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Nanotechnologies applied to Medicine : Nanomedicine Regenera4ve Medicine Diagnos4c and Imaging Drug delivery and therapeu4cs -­‐  Medical devices -­‐  Nanocarriers From Adeli et al, Chem .Soc. Rev. ,2013 =&,(&.73&M/4,+$$,6$7"#$D.7$K#+#3*4,+$+*+,-*33&#3.$$
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Brain
Lung
Heart
Liver
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Intestines
Kidney
Organs
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Retention
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effect (EPR effect)
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Peer et al, Nature Nanotechnology, 2007, 2(12), 751
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4 hrs.
24 hrs.
48 hrs.
96 hrs.
Harrington et al, Clin Cancer Res, 2001, 7, 243
@9A$#P#-7$*+($7/5,3$78'#$
LNC
•! Tumor uptake of
24h
nanocarriers after IV
injection: comparison of
different tumor models
–! Increased accumulation of
nanocarriers with tumor
vascularization
LNE
•! HUH-7 (liver)
•! HEK (kidney)
•! U87MG (brain)
•! TSA/pc (breast)
Hirsjärvi et al, Nanomedicine, 2013, 9, 375
6
EPR-­‐nega4ve tumors and nanomedicines •  Use of pharmacological agents –  Increase of systolic blood pressure (angiotensin II) –  Increase of EPR effect (NO-­‐releasing agents),
Fang et al, Adv Drug Deliv Reviews, 2011, 63, 136
… •  New nanomedicines and change of the route of administra4on to induce new an4tumoral ac4vity profile –  Chemotherapy Unmet Medical Need:
Metastatic Lung Cancer (NSCLC)
5-year survival rate decreases drastically with the implication of metastases in
lymph nodes with 7% survival rate where mediastinal lymph nodes are
invaded (N3) instead of 42% without any metastasis in lymph nodes (N0)
Lung metastasis model
Detterbeck et al, Chest 2009
*
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Lipid Nanocapsules (LNC)
! Biomimetic System: to mimic the structure of a lipoprotein
!! Ø < 100nm, monodisperse and stable
!! Only FDA-approved excipients
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$
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(Heurtault B. et al, Pharm. Res., 2002)
50 nm
Biodistribution study –Results (1)
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IV administration of LNCs
Biodistribution study –Results (2)
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SC administration
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Accumulation in mediastinal lymph nodes only
observed after subcutaneous administration
Lipid Nanocapsules: Lymph node targeting
after SC administration
Wauthoz et al, Nanomedicine, in press
Antitumor efficacy – Metastatic lung tumor model
(Ma44-3)
n = 10 per group Antitumor efficacy – Metastatic lung tumor model
(Ma44-3)
Conclusion: similar antitumor
efficacy between all the
gemcitabine formulations.
However,!
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Wauthoz et al, Nanomedicine, in press
Mechanism of action of gemcitabine and the drugloaded LNC
Lung tumor Lung tumor Less cells invading medias9num nodes Same an9tumor efficacy Medias9nal metastases More cells invading medias9num nodes but partly killed by GemC12-­‐LNC The GemC12-­‐LNC injected SC show a real poten9al as an adjuvant chemotherapy aLer surgery of the primary tumor EPR-­‐nega4ve tumors and nanomedicines •  Use of pharmacological agents –  Increase of systolic blood pressure (angiotensin II) –  Increase of EPR effect (NO-­‐releasing agents),
… Fang et al, Adv Drug Deliv Reviews, 2011, 63, 136
•  New nanomedicines and change of the route of administra4on to induce new an4tumoral ac4vity profile –  Chemotherapy –  Radiotherapy A*(&,*-42#$%&'&($)*+,-*'./0#.$
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Low " emission (155 keV)
Half-life (17h)
7&%,&4"-+4&*
50
nm
188Re-SSS
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for in situ radiotherapy
Local administration
9L glioma cell
injection
!!!!"'%
Model
Induction
8 grays
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!!"(%
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%
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%
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Tumoral growth
follow-up
SURVIVAL CURVES
!%
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% !!"#$%
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188Re-LNC
for in situ radiotherapy
60
saline solution (n=6)
40
blank LNCs (n=6)
188Re-perrhenate (n=6; 2x8Gy)
20
external beam radiotherapy (n=6; 2x8Gy)
LNC188Re-SSS (n=6; 2x8Gy)
0
20
40
60
80
100
Days following 9L cell implantation
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120
Nanovectorized
radiotherapy
External
beam
radiotherapy
80
% of survival
'HQ*
'Q*
'HQ*
'Q*
'BRC*
Controls
100
'Q*
MRI follow-up
!! Tumor eradication and increase in
median survival time of 257% /
External Beam Radiotherapy
!! Mechanism: Induction of an
adaptative immune response
Vanpouille-Box et al, Biomaterials, 2011,32(28),6781
Conclusion: contribu4on of nanomedicines to cancerology •  EPR-­‐posi4ve tumors: +++ •  EPR-­‐nega4ve tumors: –  Design of nanocarriers having new proper4es (i.e. lymphotropism,…) –  Exploring other routes of administra4on to reveal new biodistribu4on profiles –  Sefng new paradigms: nano-­‐immunotherapy,… g/&00*/5#$=*.4*7$
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NICHE
INSERM U 1066
RADIOHEAD
IRAD
LNC formulation
Fractioning of bicontinuous systems
by thermical effect (PIT process)
API + thermical shock
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+
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+
+
+
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nm
Portfolio of 6 patents
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+
+
+
Preliminary toxicity study
(towards a preclinical phase I package)
•  Determination of the Maximum Tolerated Dose and the
Lethal Dose 50 (single dose toxicity)
MTD (mg/kg) LD 50 (mg/kg) Blank LNC > 288 Not reached Taxol ® 12 19,5 PTX LNC 96 216 •  Repeated-dose toxicity study: 12 mg/kg/d IV during 5 consecutive days
• 
Identical weights at J1, no weight loss
• 
No mortality, no apparent toxicity, no behavior alteration
• 
Autopsy : macroscopic observation: normal
• 
Weight of organs not statistically different
• 
No lipid accumulation in the liver, spleen and kidneys
• 
No pulmonary inflammation
J. Hureaux et al, Pharm Res, 2010, 27(3), 21