Nanoparticles find favour in diagnosis, therapy

Here's a good overview of nanotech uses in medicine. Thanks to The Hindu.

http://www.hindu.com/seta/2007/11/29/stories/2007112950081300.htm

Nanomedicine is very powerful because a single protein inside a living cell can be tracked
Nanomedicine involves the design, manufacture, administration, and monitoring of drugs and diagnostic/therapeutic devices that use nanoparticles about 1-100 nanometres in size. (1 nm = 10{+-}{+9} m, a strand of human hair is 80,000 nm thick and a red blood cell is 5000 nm in diameter).

The nanoparticles exhibit properties (strength, electrical conductivity, elasticity, colour etc.) that same materials do not have at micro or macro sizes.Bioavailability

The efficacy of any drug depends strongly on its bioavailability — referring to the presence of the drug in the part of the body where it is needed.

Drug delivery mechanisms focus on increasing bioavailability and the residence time.
Nanoparticles do both. Generally they assist in diagnosis (as contrast agents in ultrasonography, MRI imaging), delivery (by residing for a long time), treatment (by penetrating through cell walls and into cytoplasm inside the nucleus of the cell), accessing areas (crossing blood-brain barrier) and stimulating the body’s innate repair mechanism. Quantum dots are nanoparticles that glow when exposed to ultraviolet light. They shine longer and brighter than today’s fluorescent dyes, and are used, both in vitro and in vivo, as luminescent tags to track proteins.

Detecting cancer
This is very powerful because a single protein inside a living cell can be tracked. As the colour of a nanoparticle depends on its size (2 nm size particles glow bright green and 5 nm particles appear dark red) different proteins in a cell can be detected (for each has a colour).
Cancer is detected using the amount of specific proteins (also called biomarkers) in the blood. Using nanoparticles, as few as 100 molecules of Prostate Specific Antigen (PSA), or Cardiac Troponin I [cTnI] in a drop of blood can be detected.

Cadmium selenide quantum dots seep into malignant tumours and assist doctors in identifying their location and size.

Nanosphere Inc. has developed ‘Verigene system’, that, according to its web site, “uses gold nanoparticles (13-20 nm diameter) functionalised with either a defined number of antibodies that are specific to a particular protein of interest” to detect proteins in blood.

In photodynamic therapy, gold coated nanoshells, 120 nm diameter, have conjugating antibodies/peptides that make them get attached to cancerous cells.
When a tumour is irradiated by infrared laser, gold gets heated thereby killing the cancer cells.
Dendrimer is a synthetic molecule with branches (emanating from a core) and having hooks that can latch onto cells. Folic acid is attached to a few of the hooks, and anti-cancer drugs to others.
The carcinogenic cells easily absorb the folic acid and along with it the drugs enter the cells. This is targeted delivery without harming the good tissue. Antiemetic drugs

Nanometre sized particles of pharmaceutical compounds (produced using a proprietary technology) are used to manufacture antiemetic and other drugs (to treat high cholesterol, anorexia, cachexia, and during renal transplant).

One product that treats ovarian cancer uses a liposome to encapsulate the drug to prevent “detection and destruction by immune system.”

Another combines the active ingredient with a natural protein called albumin into a nanoparticle 1/100th the size of a red blood cell, to cross cell walls of a tumour.

Chemotherapy-induced nausea and vomiting or postoperative nausea and vomiting is prevented by an antiemetic based on nanotechnology.Blood-brain barrier
Unlike conventional antiemetic which targets nausea and vomiting signals in the gut, this works by crossing the blood-brain barrier and antagonising the NK1 receptors in the brain thereby preventing the occurrence of a vomiting reflux. However, it does not affect other receptors such as serotonin, and dopamine. Tissue removed by surgery must be replaced by growing new cells.
For this a biocompatible and biodegradable scaffolding of nanostructured polymer is “seeded” with cells taken from the patient. The cells regenerate fast and the scaffolding slowly dissolves. Peptide Amphiphiles assist in cell growth and are used to treat bone injuries.

