Technology Scanning
Usually applied by companies to explore opportunities for expansion or threat assessment from competitors
New markets, new products, new technologies Foresight: Wise anticipation that leads to action Structured procedures for opportunity search
Types of scanning
(i) Exploratory gazing. (ii) Structured scanning. (iii) Directed viewing. (iv) In depth probing
Structured scanning
Preparation. Observation. Interpretation. Evaluation.
To find
(i) Landmark technologies (ii) Targeted technologies (iii) Market ideas
Van Wyk, R.J. Copyright 2000, Center for the Development of Technological Leadership, (now Technological Leadership Institute) 1300 South Second Street, Minneapolis, MN 55454
Used
Van Wyk, R.J. Copyright 2000, Center for the Development of Technological Leadership, (now Technological Leadership Institute) 1300 South Second Street, Minneapolis, MN 55454
http://nano.cancer.gov/learn/impact/diagnosis.asp
Two things necessaryspecifically identify a cancerous cell and something that enables it to be seen.
Antibodies that identify specific receptors found to be overexpressed in cancerous cells can be coated on to nanoparticles which produce a high contrast signal on MRI or CT scans. Inside the body, the antibodies on these nanoparticles bind selectively to cancerous cells, effectively lighting them up for the scanner. Nanotechnology will enable the visualization of molecular markers that identify specific stages and types of cancers, allowing doctors to see cells and molecules undetectable through conventional imaging.
http://nano.cancer.gov/learn/impact/diagnosis.asp
Nanoparticles such as quantum dots, which emit light of different colors depending on their size, could enable the simultaneous detection of multiple markers. The photoluminescence signals from antibody-coated quantum dots could be used to screen for certain types of cancer. Different colored quantum dots would be attached to antibodies for cancer biomarkers to allow oncologists to discriminate cancerous and healthy cells by the spectrum of light they see.
http://nano.cancer.gov/learn/impact/diagnosis.asp
http://nano.cancer.gov/learn/impact/treatment.asp
Nanocarriers
Conventional chemotherapy employs drugs that are known to kill cancer cells effectively. But these cytotoxic drugs kill healthy cells in addition to tumor cells, leading to adverse side effects such as nausea, neuropathy, hair-loss, fatigue, and compromised immune function.
Nanoparticles can be used as drug carriers for chemotherapeutics to deliver medication directly to the tumor while sparing healthy tissue. Nanocarriers have several advantages over conventional chemotherapy. They can:
protect drugs from being degraded in the body before they reach their target. enhance the absorption of drugs into tumors and into the cancerous cells themselves. allow for better control over the timing and distribution of drugs to the tissue, making it easier for oncologists to assess how well they work. prevent drugs from interacting with normal cells, thus avoiding side effects.
http://nano.cancer.gov/learn/impact/treatment.asp
Passive Targeting
There are now several nanocarrier-based drugs on the market, which rely on passive targeting through a process known as "enhanced permeability and retention." Because of their size and surface properties, certain nanoparticles can escape through blood vessel walls into tissues. In addition, tumors tend to have leaky blood vessels and defective lymphatic drainage, causing nanoparticles to accumulate in them, thereby concentrating the attached cytotoxic drug where it's needed, protecting healthy tissue and greatly reducing adverse side effects.
http://nano.cancer.gov/learn/impact/treatment.asp
Active Targeting
On the horizon are nanoparticles that will actively target drugs to cancerous cells, based on the molecules that they express on their cell surface.
Molecules that bind particular cellular receptors can be attached to a nanoparticle to actively target cells expressing the receptor. Active targeting can even be used to bring drugs into the cancerous cell, by inducing the cell to absorb the nanocarrier.
Active targeting can be combined with passive targeting to further reduce the interaction of carried drugs with healthy tissue. Nanotechnology-enabled active and passive targeting can also increase the efficacy of a chemotherapeutic, achieving greater tumor reduction with lower doses of the drug.
http://nano.cancer.gov/learn/impact/treatment.asp
Schematics - Reproduced from Sahoo and Labhasetwar, 2003 with kind permission from Drug Discovery Today. http://www.cancer-therapy.org/CT3A/HTML/13.%20Orive%20et%20al,%20131-138%20.html 2005
Nanospheres
Bovine serum albumin nanospheres containing Santhi, 5-fluorouracil show higher tumour inhibition 2002 than the free drug Micelle delivery of doxorubicin increases cytotoxicity to prostate carcinoma cells Ultra fine silica based nanoparticles releasing water insoluble anticancer drug Radiation-guided drug delivery of liposomal cisplatin to tumor blood vessels results in improved tumour growth delay Targeted delivery within dendrimers improved the cytotoxic response of the cells to methotrexate 100-fold over free drug McNaealy, 2004 Roy, 2003
Micelles
Geng, 2004
Dendrimers
Quintana, 2002
SLN powder formulation of all-trans retinoic acid may have potential in cancer chemoprevention and therapeutics. http://www.cancer-therapy.org/CT3A/HTML/13.%20Orive%20et%20al,%20131-138%20.html 2005
SLN particles
Soo-Jeong, 2004
A whole range of delivery agents are possible but the main components typically include a nanocarrier, a targeting moiety conjugated to the nanocarrier, and a cargo (such as the desired chemotherapeutic drugs).
