabral, et al. Nat Nanotech (2011)

Size of nanodevices determined their tumor penetration

Intratumoral microdistribution 1 h post-injection

0

20

40

60

80

100

-100 -80 -60 -40 -20 0

Length (mm)

Inte

nsity (

%V

ma

x)

30-nm nanodevices/70-nm nanodevices/Colocalization


modulated nanodevices in pancreatic tumorsIntratumoral microdistribution 1 h post-injection

Vessel

30-nm nanodevices70-nm nanodevices

BxPC3



modulated nanodevices in pancreatic

tumorsIntratumoral

microdistribution

24 h post-injection


30-nm nanodevices/

70-nm nanodevices/

Colocalization

Treatment of spontaneous pancreatic cancer

tumors by nanodevices

ControlNanodevices

Nanodevices prevented

ascites

Survival rate of pancreatic cancer

spontaneous mouse

0

20

40

60

80

100

0 10 20 30 40 50 60 70

Ove

rall

su

rviv

al (%

)

Time (day)

dose: 2mg/kg every week

30-nm Nanodevices

Control

(Saline)

80

60

40

20

0

0 15 30 45 60 75

Time (days)

p<0.001

Nanodevices significantly extended the survival of mice, avoiding

metastasis formation

90 105

Mice at day 60

Clinical treatment of refractory pancreatic cancerCharacteristics of pancreatic cancer

・Stromal barrier prevents the penetration of drugs.・In many cases, invasion and metastasis is observed

・Five-year survival rate is the lowest in the major organs cancer (less than 10%)

Pancreatic cancer

patient（69 years

old）CTimage Stage IV

pancreatic

cancer

・There are metastasis

to liver. Thus, surgery

and radiation are not

enough to del with the

tumor ・Only way is

chemotherapy Major problem Survival 3 -6months

○Drug is eliminated from the body

○Drug can not reach the cancer cells

○Drug also acts on normal cells

Hospitalization for administration

Ineffective

Side effects

However, for

conventional

chemotherapy

With traditional

treatment：

With nanodevice

treatment:

Metastasis

After treatmentBefore Liver

metastasis

disappeare

d after

treatment

○No need of hospitalization

Extend survival for more than 3 years

○Broad therapeutic range

Nanodevice treatment

Longlife

Find cancer

Selective action

Pass barrier

○Low side effects

Nanodevices for therapy and diagnosis:

Theranostic nanomedicine

MRIX-ray

PET

Several imaging functionalities

can be combined into nanodevices

Imaging tumor

microenvironment

Manganese in

nanodevices responding

to tumor environment

tumor

MRI

Tumor hypoxia imagingImmediate visualization

immediately therapeutic effect

Nanodevices can

enhance sensitivity

to existing contrast

agents

Gadolinium in

nanodevices for small

metastasis diagnosis

t

u

m

o

r

Real-time efficacyHigh sensitivity

Hypoxia

staining

Nanodevice-enhanced 3D MRI of tumors

50 µm

Before administration of nanodevices After administration of nanodevices

-Nanodevices can provide microstructural information of tumors

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)

Dr. Ichio AokiDr. Daisuke KokuryoNational institute of Radiological Sciences

Prof. Mitsuru UesakaDepartment of Nuclear Engineering, The University of Tokyo

Prof. Kohei MiyazonoAssoc. Prof. Mitsunobu KanoDr. Caname IwataDepartment of Molecular Pathology, The University of Tokyo

Dr.Yasuko Terada

SPring 8

Assoc. Prof. Hiroshi NishiharaTranslational PathologyGraduate School of MedicineHokkaido University

AcknowledgementsKataoka Lab., The University of TokyoProf. Kazunori Kataoka

The Anticancer GroupDr. Yutaka MiuraDr. Yu Matsumoto, MDDr. Stephanie DeshayesDr. Sabina QuaderDr. Kazue MizunoDr.Mi PengMiwako Kimura, MDYuki Mochida Huailiang WuJooyeon AhnJun MakinoHungChi YenMasato SasanoNaoki YamadaSurasa NagachintaChida TsukasaKitikhun HiangratSurachet imlimthan

http://www.bmw.t.u-tokyo.ac.jp

http://www.bmw.t.u-tokyo.ac.jp/

For more info:

http://www.bioeng.t.u-tokyo.ac.jp/

Kataoka LaboratoryDepartment of Bioengineering

Webpages

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.u-

tokyo.ac.jp/g30_hp/international-

bioengineering.html

International Bioengineering Program

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