Nanoscale materials are used for developing synthetic bone and coating artificial joints.
Silver kills microbes by preventing the transport of electrons and cell replication. Hence nanocrystalline silver is used as an antimicrobial coating on wound dressings and catheters.
The toxicity of nanomaterials over long periods is yet to be determined. Due to their unusual properties, the toxicity data corresponding to large scale particles cannot be extrapolated.
The high reactivity (due to large surface) and high mobility (due to size) may cause high toxicity.

The increase in bioavailability warrants close monitoring. The impact on cellular and tissue functions, path traversed in the body, and unknown reactions are also areas of concern.
Many quantum dots are toxic, but studies have shown that protective coatings may eliminate toxicity.

S. CHELLAIAH
(The author is Consultant, Satyam Computer Services Ltd. Email: chellaiah_s@satyam.com )

Lipid Nanoparticle delivery of gene therapy

This sounds pretty exciting. I know a group in the Czech Republic working on a very similar delivery approach. I wonder how they targeted the nanoparticles to the tumor cells- probably via the Enhanced Permiability and Retention ("EPR") effect, in other words by sizing the nanoparticles appropriately to be absorbed by the leaky vasculature of tumor cells. Impressive that they were able to achieve delivery of enough nanoparticles to the tumor sites to be able to measure the FUS1 expression! Any thoughts on this?

http://www.nanotechwire.com/news.asp?nid=4565&ntid=190&pg=1

Intravenous nanoparticle gene therapy shows activity in stage IV lung cancer

A cancer-suppressing gene has been successfully delivered into the tumors of stage 4 lung cancer patients via an intravenously administered lipid nanoparticle in a phase I clinical trial at The University of Texas M. D. Anderson Cancer Center. The gene, FUS1, also was found to be active in the metastatic non-small cell lung cancer tumors.

"We've treated 13 patients in this first-in-human study and we've seen an exciting proof of concept with no significant drug-related toxicity," says principal investigator Charles Lu, M.D., associate professor in M. D. Anderson's Department of Thoracic, Head and Neck Medical Oncology.

Blinded analysis of pretreatment and post-treatment biopsies of three patients' tumors show that expression of FUS1 was absent from pretreatment samples while a high level of FUS1 was expressed in tumors after treatment. FUS1 can induce apoptosis - programmed cell death - in cancer cells but is frequently lost when normal cells become cancerous.

Lu presented a poster on the study on April 17 at the late-breaking abstract session of the American Association for Cancer Research annual meeting in Los Angeles.

Other attempts at gene therapy have employed an adenovirus to deliver the therapeutic gene. "Here we are using a non-viral, non-infectious delivery system," Lu says.

The only clinically significant side effect so has been fever, but Lu says premedication with a steroid and diphenhydramine has eliminated that so far.

Previous gene therapy clinical trials also involved direct injection into tumors. "This is the first time anyone has shown that a gene can be injected and then be taken up and expressed in cancer cells at distant sites," said Jack Roth, M.D., professor of the M. D. Anderson Department of Thoracic and Cardiovascular Surgery and a pioneer in the field of gene therapy.

FUS1 can induce apoptosis - programmed cell death - in cancer cells but is absent in those cells. The FUS1 nanoparticle formulation was developed and tested in Roth's lab. It advanced to phase I clinical trial after a promising test on human non-small cell lung cancer in a mouse model.

FUS1 was discovered by a research team led by Roth at M. D. Anderson and by John Minna, M.D., of the Department of Internal Medicine and Pharmacology, Hamon Center for Therapeutic Oncology Research, at The University of Texas Southwestern Medical Center at Dallas. Roth and Minna are the co-principal investigators of a National Cancer Institute Specialized Program of Research Excellence in Lung Cancer.

