Nanomagnets Guide Stem Cells To Damaged Tissue

ScienceDaily (Oct. 22, 2009)

Microscopic magnetic particles have been used to bring stem cells to sites of cardiovascular injury in a new method designed to increase the capacity of cells to repair damaged tissue, UCL scientists have announced.

The cross disciplinary research, published in The Journal of the American College of Cardiology: Cardiovascular Interventions, demonstrates a technique where endothelial progenitor cells – a type of stem cell shown to be important in vascular healing processes – have been magnetically tagged with a tiny iron-containing clinical agent, then successfully targeted to a site of arterial injury using a magnet positioned outside the body.

Following magnetic targeting, there was a five-fold increase in cell localisation at a site of vascular injury in rats. The team also demonstrated a six-fold increase in cell capture in an in vitro flow system (where microscopic particles are suspended in a stream of fluid and examined to see how they behave).

Although magnetic fields have been used to guide cellular therapies, this is the first time cells have been targeted using a method directly applicable to clinical practice. The technique uses an FDA (U.S. Food and Drug Administration) approved agent that is already used to monitor cells in humans using MRI (magnetic resonance imaging).

Dr Mark Lythgoe, UCL Centre for Advanced Biomedical Imaging, the senior author on the study, said: "Because the material we used in this method is already FDA approved we could see this technology being applied in human clinical trials within 3-5 years. It's feasible that heart attacks and other vascular injuries could eventually be treated using regular injections of magnetised stem cells. The technology could be adapted to localise cells in other organs and provide a useful tool for the systemic injection of all manner of cell therapies. And it's not just limited to cells – by focusing tagged antibodies or viruses using this method, cancerous tumours could be much more specifically targeted"

Panagiotis Kyrtatos, also from the UCL Centre for Advanced Biomedical Imaging and lead researcher of the study, added: "This research tackles one of the most critical challenges in the biomedical sciences today: ensuring the effective delivery and retention of cellular therapies to specific targets within the body.

"Cell therapies could greatly benefit from nano-magnetic techniques which concentrate cells where they are needed most. The nano-magnets not only assist with the targeting, but with the aid of MRI also allow us to observe how the cells behave once they're injected."

This work was supported by public and charitable funding from the UCL Institute of Child Health (Child Health Research Appeal Trust), The British Heart Foundation, the Alexander S. Onassis Public Benefit Foundation and the Biotechnology and Biological Sciences Research Council (BBSRC).

---

Journal reference:

1. Panagiotis G. Kyrtatos, Pauliina Lehtolainen, Manfred Junemann-Ramirez, Ana Garcia-Prieto, Anthony N. Price, John F. Martin, David G. Gadian, Quentin A. Pankhurst, Mark F. Lythgoe. Magnetic Tagging Increases Delivery of Circulating Progenitors in Vascular Injury. JACC Cardiovascular Interventions, 2009; 2 (8): 794 DOI: 10.1016/j.jcin.2009.05.014

Adapted from materials provided by University College London.

Source

NexBio

NexBio - another possible company cohort for NanoViricides:

Fludase® (DAS181) is a broad-spectrum drug candidate for the prophylaxis and treatment of respiratory infections by all types of influenza virus, including the types of virus that may cause a potential influenza pandemic, as well as all types of parainfluenza virus. Fludase® is currently in phase I clinical development, and has successfully completed its First-In-Man trial.

MECHANISM OF ACTION: FLUDASE® BLOCKS IFV ENTRY INTO CELLS

Fludase® is a recombinant fusion protein (see figure 1) that inactivates viral receptors on the cells of the human respiratory tract, thereby preventing influenza and other viruses such as parainfluenza from both infecting the human body and amplifying in already-infected individuals.

In the human respiratory tract, cell-surface sialic acids act are the host cell receptors for all influenza A and B and parainfluenza viruses. Fludase® works by inactivating these sialic receptors in the airway epithelium, therefore preventing viral entry into cells.
Source

Finally, I would like to express my gratitude for the support of the National Institutes of Health and the National Institute of Allergy and Infectious Disease, without which our critical research would not be possible.

Mang Yu
CEO
Source

NexBio is a five-year-old biotechnology company located in San Diego, California, founded to create and commercialize novel, broad-spectrum biopharmaceuticals to prevent and treat current and emerging life-threatening human disease. All funding to date has been from the National Institutes of Health in the form of grants and contracts, totaling ~$63 million.
Source

• NexBio lives off grants, year after year, $63 Million in 5 years, so far.
• I note that NexBio uses the sialic acid stuff in their virus fighting efforts. They block the virus from attaching to the cell it is targeting by interfering with the sialic acid attachment points on cells. They block those attachment points with a covering chemical so the virus has no way to attach to the cell it seeks. I think they do their thing on the cells themselves and do not do anything to the virus directly. NNVC does attack the virus directly and immobilizes it by making the cide look to the virus like a cell with the same sialic acid attachment points that the virus attaches to and becomes trapped unable to infect any cells themselves.