http://www.nature.com/nnano/journal/v2/n12/fig_tab/nnano.2007.387_F3.html
Schematic diagram of the drug conjugation and entrapment processes. The chemotherapeutics could be bound to the nanocarrier, as in the use of polymer drug conjugates, dendrimers and some particulate carriers, or they could be entrapped inside the nanocarrier.
http://www.nature.com/nnano/journal/v2/n12/fig_tab/nnano.2007.387_F3.html
Mechanisms by which Nanocarriers Can Deliver Drugs to Tumors Polymeric nanoparticles are shown as
representative nanocarriers (circles). Passive tissue targeting is achieved by extravasation of nanoparticles (NP) through increased permeability of the tumor vasculature and ineffective lymphatic drainage (EPR effect). Active cellular targeting (inset) can be achieved by functionalizing the surface of NP with ligands that promote cell-specific recognition and binding. The nanoparticles can (i) release their contents in close proximity to the target cells; (ii) attach to the membrane of the cell and act as an extracellular sustained-release drug depot; or (iii) internalize into the cell.
http://www.nature.com/nnano/journal/v2/n12/fig_tab/nnano.2007.387_F1.html
Quantum Dots
Raw quantum dots, 2-8 nm are toxic, CdSe or CdTe cores with ZnS shell But they fluoresce brilliantly, better than dyes (imaging agents) Coat with tri-n-octyl-phosphine
oxide (TOPO), then polymer to prevent toxicity
Add polyethylene glycol (PEG) to improve biocompatibility Add other links to attach to target receptors Only way of clearance of protected QDs from the body is by slow filtration and excretion through the kidney
http://www.azonano.com/Details.asp?ArticleID=1726
Quantum Dots
A research team from Quantum Dot Corporation and Genentech proved the potential of QDs to identify live breast cancer cells that are likely to respond to an anti-cancer drug QD technology helps cancer researchers to observe fundamental molecular events occurring in the tumor cells by tracking the QDs of different sizes and thus different colors, tagged to multiple different biomoleules, in vivo by fluorescent microscopy. QD technology holds a great potential for applications in nanobiotechnology and medical diagnostics where QDs could be used as labels. Use of QDs in humans requires extensive research to determine the long-term effects of administering QDs.
http://www.azonano.com/Details.asp?ArticleID=1726
Nanoshells
http://blogs.chron.com/sciguy/archives/2008/07/at_long_last_na.html
Nanoshells
Developed by Drs. Naomi Halas and Jennifer West Rice University 1994
Nanoshells have a core of silica and a metallic outer layer. These nanoshells can be injected safely, as demonstrated in animal models. Because of their size, nanoshells will preferentially concentrate in cancer lesion sites. This physical selectivity occurs through a phenomenon called enhanced permeation retention (EPR).
Can further decorate the nanoshells to carry molecular conjugates to the antigens that are expressed on the cancer cells themselves or in the tumor microenvironment. This second degree of specificity preferentially links the nanoshells to the tumor and not to neighboring healthy cells.
http://singularityhub.com/2009/12/14/nih-guides-nanomedicine-towards-killing-cancer/
Nanoshells
Externally supply energy to these cells. The specific properties associated with nanoshells allow for the absorption of this directed energy, creating an intense heat that selectively kills the tumor cells. The external energy can be mechanical, radio frequency, optical - the therapeutic action is the same. The result is greater efficacy of the therapeutic treatment and a significantly reduced set of side effects.
Videos
http://www.youtube.com/watch?v=uyhxRIvw_cY&feature=player_embedded & http://singularityhub.com/2009/12/14/nih-guides-nanomedicine-towards-killingcancer/
In clinical trials as AuroLaseof June 08 via Nanospectra founded by Halas and West.2
http://www.nanospectra.com/documents/NanospectraPilotHNTrial2008-07-01.pdf
Approved 05 In Market 3
http://www.starpharma.com/vivagel.asp http://nano.cancer.gov/learn/now/clinical-trials.asp
Starpharma - Dendrimers
Dendrimers can be divided into three sections:
1. the multivalent surface, containing a high number of potential reactive sites 2. the outer shell just below the surface, 3. the core in case of higher generation dendrimers.