"As a clinician, I am very cautious about saying that we have shown clinical activity at this point. We have some encouraging data. The number of patients is too small to draw any definite conclusions, however," Lu said.

Three patients of eight who received two or more doses experienced stable disease for three to seven months. Median survival time for all patients is 14.6 months, which Lu notes compares favorably to a seven-month median survival time for patients receiving second line therapy.

All patients on the trial had been treated with front line cisplatin combination chemotherapy, which failed to halt their disease. The clinical trial continues. No maximum tolerated dose has been established, Lu says.

The nanoparticle delivery system consists of a plasmid gene expression cassette loaded with DNA that encodes the FUS1 protein. This is wrapped tightly in a form of cholesterol to protect it from the body's defense mechanisms. The nanoparticles accumulate mainly in the lungs, particularly in the tumors, where the genes repeatedly express FUS1 tumor-suppressing proteins.

Lung cancer is the leading cause of cancer death in the United States, causing 160,000 deaths annually. About 80 percent of lung cancer is of the non-small cell type.

Other investigators on the project with Lu and Roth are Nancy Smyth Templeton, Ph.D., assistant professor in the Departments of Molecular and Cellular Biology and of Molecular Physiology and Biophysics at Baylor College of Medicine, who developed the lipid nanoparticle; Carmen Sepulveda, Ph.D., and John McMannis, Ph.D., M. D. Anderson Department of Stem Cell Transplantation; Lin Ji, Ph.D., Rajagopal Ramesh, Ph.D., and Gitanjali Jayachandran, Ph.D., all of the M. D. Anderson Department of Thoracic and Cardiovascular Surgery; Sean O'Connor, Ph.D., Coordinator of Regulatory Compliance in the GMP laboratory at M. D. Anderson; Marshall Hicks, M.D., and Reginald Munden, M.D., of the M. D. Anderson Department of Diagnostic Radiology; and J. Jack Lee, Ph.D., of the M. D. Anderson Department of Biostatistics.

The clinical trial was funded by the NCI SPORE grant and the William H. Goodwin Family Fund. FUS1 nanoparticle technology has been licensed to Introgen Therapeutics, Inc., which has no involvement with this study.

Introgen holds a licensing agreement with M. D. Anderson Cancer Center to commercialize products based on licensed technologies, and has the option to license future technologies under sponsored research agreements. The University of Texas System owns stock in Introgen. These arrangements are managed by M. D. Anderson in accordance with its conflict of interest policies.

Nanoparticle gene therapy studied
HOUSTON, April 18 (UPI) -- U.S. medical researchers have delivered a cancer-suppressing gene into tumors of lung cancer patients using a lipid nanoparticle.

The research involved stage 4 lung cancer patients and the intravenously administered lipid nanoparticle in a phase I clinical trial at The University of Texas M.D. Anderson Cancer Center.

The gene, FUS1, was found to be active in the metastatic non-small cell lung cancer tumors.

"We've treated 13 patients in this first-in-human study and we've seen an exciting proof of concept with no significant drug-related toxicity," said principal investigator Dr. Charles Lu.

Blinded analysis of pre-treatment and post-treatment biopsies of three patients' tumors showed expression of FUS1 was absent from pre-treatment samples, while a high level of FUS1 was expressed in tumors after treatment. FUS1 can induce apoptosis -- programmed cell death -- in cancer cells, but is frequently lost when normal cells become cancerous.

Lu presented the study Tuesday in Los Angeles during the annual meeting of the American Association for Cancer Research.

Copyright 2007 by United Press International. All Rights Reserved.

Will the plague pathogen become resistant to antibiotics? (via NewsRx)

April 3rd, 2007

(NewsRx.com) -- A small piece of DNA that helps bacteria commonly found in U.S. meat and poultry resist several antibiotics has also been found in the plague bacillus Yersinia pestis, gene sequence researchers report.