• I found this:

Hemagglutinin, displayed at left, is one of two virally-coded integral envelope proteins of the influenza virus. Hemagglutinin is responsible for host cell binding and subsequent fusion of viral and host membranes in the endosome after the virus has been taken up by endocytosis. In the first step of infection it binds to sialic acid residues of glycosylated receptor proteins on target cell surfaces.
Source

• So...I guess NNVC targets the sialic acid binding bits on the virus (making the virus think the cide particles are the host cells by presenting sialic acid binding sites for the virus to attach to), whereas NexBio tagets the sialic acid itself on the cell that the virus is looking to bind to and covers it so the virus can't find it. Two sides of the same coin perhaps?

• Re the government giving grants:
• Wouldn't it make sense to combine the likes of NNVC and NexBio into one grant? More bang for the buck? They certainly are similar!

• Re NexBio funding:

Corporate funding to date has been entirely non-dilutive, consisting of five grants totaling $13M, together with a BAA
Contract for $49.8M to support Fludase(R) development, all from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.
Source

• Re NexBio IP:

United States Patent Application 20050004020
Kind Code A1
Yu, Mang ; et al. January 6, 2005

Broad spectrum anti-viral therapeutics and prophylaxis

Abstract

The present invention provides new compositions and methods for preventing and treating pathogen infection. In particular, the present invention provides compounds having an anchoring domain that anchors the compound to the surface of a target cell, and a therapeutic domain that can act extracellularly to prevent infection of the target cell by a pathogen, such as a virus. Preferred target cells are epithelial cells. The invention provides compositions and methods for preventing viral diseases, such as influenza, using compounds having anchoring domains that can bind target cells linked to enzymatic activities that can act extracellularly to interfere with viral infection of target cells. The invention also provides compositions and methods for preventing viral diseases such as influenza using compounds having anchoring domains that can bind target cells linked to protease inhibitors that can act extracellularly to interfere with viral infection of target cells.
Source

United States Patent Application 20050112751
Kind Code A1
Fang, Fang ; et al. May 26, 2005

Novel class of therapeutic protein based molecules

Abstract

The present invention provides new compositions and methods for preventing and treating pathogen infection. In particular, the present invention provides compounds having an anchoring domain that anchors the compound to the surface of a target cell, and a therapeutic domain that can act extracellularly to prevent infection of a target cell by a pathogen, such as a virus. The present invention also comprises therapeutic compositions having sialidase activity, including protein-based compounds having sialidase catalytic domains. Compounds of the invention can be used for treating or preventing pathogen infection, and for treating and reducing allergic and inflammatory responses. The invention also provides compositions and methods for enhancing transduction of target cells by recombinant viruses. Such compositions and methods can be used in gene therapy.
Source

2 results found in the Worldwide database for:
NexBio as the applicant
(Results are sorted by date of upload in database)

1 TECHNOLOGY FOR THE PREPARATION OF MICROPARTICLES in my patents list
Inventor: MALAKHOV MICHAEL [US] ; FANG FANG [US] Applicant: NEXBIO INC [US] ; MALAKHOV MICHAEL [US] (+1)
EC: IPC:

Publication info: WO2009015286 (A2) — 2009-01-29

2 TECHNOLOGY FOR PREPARATION OF MACROMOLECULAR MICROSPHERES in my patents list
Inventor: MALAKHOV MICHAEL P [US] ; FANG FANG [US] Applicant: NEXBIO INC [US]
EC: A61K9/14; A61K9/00M20B; (+9) IPC: A61K9/16; A61K38/16; A61K38/48; (+3)

Publication info: KR20080090525 (A) — 2008-10-08
Source

• Re relevance?

• Not sure but interesting insofar as viral infection is attacked using targeting on cells. And, more importantly, if NexBio can garner $63million in government grants for their R&D and manufacture can we be far behind?

Refs:
WIPO
WO/2009/015286
WO/2007/114881

• Note (From WO/2007/114881):

As used herein, an emulsion is defined as a colloid of two immiscible liquids, a first liquid and a second liquid, where the first liquid is dispersed in the second liquid. As used herein, surfactants (or "surface-active agents") are chemical or naturally occurring entities which, when dissolved in an aqueous solution, reduce the surface tension of the solution or the interfacial tension between two or more phases in solution. The surfactant molecules generally are amphiphilic and contain hydrophilic head groups and hydrophobic tails. The surfactant molecules can act as stabilizers and/or improve flowability characteristics of the microparticles provided herein.

