Transcript The Delphi Method Applied to Nanomedicine for Treating Cancer

The Delphi Method Applied
to
Nanomedicine
for
Treating Cancer
Presented to the
Minnesota Futurists
May 2, 2009
By George Kubik and David Keenan
Cancer Treatment Background
• April 15, 2009 Applications with targeted nanoparticles
are expected to revolutionize molecular imaging and
cancer therapy.
• Cancer researchers are looking to nanoparticles as
agents in various nanomedicine applications – as a drug
carrier capable of localizing, attaching to, and directly
releasing drugs into the cell nucleus; as a cellular
biomarker; and as imaging and therapy agent in cancer
medicine.
• In today's chemotherapy, together with radiation and
surgery, doctors are pumping the patient full of cytotoxic
drugs, that go everywhere in the body, with the hope that
enough of the drugs reach the cancer cells and target
their nuclear DNA to damage it or destroy the cell.
www.nanowerk.com/spotlight/spotid=10099.php
Cancer Treatment Background
• Not only do chemotherapeutic techniques have a range of
often serious side effects, mainly affecting all the fastdividing cells of the body, it also has been shown that often
less than 1% of the administered drug molecules enter
tumor cells and bind to the nuclear DNA.
• Complication: Drug resistance of cancer cells. One of the
main causes of failure in the treatment of cancer. Dividing
cancer cells acquire genetic changes at a high rate, which
means that the cells in a tumor that are resistant to a
particular drug will survive and multiply. The result is the
re-growth of a tumor that is not sensitive to the original
drug.
• Cancer researchers are experimenting with nanoparticles
as both contrast agent and drug carrier capable of
pinpointing and destroying individual cancer cells.
www.nanowerk.com/spotlight/spotid=10099.php
Nanomedicine Background
• One of the greatest challenges in developing and using
cancer drugs is delivering them to the diseased tissues
without poisoning the patient's entire body.
• Size alone gives even simple nanoparticle therapies
special properties that determine their movement into
and throughout tumors.
• Nanoparticles smaller than 10 nm are, like so-called
small-molecule drugs, rapidly eliminated through the
kidney, whereas particles larger than 100 nm have a
difficult time moving through a tumor.
• Particles within the 10- to 100-nm range travel
throughout the bloodstream to seek out tumors, although
they are unable to escape into most healthy tissues
through blood vessel walls.
http://www.sciam.com/article.cfm?id=nanomedicine-targets-cancer
Nanomedicine Background
• Because tumors, in contrast, have abnormal blood
vessels whose walls are riddled with large pores,
nanoparticles can leak into the surrounding tumor tissue.
• As a result, nanoparticles have a tendency to
accumulate in tumors while minimizing effects on other
parts of the body and avoiding the traditional ravishing
side effects of cancer drugs.
http://www.sciam.com/article.cfm?id=nanomedicine-targets-cancer
Research and Markets:
Nanotechnology: Vol. 5: Nanomedicine
• 30Apr09 www.researchandmarkets.com/research/77b071/nanotechnology_vo
Key Topics Covered:
• The next waves of medical innovations
– IMAGING, DIAGNOSTICS AND DISEASE TREATMENT BY
USING ENGINEERED NANOPARTICLES - THE FIRST
MEDICAL APPLICATIONS ARE COMING TO THE PATIENTS'
BEDSIDE...
• Nanoengineered ultrasound and MRI imaging contrast agents
• Nanoparticles for cancer detection and therapy
– IMAGING AND PROBING THE INNER WORLD OF CELLS MAJOR ADVANCES IN MEDICINE HAVE ALWAYS BEEN
DRIVEN BY NEW TECHNOLOGIES
• From molecular machines to cells: imaging with cryoelectron
microscopy
• Optical imaging at the nanoscale
• Nanostructured probes for in vivo gene expression
• Analysis of Dynamic Cytoskeleton Functions by Fluorescent
Speckle Microscopy
• Transport, assembly and proof-reading: harnessing the engineering
Video Links
• Cancer Detection with Gold Nanoparticles – May 27, 2007
http://www.youtube.com/watch?v=uyhxRIvw_cY&feature=related
• Nanoparticle Carrying Capacity – March 27, 2008
http://www.youtube.com/watch?v=TVch-fDzet8&feature=related
• Nanotechnology In Drug Delivery - March 16, 2008
http://www.youtube.com/watch?v=ybK5TIGNNFA&NR=1
• Nanomedicine for Brain Tumors – July 3, 2008
http://www.youtube.com/watch?v=gJgmi-D12pk
• Nanomedicine Cancer Drug Delivery from
PlayGenSeriousGames – sponsored by Wellcome Trust
http://www.youtube.com/watch?v=tPAO0WHoaX0 (1st) February 11, 2008
http://www.youtube.com/watch?v=DEcof9HlUvk (2nd) February 11, 2008
http://www.nanomission.org/ The Game Site
Play
NanoBiotix Example
• Inert nanoparticles designed to absorb
X-rays are injected into a tumor to cause
more targeted treatment compared to surrounding tissue
• http://www.nanobiotix.com/ video link
• ‘Proof-of-concept’ preclinical study conducted by the
French National Institute for Health
and Medical Research validated
applicability to treatment of
glioblastomamultiforme, one of the
most prevalent brain tumors. 09Apr09
Gold Nanorod Approach
• Raghuraman Kannan, Kattesh Katti, and colleagues at
the Univ. of Missouri investigate design and development
of targeted gold nanorods.