The ability to resist many of the antibiotics used against plague has been found so far in only a single case of the disease in Madagascar. But because the same ability is present in other kinds of bacteria from a broad range of livestock, antibiotic resistance could potentially spread to other Y. pestis and also other bacterial pathogens. In a paper published March 21 in the new journal PLoS ONE, the authors say this possibility "represents a significant public health concern."

More: http://www.newsrx.com/articles/524456.html

No Carrier Necessary: This Drug Delivers Itself

Release Date
03/07/07
Contact
Ellen Goldbaum
goldbaum@buffalo.edu
716-645-5000 ext 1415

BUFFALO, N.Y. -- The problem of efficiently delivering drugs, especially those that are hydrophobic or water-repellant, to tumors or other disease sites has long challenged scientists to develop innovative delivery systems that keep these drugs intact until reaching their targets.
Now scientists in the University at Buffalo's Institute for Lasers, Photonics and Biophotonics and Roswell Park Cancer Institute have developed an innovative solution in which the delivery system is the drug itself.
They describe for the first time in Molecular Pharmaceutics a drug delivery system that consists of nanocrystals of a hydrophobic drug.
The system involves the use of nanocrystals measuring about 100 nanometers of pure HPPH, (2-devinyl-2-(1'-hexyloxyethyl) pyropheophorbide), a photosensitizer currently in Phase I/II human clinical trials at RPCI for treating various types of cancer.
The UB researchers found that the nanocrystals of HPPH were taken up by tumors in vivo, with efficacy comparable to conventional, surfactant-based delivery systems.
A patent has been filed on this work.
"In this case, the drug itself acts as its own carrier," said Haridas Pudavar, Ph.D., UB research assistant professor of chemistry and a co-author.
The nanocrystals present a major advantage over methods of delivery involving other carriers, according to Paras Prasad, Ph.D., SUNY Distinguished Professor in the Department of Chemistry in UB's College of Arts and Sciences, executive director of the institute and a co-author.
Because other delivery systems, especially those containing surfactants, commonly used with HPPH and many other drugs, may add to the toxicity in the body, they have been considered imperfect solutions.
"Unlike formulations that require separate delivery systems, once this drug is approved, no additional approvals will be needed," said Prasad.
"Our published data in animal models demonstrate no difference in drug activity with the nanocrystal formulation," said Ravindra Pandey, Ph.D., Distinguished Professor of Biophysical Sciences at RPCI and a co-author on the paper.
"This is a case where the easiest formulation works the best," added Indrajit Roy, Ph.D., UB research assistant professor of chemistry and another co-author.
The researchers found that because HPPH is amphiphillic, i.e., partially soluble in water and oil, nanocrystals of it will self-assemble, that is, in solution the molecules aggregate, but not into such big clusters that they settle to the bottom.
"It's a controlled formation of a colloidally stable suspension of nanosized crystals," explained Tymish Ohulchanskyy, Ph.D., UB senior research scientist and a co-author.
The researchers originally were investigating nanocrystals as a delivery method for hydrophobic dyes in bioimaging applications, another promising use for nanocrystals that they continue to pursue.
Further in vivo studies with HPPH nanocrystals are being conducted by scientists at UB and RPCI, including Pandey and Allan R. Oseroff, M.D., Ph.D., chair of the department of dermatology at RPCI and in UB's School of Medicine and Biomedical Sciences.
The UB/RPCI team is exploring the use of the same technique for delivering other hydrophobic drugs, including those used in chemotherapy.
Additional co-authors on the paper are Koichi Baba, Ph.D., former postdoctoral research associate in the UB Department of Chemistry, and Yihui Chen, Ph.D., postdoctoral research associate at RPCI.
The nanocrystal research was supported by the National Institutes of Health, the John R. Oishei Foundation and UB's New York State Center of Excellence in Bioinformatics and Life Sciences with additional support from RPCI.
In related work, the UB researchers have achieved improved depth penetration of HPPH using two-photon photodynamic therapy, research that recently was published in the Journal of the American Chemical Society.
The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York.