• Note as to particle sizing (From WO/2007/114881):

The geometric size of microspheres produced by the two methods was assessed by light microscopy and found to be essentially identical (range of 1.5 - 3.0 microns) [1500nm-3000nm] for both methods.

Targeted Nanoparticles Deliver Therapeutic DNA to Cancer Cells

12/25/2008 11:22:47 PM

Given that cancer is a disease caused by gene mutations, cancer researchers have been striving to develop gene therapies aimed at correcting these mutations. However, these efforts have been hobbled by the difficulty in safely and efficiently delivering anticancer genes to tumors. Nanoparticles, however, may solve these delivery issues, and two recently published studies, using two different types of nanoparticles, lend credence to that hypothesis.

Miqin Zhang, Ph.D., PI of the Nanotechnology Platform for Pediatric Brain Cancer Imaging and Therapy project at the University of Washington in Seattle, led a group of researchers that developed a targeted polymer nanoparticle that efficiently delivered a model gene into two types of cancer cells. More importantly, the gene functions properly once it enters the targeted cells. In the second study, Mansoor Amiji, Ph.D., PI of the Nanotherapeutic Strategy for Multidrug Resistant Tumors Platform Partnership at Northeastern University, and doctoral student Padmaja Magadala, M.S., used gelatin-based nanoparticles and a different targeting agent to efficiently deliver the same model gene to human pancreatic tumor cells. As in the first study, the delivered gene functioned properly inside the tumor cells.

The nanoparticle developed by Dr. Zhang’s group was made of two polymers—polyethyleneimine (PEI) and polyethylene glycol (PEG)—linked to chlorotoxin, a small protein isolated from scorpion venom. Previous research by several research teams had shown that chlorotoxin binds many types of tumors, including gliomas and medulloblastomas, two types of brain cancer. PEI forms stable nanoparticles that bind deoxyribonucleic acid (DNA), but the resulting nanoparticles can be toxic. Adding PEG to the nanoparticles provides a biocompatible surface that greatly reduces the toxicity of PEI.

As a test, Dr. Zhang and her colleagues used these nanoparticles to deliver DNA that codes for green fluorescent protein (GFP), which is used widely to study gene expression. When added to tumor cells expressing the chlorotoxin receptor, the nanoparticles were quickly taken up by the cells. The cells also turned green, thanks to the expression of GFP. In contrast, nanoparticles lacking chlorotoxin were not taken up by the cells, and tumor cells lacking the chlorotoxin receptor did not take up the nanoparticles.

(The three scientists credited with discovering and developing GFP as a critical research tool were awarded the 2008 Nobel Prize in Chemistry. One of those scientists, Roger Tsien, Ph.D., is an investigator at NCI’s Center of Nanotechnology for Treatment, Understanding, and Monitoring of Cancer at the University of California, San Diego.)

Dr. Amiji’s approach differed, in that he used a peptide that targets the epidermal growth factor receptor that is overexpressed by several types of tumors, including pancreatic cancer. He also used a nanoparticle constructed from negatively charged gelatin, which readily incorporates DNA and other nucleic acids, which are positively charged at normal physiological pH. The structure of the nanoparticle material also promotes DNA to take on a supercoiled structure that is efficiently taken up and transported to the cell’s nucleus, a critical factor for gene expression to occur. To improve the biocompatibility of these nanoparticles, Dr. Amiji also used PEG to coat the nanoparticles.

When added to pancreatic cells, nearly half of the administered dose of these engineered, targeted nanoparticles were taken up by pancreatic tumor cells, a remarkably high value. More importantly, a large percentage of the transfected cells subsequently expressed GFP. In addition, the nanoparticles were not toxic to the cells, an important finding given that they did not contain any therapeutic agent.

The work from Dr. Zhang’s group, which was detailed in the paper “A ligand-mediated nanovector for targeted gene delivery and transfection in cancer cells,” was supported by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer. An abstract of this paper is available at the journal’s Web site.

View abstract

The study headed by Dr. Amiji, which was described in the paper “Epidermal growth factor receptor-targeted gelatin-based engineered nanocarriers for DNA delivery and transfection in human pancreatic cancer cells,” was also supported by the NCI Alliance for Nanotechnology in Cancer. An abstract of this paper is available at the journal’s Web site.

View abstract.