• A recent result: The design of a novel peptide-based
nanovector for carrying drug payloads to cancer sites.
This vector design exploits the high affinity that
bombesin peptides show towards gastrin-releasing
peptides (GRP). Since GRP receptors are
overexpressed in many cancers, the researchers
hypothesized that bombesin peptide can act as a vehicle
to deliver gold nanorods specifically to certain tumor
cells.
www.nanowerk.com/spotlight/spotid=10099.php
Gold Nanorod Approach
• These nanovectors show highly selective targeting to
cancer cells without harming healthy cells (they don't
show any affinity towards them).
• Stability and affinity of the nanoparticle towards tumor
cells are two important parameters in evaluating the in
vivo applicability of an agent. The degree of stability is
key in determining whether an agent can be used for in
vivo purposes. The degree of affinity of conjugates to
tumor cells determines whether it is truly going to attach
to the targeted tumor cells.
www.nanowerk.com/spotlight/spotid=10099.php
Gold Nanorod Approach
• "We investigated the two parameters for our gold
nanoconjugates" says Kannan. "With regard to stability,
we established that using thioctic acid we can add
extraordinary strength to the conjugate, making it stable
enough for in vivo purposes.
• With regard to affinity, our studies provide quantitative
data precisely estimating the affinity of conjugates
toward receptors on cells, which in the case of our
conjugates is very high."
• Kannan explains that one of the most important factors
in the development of a nanoparticle as a drug candidate
is the so-called IC50 value – the half maximal inhibitory
concentration. This value provides crucial information on
the effectiveness of a compound in inhibiting a biological
or biochemical process.
www.nanowerk.com/spotlight/spotid=10099.php
Gold Nanorod Approach
• Gold nanorods coated with bombesin attach to GRP
receptors and are taken into the cancer cell. NIR laser
energy is absorbed by the gold and kills the cell with
heat. Gold permits imaging of the process.
www.nanowerk.com/spotlight/spotid=10099.php
Polymer Nanoparticles
• 23Apr09 An interdisciplinary team of researchers at
Brigham and Women's Hospital (BWH) and the HarvardMIT Division of Health Sciences and Technology has
demonstrated a better way to deliver cancer drugs
directly to tumors by using specially engineered
nanoparticles that can inhibit a signaling pathway and
deliver a higher concentration of medication to the
specific area.
• The team constructed the nanoparticles from a
biodegradable, biocompatable, FDA-approved polymer
which they chemically engineered to deliver a MAPK
inhibitor. By inhibiting the MAPK signaling pathway,
which is involved in a majority of human tumors, the
nanoparticles hinder the multiplication of cancerous
cells and predispose those cells to the cytotoxic
effects of chemotherapeutic drugs. The team also
modified the polymer to increase drug loading 20 fold
www.emaxhealth.com/2/51/30590/delivering-cancer-drugs-directly-tumors.html
Polymer Nanoparticles
• The combination of nanoparticles and the cancer drug
cisplatin proved successful in preventing the growth of
cancerous skin and lung cells and also induced cell
death. When researchers gave the same combination to
mice with melanoma, it inhibited tumor growth and
enhanced the efficacy of the cancer drug. The entire
tumors regressed in fifty percent of mice, compared with
none in the group receiving cisplatin and the inhibitor
without nanoparticles.
• In previous work, the group demonstrated that a
combination of two drugs delivered with a nanoparticle
could exert superior anti-cancer effects. However, most
cancers converge into a few pathways for survival and
uncontrolled division. “We thought a better strategy
might be to target these pathways using nanoparticles,
almost like shutting the escape route before exposing
the cancer to the drugs,”
www.emaxhealth.com/2/51/30590/delivering-cancer-drugs-directly-tumors.html
Magnetic Targeting
• April 27, 2009 Dong-Hwang Chen Distinguished Prof.
