Guterres, 2012
Sílvia Stanisçuaski Guterres Universidade Federal do Rio Grande do Sul
Desafios e perspectivas para a nanobiotecnologia no cenário brasileiro
Guterres, 2012
1908 Ehrlich's Magic Bullet 1959
Feynman gives after-dinner talk describing molecular machines
1974
Taniguchi uses term "nano-technology" in paper on ion-sputter machining
1977
Drexler originates molecular nanotechnology concepts at MIT
First technical paper on molecular engineering to build with atomic precision
1986
First book published
First organization formed
1987
First university symposium- MIT
1988
First university course-Stanford
1989
IBM logo spelled in individual atoms
First national conference: Stanford University
1990
First nanotechnology journal
N&N: A brief history
Guterres, 2012
1991
Japan's MITI commits $200 million
Carbon nanotube discovered 1992 Taxol™ (paclitaxel) 1994
Nanosystems textbook used in first university course
1995
First industry analysis of military applications Doxil ™
1996
First European conference: European Nanotechnology Initiative, Copenhagen NASA begins work in computational nanotech
First nanobio conference: California Institute of Technology 1997
First company founded: Zyvex
First design of nanorobotic system
1998
First DNA-based nanomechanical device
1999
First Nanomedicine book published, First safety guidelines
N&N: A brief history
Guterres, 2012
2000
President Clinton announces U.S. National Nanotechnology Initiative
2001-2017 First 25 Brazilian Networks on Nanotechnology
Brazilian government has invested, through its universities and research centers, approximately R$ 160 million on nanotechnology research 2002
First nanotech industry conference
2003
Congressional hearings on societal implications
2005
Nanoethics meeting 2008 Brazil: INCTs 16 National Institutes of Science and Technology committed to the advancement of knowledge in various nanotechnologies
N&N: A brief history
Guterres, 2012
2009
An improved walking DNA nanorobot First Brazilian product based on Nanotecnnology
2010
DNA-based 'robotic' assembly begins 2012 130 companies working with research and development 2012 Ministry of Science, Technology and Innovation organized in 2012, the Interministerial Committee for Nanotechnology 2013-2018 Brazil launched an Initiative to make Nanotechnology “the most innovative Brazilian industry” SisNano R$ 440 million (2013 and 2014) 2015 Brazil participates of Nanoreg 2016 New INCTs
N&N: A brief history
Guterres, 2012
NANOTECNHOLOGY IN HEALTH
Therapeutics
Nanomedicines
Diagnosis Theranostics Personal care
Nanocosmetics
Guterres, 2012
NANOENCAPSULATION TECHNIQUES products containing coated particles act as drug delivery systems
NAN
O D
ELIV
ERY S
YSTEM
S
To control the drug delivery to the site of
action
To control the kinetics of drug release
To dissolve/deaggregate during or after releasing
the drug
Guterres, 2012
A comprehensive analysis of the worldwide state of investigational and approved nanomedicine products as of January 2012 has identified 67 commercialized nanodevices and 33
marketed
nanotherapeutics. A total of 25 devices and 122 therapeutics currently in development accounted for 789 ongoing clinical trials.
International Journal of Nanomedicine 2014:9 4357–4373
Cancer de mama 52
CA Pulmão (células não pequenas) 20 CA Pancreas 19 Tumores sólidos 15 Dental 10 Cancer de cabeça e pescoço 9 Cancer de estomago 5 Melanoma
Glioma 5 CA Fígado 4
CA Próstata 4 Restenose 4
Paclitaxel 120
Nanoparticles 23 ago 2016 243 studies
Nanomaterials can be divided into two groups:
Soluble and/or biodegradable nanoparticles which disintegrate into their
molecular components
e.g. liposomes and nanoemulsions
Risk assessment based on mass metrics may be
adequate for the soluble nanoparticles;
Insoluble and/or biopersistent nanoparticles
e.g. TiO2, fullerenes, quantum dots
Risk assessment may require other metrics, such as the number of
particles, and their surface area as well as their
distribution
Public policy program consisting of various actions geared towards nanotechnology becoming the most innovative Brazilian industry”.
Nanotechnology can strengthen and “increase the competitiveness of the national economy”.
CENANO
Laboratório de Química de Nanoestruturas de
Carbono
LIN
Let’s begin by showing worldwide data
Market of products that incorporate nanotechnologies was US$135 billion
Expected market: US$3.3 trillion
http://tnsolution.com.br/en/2016/01/26/the-advances-of-nanotechnology-in-brazil/
The big markets
①chemical industry
②semiconductors
③pharmacy
④automotive
⑤defense
⑥antimicrobials
2018
2007 2018
Russian Federation: 500 companies were engaged in manufacturing nanotech (2013, according to the
state corporation Rusnano)
A COMPARISON...