Sugary Foods Raise Pancreatic Cancer Risk

Wednesday, February 7, 2007 (via lifescript.com)

If you needed another reason to put away the six-packs of soda and boxes of frosted cereal, a new study warns that a diet high in refined sugars can increase the risk of pancreatic cancer. Published in the American Journal of Clinical Nutrition, the study by Swedish researchers followed dietary habits and pancreatic cancer diagnoses in nearly 80,000 adults over the course of seven years. Researchers concluded that, on average, eating five or more daily servings of refined sugar raises the risk of being diagnosed with pancreatic cancer by 69%. The sugary foods most responsible for increasing cancer risk were among the most popular items in many adults' diets: sugar packets added to coffee or tea, sugary cereals, soft drinks, and sweetened stewed fruits and soups. The study's authors planned further research, but hypothesized that pancreatic cancer risk may be linked to the body's sensitivity to the hormone insulin.

Roche gets European approval for Tarceva, angiogenisis inhibitor

Tarceva : European approval for pancreatic cancer treatment Important new therapy option for patients suffering from one of the deadliest cancers

Roche's innovative cancer drug Tarceva (erlotinib), has been approved today by the European Commission for the treatment of patients with metastatic pancreatic cancer, in combination with a standard chemotherapy, gemcitabine. Tarceva is the first treatment in over a decade to have shown a significant survival benefit in treating patients with this devastating disease. Pancreatic cancer has the highest one-year mortality rate of any cancer and is Europe's sixth deadliest cancer. (1)

"This is a much needed treatment advance for patients suffering with this difficult-to-treat disease," said William M. Burns, CEO Roche Pharmaceuticals. "The approval of Tarceva in combination with gemcitabine chemotherapy offers patients and their families some real hope."

The approval was based on data from the pivotal PA.3 Phase III Study (2), which show that for patients with metastatic disease, treatment with Tarceva plus gemcitabine results in significantly longer survival (25 percent) compared to gemcitabine alone. In addition, a higher percentage of these patients were alive at 12 months in the group treated with Tarceva plus gemcitabine, compared to those treated with chemotherapy alone (21 percent v. 15 percent). The approval follows a positive recommendation from the European Committee for Medicinal Products for Human Use (CHMP) in December 2006.

Pancreatic cancer is the sixth most frequently occurring cancer in Europe (1). In 2002, there were more than 78,000 new cases of pancreatic cancer diagnosed in Europe, with a death rate of approximately 82,000 people per year (3). Pancreatic cancer is difficult to treat as it is often resistant to chemotherapy and radiotherapy and tends to spread quickly to other parts of the body, leading to a short life expectancy.
"Tarceva generates renewed optimism for patients and physicians," said Professor Eric Van Cutsem, of the University Hospital of Gasthuisberg, Belgium. "This approval marks a clear step forward in providing them with another treatment option for battling this terrible disease."

About the PA3 (2) study
The results of the double-blind, placebo-controlled Phase III study conducted by the National Cancer Institute of Canada, Clinical Trials Group at Queens University and involving 569 patients showed:
- Treatment with Tarceva plus gemcitabine in patients with metastatic pancreatic cancer resulted in significantly improved overall survival compared to gemcitabine alone (25%)
- 21% of these patients receiving Tarceva plus gemcitabine were alive after one year, compared to 15% on gemcitabine alone
- Overall, patients receiving Tarceva plus gemcitabine experienced significantly longer progression-free survival of 30%
- Tarceva plus gemcitabine was generally well tolerated by patients

Tarceva plus gemcitabine is already approved for the treatment of locally advanced, unresectable or metastatic pancreatic cancer in 15 countries including America and Australia. Tarceva is approved in the US and across the European Union for patients with locally advanced or metastatic non small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen.