Chemical Engineering at National Cheng Kung University
in Tainan, Taiwan,
• According to Chen, the type of nanocarrier designed by
his group provides several advantages such as
1) magnetic guiding to the desired target area and fixing them at
the local site while the medication is released and acts locally;
2) surface functionalization by gum arabic provides an opportunity to
allow directing the therapeutic agent to selected cells away
from other cells and provides a method for targeting a therapeutic
agent into selected cells;
3) the combined properties of fluorescence and magnetism
associated with nanoparticles offer new opportunities for in vitro and
in vivo imaging; and
4) indirect photo-triggering-on-demand drug release by efficient
up-converting energy of the near-IR (NIR) light to higher energy and
intraparticle energy transfer from the dye-grafted magnetic
nanoparticle to the linker for photo-cleavage."
http://www.nanowerk.com/spotlight/spotid=10275.php
Magnetic Targeting
• Iron core allows particles to be
magnetically guide to tumor.
• Chen and group design a new
class of drug nanocarriers
capable of on demand drug
release by efficient upconverting energy of NIR light
(skin penetrating near infrared)
to higher energy and
intraparticle energy transfer for
drug release.
• The result is a multifunctional
nanoparticle that can efficiently
absorb the energy of NIR light
and emit light of higher energy
for triggering drug release by
cleavage of a photosensitive
linker.
http://www.nanowerk.com/spotlight/spotid=10275.php
IT 101
• Newer nanoparticles for example IT-101, which has already
undergone human safety testing in phase I trials, have
more complex designs that provide multiple functions.
– IT-101 is a 30-nm particle assembled from polymers joined to the
small-molecule drug camptothecin, which is closely related to two
chemotherapy drugs approved by the FDA: irinotecan and
topotecan.
– The IT-101 particles are designed to circulate in the patient's blood
and they remain there for more than 40 hours, whereas
camptothecin by itself would circulate for only a few minutes. This
long circulation period allows time for IT-101 to escape into tumors
and accumulate there.
– The particles then enter tumor cells and slowly release the
camptothecin to enhance its effects.
– As the drug is released, the rest of the nanoparticle components
disassemble and the small individual polymer molecules harmlessly
exit the body through the kidneys.
http://www.sciam.com/article.cfm?id=nanomedicine-targets-cancer
IT 101
• Calando’s lead drug candidate, IT-101,
is comprised of Cyclosert™ in
combination with the anticancer
compound camptothecin for systemic treatment of cancer.
• A natural compound found in the bark of the Chinese
camptotheca acuminata tree, Camptothecin has potent
anticancer properties against a
broad spectrum of tumor cell lines.
• Method of action: inhibits the
enzyme topoisomerase 1, which is
key to the winding and unwinding
process of DNA that is an essential
step in cell division and replication.
• Interrupting this process prevents
DNA replication and leads to cell death.
http://www.insertt.com/it-101.html Calando Pharmaceutical, Pasadena, CA site
IT 101
• In the clinical trials, dosages of the drug were achieved that
provided high quality of life without the side effects, such
as vomiting, diarrhea and hair loss typical of
chemotherapeutics, and with no new side effects.
• The general high quality of life while on treatment is exciting,
and although phase I trials focus on establishing safety, the
tests also provided evidence that the drug was active in
patients. That is encouraging because patients in phase I
cancer trials have had numerous courses of standard
therapy that failed before entering the trial.
• After completing the six-month trial, several of these
patients have remained on the drug on a compassionate
use basis, and long-term survivors of approximately one
year or more include patients with advanced lung, renal
and pancreatic cancers.
http://www.sciam.com/article.cfm?id=nanomedicine-targets-cancer
IT 101
• Because the side-effect profile of this drug is so low, it will
next be tested in a phase II (efficacy) trial in women
diagnosed with ovarian cancer who have undergone
chemotherapy. Instead of simply "waiting and watching" for
the cancer to progress, IT-101 will be given as maintenance
therapy in the hope of preventing disease progression.
• These observations from IT-101 testing and similarly
encouraging news from trials of other nanoparticle-based
treatments are beginning to provide a picture of what may
be possible with well-designed nanotherapeutics.
• Indeed, the next generation of synthetic nanoparticles,
which are far more sophisticated, offers a glimpse of the real
potential of this technology and the importance these drugs
will hold for the systems-based view of disease and
treatment.
http://www.sciam.com/article.cfm?id=nanomedicine-targets-cancer
Nanomedicine Future
For cancer, the very exciting promises that should be
realized over the next 10 years are:
1. That presymptomatic blood diagnoses will catch fledgling
cancers that can be cured by conventional therapy;
2. That cancers of a particular tissue (for example, breast
or prostate) will be stratified into distinct types that can
be matched with drugs that provide very high cure rates;
3. The identification of disease-perturbed networks will
allow more rapid development of drugs that are less
expensive and far more effective.
• This new approach to medicine therefore has the
potential to transform health care for virtually everyone
living today..
http://www.sciam.com/article.cfm?id=nanomedicine-targets-cancer
Issues for Discussion
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Time until Phase III trials complete (5 yr?)
Safety Concerns
Regulatory Approval
Training of Physicians
Price of Treatment
Insurance Coverage
Should cancer be cured?