Brazil: 130 companies working with nanotechnoloy (J. Hazard. Toxic Radioact.
Waste, 2016, 20(1): B4014002)
❶What is the problem to be solved?
❷Are there tools available to solve the problem?
❸Is there expertise to use them?
The rational design a new nanomedicine
Lipid-core nanocapsules (LNC) are formed by an organogel surrounded by poly(epsilon-
caprolactone) and stabilized by polysorbate 80
An original soft nanocarrier
Biodegradability: a critical requirement for nanoparticulate brain delivery systems, i.e.
over a time frame of a few days.
Guterres, 2012
What is the chemical structure of this nanocapsule?
Capric/caprylic triglyceride
Sorbitan monostearate
Poly(e-caprolactone)
Polysorbate 80
-100 -50 0 50 100 150 200
NC-EM
NC-DIC
Heat flow
(exo
)
Temperature (C)
NS-EM
NS-DIC
Cruz, L; et al. Int J Pharm, 2006. Müller, C.R; et al. Pharmazie 2001.
DSC SAXS
TEM
Jager, E. et al; JBN, 2009.
DLS
Venturini, A. et al; COLSUA, 2011
MLS
molecular
macromolecular
supramolecular TEM
Bulcão, R. et al; Toxic Sci, 2013.
200 nm 200 nm
Prof. Adriana Raffin Pohlmann
Guterres, 2012
ROUTES
Parenteral
Skin
Oral
Eyes
Brain
Lung
Vaginal
Non-toxicity of these nanocapsules per
se is a requirement for their application
ARE THE LIPID CORE NANOCAPSULES SAFE?
Acute cardiotoxicity of lipid core nanocapsules in rats by intravenous administration
Toxicol. Res., 2016, 5, 168–179
Troponin: highly specific marker for myocardial infarction or heart muscle cell death
Aspartate transaminase (AST) Alkaline phosphatase (ALP)
Number of nanocapsules per milliliter per kg.
Rat groups treated with LNC did not demonstrate alteration on electrocardiographical and ecocardiographical analyses
No important differences on biochemical, hematological and histophalogical analysis were found
Electrocardiograms findings Blood pressure evolution
Acute cardiotoxicity of lipid core nanocapsules in rats by intravenous administration
Rats treated with LNC had no toxic
effects and no death occurred
Relative weight of organs
Histopathological analyses
Biochemical parameters in blood and urine
Microalbumin and NAG activity
Serum complement C3 and hs-CRP.
In Vitro Hematological Tests
Toxicological Sciences 132(1), 162–176 2013
IP route
Acute and Subchronic Toxicity Evaluation of Poly(ɛ-Caprolactone) Lipid-Core Nanocapsules in Rats
Do poly(epsilon-caprolactone) lipid-core nanocapsules induce oxidative or inflammatory damages after in vivo subchronic treatments?
Sub-chronic evaluations Oxidative damage? Inflammatory damage?
Protein damage Antioxidant enzymes Lipid peroxidation GSH levels
Cytokines IL-10 1L-6
Tissues Liver Kidney Heart Brain
IP route: no damages were induced
No dose-dependent or systematic alterations observed
Toxicol. Res., 2015, 4, 994
Prof. Solange Garcia
Guterres, 2012
ROUTES
Parenteral
Skin
Oral
Eyes
Brain
Lung
Vaginal
application
ARE THE LIPID CORE NANOCAPSULES SAFE?
Guterres, 2012
ROUTES
Parenteral
Skin
Oral
Eyes
Brain
Lung
Vaginal
Some examples of their
effectiveness
ARE THE LIPID CORE NANOCAPSULES EFFICIENT?
BBB: non fenestrated brain
microvessel endothelial cells characterized by tight junctions
which form a continuous almost impermeable cellular barrier
BBB prevents 98% of
neuropharmaceuticals to reach their targets in the CNS.
Nanoparticles as an efficient strategy to deliver drugs to
the tissue?
Our motivation
Rhodamine B-labeled lipid-core nanocapsules (Rho-LNC).
Cerebral microvessels of mice intravenously treated (A and B)
Cerebral microvessels of mice orally treated (C and D)
Intr
avit
al m
icro
sco
py
Lipid-core nanocapsules are efficient shuttles to reach the brain tissue
Prof. Sandra Farsky
Lipid-core nanocapsules can be sterilized and isotonized
Physicochemical
parameters
LNCG LNCGS
Zeta Potential (mV) -10.60 ± 0.61 -13.86 ± 2.92
Particle number density
(particles.ml-1)
1.16 x1013± 5.22 x1011 1.17 x1013± 3.41 x1011
Superficial area (m2.ml-1) 1.41 ± 0.03 1.44 ± 0.03
pH 5.8 ± 0.3 6.3 ± 0.1
Flux index 1.07 ± 0.01 1.05 ± 0.01
Viscosity (cP) 1.18 ± 0.02 1.15 ± 0.06
Frezzing temperature (oC) - 0.520 ± 0.002 - 0.523 ± 0.002
LNC physicochemical characteristics before (LNCG) and after (LNCGS) autoclaving and isotonizing.