Starpharma Melbourne, Australia (SPX:ASL, SPHRY:OTCQXADR) Sales ~ $10M 09, 08 not yet profitable US Division Dendritic Nanotechnologies, Mt. Pleasant, MI
http://www.starpharma.com/about-starpharma.asp
2
http://dnanotech.com/glossary.php
3
3 http://dnanotech.com/targetedDrugDelivery.php
http://www.starpharma.com/data/product-pipeline-002.pdf
At the Center of Nanotechnology for Treatment, Understanding, and Monitoring of Cancer (NANO-TUMOR) (UCSD CCNE), Dr. Thomas Kipps developed a chemically engineered adenovirus nanoparticle to deliver a molecule that stimulates the immune system. Phase I clinical trials, being run jointly by Memgen and the Leukemia & Lymphoma Society, are underway in patients with chronic lymphocytic leukemia. An ongoing Phase I dose escalation study is evaluating patients who received direct intranodal injection of the chemically-engineered virus. Systemic clinical effects have been observed with a single injection with significant reductions in leukemia cell counts and reductions in the size of all lymph nodes and spleen. One patient went into complete remission.
http://nano.cancer.gov/learn/now/clinical-trials.asp
http://nano.cancer.gov/learn/now/clinical-trials.asp
http://nano.cancer.gov/learn/now/clinical-trials.asp
Doxil - Approved
Approved for Ovarian Cancer AIDS-related Karposis Multiple Myeloma The STEALTH liposome methoxypolyethylene glycol (mPEG) containing Antitumor antibiotic Interferes with cell division Half life 55 hours in humans ~ 100 nm size
Produced by Ben Venue Labs, - Bedford, OH, contract mfg Div. of Boeringer Ingelheim Distributed by Centocor Ortho Biotech, Inc Horsham, PA private, Div. of J&J STEALTH and DOXIL are trademarks of ALZA Corporation, Div. of J&J
Sarcoma
http://www.doxil.com/assets/DOXIL_PI_Booklet.pdf
Abraxane - Approved
Approved for Breast Cancer Albumin-bound Paclitaxel Paclitaxel powerful anticancer drug not water soluble Abraxane is water soluble reduces treatment to 30 min from 3 hrs for solvent version & its side effects ~130 nm
American Pharmaceutical Partners and American BioScience, Inc approved by FDA 05Jan05 Produced by Abraxis BioScience Los Angeles, CA Not yet profitable ABII:NASDAQ
http://www.abraxisbio.com/rnd_platform_nab.htm
Drugs are delivered to tumors by leaky junctions in the blood vessels. Drugs also bind to albumin and are transported in the blood and delivered to tumors. This is accomplished first by taking advantage of the transport system (gp60 pathway) across the endothelial cells and then concentrating within the tumor interstitium by its affinity for SPARC (Secreted Protein Acidic and Rich in Cysteine). Finally, the water insolubility of many active chemotherapy agents is overcome by using proteins instead of additional chemicals to dissolve the active drug.
1 http://singularityhub.com/2009/09/01/newest-breathalyser-knows-if-you-have-lung-cancer/ 2 http://www.cnn.com/2009/HEALTH/08/18/nanotech.cancer.nano.tumors/ 3
http://news.bbc.co.uk/2/hi/7935592.stm
1 http://www.foresight.org/nanodot/?p=3018
2 http://www.nanowerk.com/spotlight/spotid=12962.php
http://www.nanowerk.com/spotlight/spotid=13428.php
Cautionary notes
Why is x not listed? Success or failure of a clinical trial Lots of different cancers
Summary
Cancer Study
Quantum dots improve study of cell biology of diseases
Cancer Detection
Nanoparticle imaging agents improve early detection Nanosensors aid in screening
Cancer Treatment
Wide variety of nanoparticles as drug or gene delivery vehicles Nanoparticles as absorbers for IR energy for heat death
Multi-function Approaches
Efforts to combine detection, collection at tumor sites, observation and treatment
Possible Futures
With first approvals, a few nano-drugs are in the market. Several more will follow. A few will fail consequences. Insurance reimbursement may lag
High initial cost may limit who gets to benefit
Scale-up of new technology drugs may limit availability Some early company success stories will fail or wallow
Difficult to grow Difficult to leverage technology Difficult to recoup start-up costs Difficult management issues, legal, IP, etc
Coming Attractions