Transcript Nanotechnology for Therapy

Nanotechnology for Therapy
BIOE298DP
Drug Delivery
Because of their small sizes, nanoparticles are taken by cells where
large particles would be excluded or cleared from the body
1
•
A nanoparticle carries the pharmaceutical
agent inside its core, while its shell is
functionalized with a ‘binding’ agent
2
•
Through the ‘binding’ agent, the ‘targeted’
nanoparticle recognizes the target cell. The
functionalized nanoparticle shell interacts
with the cell membrane
•
The nanoparticle is ingested inside the cell,
and interacts with the biomolecules inside
the cell
•
The nanoparticle particles breaks, and the
pharmaceutical agent is released
3
4
Source: Comprehensive Cancer Center Ohio University
Revisiting the Importance of Size in Distributive
Properties of Probes
A Drug Delivery Nanoparticle
Nanoparticles for drug delivery can be metal-, polymer-, or lipid-based. Below (left) an
example of the latter, containing SiRNA encapsulated, and functionalized with an specific
antibody. SiRNA can control often lethal inflammatory body responses, as shown in the
microscopic images below (right)
antibody
lipid
SiRNA
Science 2008, Vol. 316, pp 627-630
Healthy tissue
Sick tissue treated with non-targeted
nanoparticles
Sick tissue treated with targeted nanoparticles
Clinical Example of EPR
Doxil is a polyethylene glycol
coated liposomal formulation
of doxorubicin.
Marketed by Ben Venue Laboratories of J&J. Outside the US,
Doxil is known as Caelyx (Janssen).
Approved by the FDA for treatment of ovarian cancer and
multiple myeloma and an AIDS-related cancer.
Example of an Approved Anticancer Agent
Protein-bound paclitaxel is an injectable formulation of paclitaxel, a mitotic
inhibitor drug used in the treatment of breast cancer, lung cancer and pancreatic cancer.
Paclitaxel
Albumin
Targeted Nanoparticle
A dual Nanoparticle, the targeting
ligand allow it to diagnose if a cell is
healthy or sick, and bind specifically to
the tumorous cell
Once inside the cell, the polymeric
nanoparticle degrades and the
anticancer agent is set free
Imaging
agent
An imaging agent can be
added as well
Annu. Rev. Biomed. Eng. 2007. Vol. 9, pp. 257–88
The pH stimuli sensitive systems
The pH of the pathological tissue is lower than the
normal tissue, e.g. at the site of inflammation pH
drops from 7.4 to pH 6.5. The same is observed in
the case of infarcts.
Also, the pH is lower in the tumor mass (pH 6.5) than
the surrounding tissue (pH 7.4).
The microenvironment of a tumor is acidic because
insufficient oxygen in tumors leads to hypoxia and
causes production of lactic acid.
pH Sensitive NanoCarrier As a Theranostic
Platform
AuNPs for cancer imaging (A) enzyme sensitive AuNPs for NIRF imaging, (B) tumor targeting:
AuNPs for NIRF/CT dual imaging, and (C) schematic illustration of PEGylated DoxAuNP@CaP for
theranosis.
Ultrasound Mediated Therapy
Subcutaneously implanted rat prostate carcinomas
seven minutes after administration of unspecific
microbubbles (L) and RGD-coated microbubbles (R)
Nanotubes
Carbon nanotubes have been found to have a very interesting property, they release
heat when exposed to radio frequencies
Chemical properties of nanotubes allow them to be easily functionalized
For this studies the nanotubes were produced by the CoMoCAT
procedure, and functionalized with the polymer Kentera
Source: www.nanotechweb.org
CoMoCAT nanoparticles
with grown nanotubes
Source: Southwest nanotechnologies
Heat Release Tests
Suspensions of nanotubes at different
concentrations were remotely irradiated
with radio waves, resulting in heating
correlated to the concentration of
nanotubes in suspension
250mg/L
50mg/L
0mg/L
Radiowaves
Nanotube suspension
Source:Hamamatsu Nanotechnology
Cancer 2007;Vol.110, pp. 2654–2665
Cytotoxicity tests
The following human cells were grown with 24h contact with 500mg/L nanotube
solutions:
Hepatocellular carcinoma Hep3B
Hepatocellular carcinoma HepG2
Panc-1 pancreatic adenocarsinoma
The results shown correspond to fluorescence
cytometric results, the segments represent stages
of cellular growth, which appear unaltered despite
the presence of the nanotubes. NO CYTOTOXICITY
Cancer 2007;Vol.110, pp. 2654–2665
Intracellular Accumulation of Nanotubes
Despite the lack of cytotoxicity, bright field images clearly shows the accumulation of
nanotube structure inside the cellular structure
Culture without SWCNT’s
Also, the optical response of the cultures to other
imaging techniques is shown by this IR image
Culture with SWCNT’s
nanotubes
nanotubes
Cancer 2007;Vol.110, pp. 2654–2665
In Vivo cytotoxicity test
In the top panel, the photomicrograph of
a hepatic tumor on a rabbit.
The black stains correspond to nanotube
accumulation on the tumorous cell
The purple staining is characteristic of
live tissues
In the bottom panel, the photomicrograph of
the same hepatic tumor after 2 min. radio
frequency waves irradiation.
The brownish color is indicative of necrosis
(tissue death)
Cancer 2007;Vol.110, pp. 2654–2665
Therapy w/o Any Chemotherapeutics
Nanometer-sized particles are particularly responsive to electromagnetic and acoustic
excitations through a variety of phenomena (e.g. plasmon resonance) that lead to local
extreme conditions (e.g. heating). The nanoparticle is able to tolerate this condition, but
no so the biological material nearby
Intramuscular injections of
colloidal gold, a suspension of
gold nanoparticles, has been
used for decades to alleviate
pain linked to rheumatoid
arthritis. The mechanism is
still unknown
Source: John Hopkins Center
Colloidal gold
Source: www.wikipedia.com
An infrared beam illuminates two mice
specimens. The local temperature
increases for the mouse that received
and injection of gold nanorods.
Adv. Mater. 2009, 21, 3175–3180
Tackling Alzheimer Disease
Source: Berkeley Lab
Alzheimer
and
other
degenerative diseases are
caused my the clustering of
amyloidal beta (Aβ) protein.
Alzheimer’s brain
Healthy brain
Gold nanoparticles can
be functionalized to
specifically attach to
aggregates
of
this
protein (amyloidosis)
Functionalized nanoparticle
Source: www.internetchemistry.com
Chemical structure of Aβ-protein
Source: wwwthefutureofthings.com
Gold Nanoparticles vs. Alzheimer
• The functionalized gold nanoparticles selectively attach to the aggregate of
amyloidal protein. The microwaves of certain frequency are irradiated on the
sample.
• Resonance with the gold nanoparticles increases the local temperature and destroy
the aggregate
Before irradiation
Nanoletters 2006, Vol. 6, pp.110-115
After irradiation