AAPS PharmSciTech, Vol. 18, No. 1, February 2017 (# 2016) DOI: 10.1208/s12249-016-0493-3
Our motivation
Prof. Karina Paese
The most common primary tumors of the brain
At least half of all gliomas exhibit aggressive and malignant behavior They are poorly responsive to multimodaly therapeutic interventions, including surgery, radiotherapy and chemotherapy (Deen et al., 1993) Anticancer drugs are toxic to both tumoral and normal cells and the efficacy of chemotherapy is limited by side effects (Brigger et al., 2002) BBB limits the penetration of antineoplasic drugs into brain tumors (Gelperina et al., 2002) LNC
Glioblastoma
Indomethacin-loaded nanocapsules treatment reduces in vivo glioblastoma growth in a rat glioma model
TUMOR SIZE OF IMPLANTED GLIOMAS
Tumor size was measured 20 days after implantation of C6 cells by
three hematoxylin and eosin
Control NC
Glioblastoma
• Increase the intratumoral bioavailability of indomethacin
• Reduce the growth of implanted gliomas
LIPID CORE NANOCAPSULES
Glioblastoma
Prof. Ana Batastini
0
5
10
15
20
25
30
35
40
45
50
IndOH-NC
A1-42
2 M
50 M 100 M 50 M 100 M-
- + + +
-
- -
#
***
***
Control IndOHNC
50 M
IndOHNC
50 M
IndOHNC
100 M
A1-42
2 M
IndOHNC
100 M
% o
f P
I in
co
rpo
rati
on
Neuroprotective effects of indomethacin-loaded nanocapsules in Alzheimer’s Disease models
In vitro model: organotypic hippocampal slice cultures exposed to A1-42 peptide
0
1000
2000
3000
4000
5000
IndOH-NC
A1-42
2 M
50 M 100 M 50 M 100 M-
- + + +
-
- -
*** ***
#
IL-
6 levels
(p
g/m
l)
Neuroprotective effect is mediated by reduction of
neuroinflammation
Positive control Positive control
Negative controls
Negative controls
amyloid beta peptide
INDOH-NC attenuated Aβ-induced cell death
INDOH-NC block the neuroinflammation
Fluorescent image analysisof propidium iodide uptake
Bernardi et al., Int. J. Nanomedicine (2012)
0.00
0.25
0.50
0.75
1.00Object A
Object C
IndOH1 mg/kg
A1-42
2 nmol
- + --
- - - +
IndOH-NC1 mg/kg
+ - --
+
+
+ -
-
+
***
*****
***
Re
co
gn
itio
n in
de
xIndOH-LNC treatment reduces the memory impairment
induced by Aβ1-42 peptide In vivo model: A1-42 peptide was stereotaxically injected bilaterally into
lateral ventricles of Wistar rats
Behavioral analysis
A higher percentage of time spent exploring the novel
object was considered to be an index of enhanced
cognitive performance
Novel object-recognition task
Bernardi et al., Int. J. Nanomedicine (2012)
From lab to market: report of a successful technology transfer from
University to Industry
Chronology
2005 2009 2006 2007 2008
Project approved Nanocosméticos
Edital FINEP 2005
Funds avaliable
Agreement Ufrgs--Biolab-Finep
Planning and development of experimental activities
First stage of experimental work
Patent redaction
Round meeting tables
End of the experimental step
Prototypes
Process scaling-up
Patent application
Registration ANVISA
Marketing
Launching event PROTOPROT FPS 10 +++
2010
UFRGS: receipt of royalties
2013
New Products
2015
First ranked in BR market
1 3 4 6 9 7 26 37 98
192
327
457
651
913
1151 1226
0
200
400
600
800
1000
1200
1400
Web of science, nov 2017
Theranostic*
http://academic.hep.com.cn/fcse/CN/10.1007/s11705-014-1425-y
Perspectives Science in N&N
Chalenge: improve innovation target research areas
• Increase innovation in the Brazilian Industry: few of our domestic pharmaceutical companies have internal R&D capabilities
• Improve impact of papers
Desafios Estimular interdisciplinaridade
• Busca sistemática de integração das teorias, dos instrumentos e das fórmulas de ação científica de diferentes disciplinas
• Novas disciplinas surgem devido à integração interdisciplinar
Maior impacto da produção científica
Melhorar a comunicação com público leigo
Desafios
Ciência e a mentalidade científica ainda
não estão incorporadas de maneira plena na sociedade.
2017:
Chalenge: improve research funding ensure continuity
Brazil 2017: 44% slash to the federal science budget
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