About Tarceva
Tarceva (erlotinib) is a small molecule that targets the human epidermal growth factor receptor (HER1) pathway. HER1, also known as EGFR, is a key component of this signalling pathway, which plays a role in the formation and growth of numerous cancers. Tarceva blocks tumour cell growth by inhibiting the tyrosine kinase activity of the HER1 signalling pathway inside the cell.

Taken as an oral, once-daily therapy, Tarceva is the only EGFR-inhibitor to have demonstrated a survival benefit in lung and pancreatic cancer. Currently most lung and pancreatic cancer patients are treated wholly with chemotherapy which can be very debilitating due to its toxic nature. Tarceva works differently to chemotherapy by specifically targeting tumour cells, and avoids the typical side-effects of chemotherapy.

Tarceva is approved in the US and across the European Union for patients with locally advanced or metastatic non small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. It is also approved in the US for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine chemotherapy.
Tarceva is currently being evaluated in an extensive clinical development programme by a global alliance among OSI Pharmaceuticals, Genentech and Roche, focussing on earlier stages of NSCLC. Additionally, Tarceva is being studied in combination with Avastin in NSCLC and in a wide variety of other solid tumour types.

About Roche
Headquartered in Basel, Switzerland, Roche is one of the world's leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As a supplier of innovative products and services for the early detection, prevention, diagnosis and treatment of disease, the Group contributes on a broad range of fronts to improving people's health and quality of life. Roche is a world leader in diagnostics, the leading supplier of medicines for cancer and transplantation and a market leader in virology. Roche employs roughly 70,000 people in 150 countries and has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai. Additional information about the Roche Group is available on the Internet (www.roche.com).

All trademarks used or mentioned in this release are protected by law.


Further information
- About Roche: www.roche.com
- About Genentech: www.gene.com
- About OSI Pharmaceuticals: www.osip.com
- About cancer: www.health-kiosk.ch
- Roche in Oncology: http://www.roche.com/pages/downloads/company/pdf/mboncology05e.pdf


References
(1) Michaud DS. 2004. Epidemiology of pancreatic cancer Minerva Chir. Apr; 59(2):99-111
(2) Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A Phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. (Abstract #1, ASCO 2005)
(3) Ferlay J et al. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No. 5, Version 2.0, Lyon; IARC Press 2004

Ventana Receives FDA Approval for Rabbit Monoclonal Antibody

TUCSON, AZ, Jan 18, 2007 (MARKET WIRE via COMTEX News Network) -- Ventana Medical Systems, Inc. (NASDAQ: VMSI) today announced it has received approval from the US Food and Drug Administration (FDA) for the use of its PATHWAY(R) HER-2/neu (4B5) Rabbit Monoclonal Antibody as an aid in the assessment of breast cancer patients for whom Herceptin(R) treatment is considered. This antibody has also been approved for use on the Ventana Image Analysis System (VIAS(TM)).
The over-expression of HER2 causes breast cancer cells to grow more rapidly and renders customary chemotherapy less effective. Herceptin is a targeted therapy against the HER2 protein on breast cancer cells. PATHWAY(R) HER-2/neu (4B5) is intended for laboratory use for the semi-quantitative detection of HER2 antigen in sections of formalin-fixed, paraffin-embedded normal and neoplastic tissue on a Ventana automated immunohistochemistry slide staining device.

"We are pleased with the FDA's decision to approve Ventana's PATHWAY(R) HER-2/neu (4B5)," said Christopher Gleeson, President and Chief Executive Officer. "This new test provides pathologists and oncologists with an outstanding diagnostic tool and is the result of our continued investment in companion diagnostics. Our PATHWAY(R) HER-2/neu (4B5) diagnostic test adds to Ventana's existing companion diagnostic portfolio and further enhances the Company's position as a world leader in the development of diagnostic tests that assist physicians in the selection of targeted therapies that have the potential to improve patient care."

Herceptin(R) (trastuzumab) is manufactured by Genentech, Inc., San Francisco, CA.