Source

Cells used as vectors to carry materials to tumors, infection sites or other tissue sites

Cells used as vectors to carry materials to tumors, infection sites or other tissue sites by Monica Tele Published 11/25/2008

MIT engineers have outfitted cells with tiny "backpacks" that could allow them to deliver chemotherapy agents, diagnose tumors or become building blocks for tissue engineering. Michael Rubner, director of MIT's Center for Materials Science and Engineering and senior author of a paper on the work that appeared online in Nano Letters on Nov. 5, said he believes this is the first time anyone has attached such a synthetic patch to a cell. The polymer backpacks allow researchers to use cells to ferry tiny cargoes and manipulate their movements using magnetic fields. Since each patch covers only a small portion of the cell surface, it does not interfere with the cell's normal functions or prevent it from interacting with the external environment. "The goal is to perturb the cell as little as possible," said Robert Cohen, the St. Laurent Professor of Chemical Engineering at MIT and an author of the paper. The researchers worked with B and T cells, two types of immune cells that can home to various tissues in the body, including tumors, infection sites, and lymphoid tissues � a trait that could be exploited to achieve targeted drug or vaccine delivery. "The idea is that we use cells as vectors to carry materials to tumors, infection sites or other tissue sites," said Darrell Irvine, an author of the paper and associate professor of materials science and engineering and biological engineering. Cellular backpacks carrying chemotherapy agents could target tumor cells, while cells equipped with patches carrying imaging agents could help identify tumors by binding to protein markers expressed by cancer cells.

Supporting Information for Synthetically Functionalized Living Cells

CANCER CELL TARGETING USING NANOPARTICLES

(WO/2008/121949)

Pub. No.: WO/2008/121949 International Application No.: PCT/US2008/058873 Publication Date: 09.10.2008 International Filing Date: 31.03.2008
IPC:	A61K 9/14 (2006.01), B82B 1/00 (2006.01)
Applicants:	MASSACHUSETTS INSTITUTE OF TECHNOLOGY [US/US]; Room NE25-230, 5 Cambridge Center, Kendall Square, Cambridge, MA 02142 (US) (All Except US). ZALE, Stephen, E. [US/US]; 101 Binney Street, Cambridge, MA 02142 (US) (US Only).
Inventor:	ZALE, Stephen, E.; 101 Binney Street, Cambridge, MA 02142 (US).
Agent:	HANLEY, Elizabeth, A.; Lahive & Cockfield, LLP, One Post Office Square, Boston, MA 02109-2127 (US).
Priority Data:	PCT/US2007/007927 30.03.2007 US 60/976,197 28.09.2007 US

Title:

CANCER CELL TARGETING USING NANOPARTICLES

Abstract:

The present invention generally relates to polymers and macromolecules, in particular, to polymers useful in particles such as nanoparticles. One aspect of the invention is directed to a method of developing nanoparticles with desired properties. In one set of embodiments, the method includes producing libraries of nanoparticles having highly controlled properties, which can be formed by mixing together two or more macromolecules in different ratios. One or more of the macromolecules may be a polymeric conjugate of a moiety to a biocompatible polymer. In some cases, the nanoparticle may contain a drug. Other aspects of the invention are directed to methods using nanoparticle libraries. Source

New disease-fighting nanoparticles look like miniature pastries

July 29, 2008
By Gwen Ericson

-- Ultra-miniature bialy-shaped particles — called nanobialys because they resemble tiny versions of the flat, onion-topped rolls popular in New York City — could soon be carrying medicinal compounds through patients' bloodstreams to tumors or atherosclerotic plaques.

The nanobialys are an important addition to the stock of diagnostic and disease-fighting nanoparticles developed by researchers in the Consortium for Translational Research in Advanced Imaging and Nanomedicine (C-TRAIN) at Washington University School of Medicine in St. Louis. C-TRAIN's "smart" nanoparticles can deliver drugs and imaging agents directly to the site of tumors and plaques.

The new nanobialys weren't cooked up for their appealing shape — that's a natural result of the manufacturing process. The nanobialys answered a need for an alternative to the research group's gadolinium-containing nanoparticles, which were created for their high visibility in magnetic resonance imaging (MRI) scans.

Gadolinium is a common contrast agent for MRI scans, but recent studies have shown that it can be harmful to some patients with severe kidney disease.

"The nanobialys contain manganese instead of gadolinium," says first author Dipanjan Pan, Ph.D., research instructor in medicine in the Cardiovascular Division. "Manganese is an element found naturally in the body. In addition, the manganese in the nanobialys is tied up so it stays with the particles, making them very safe."

The bulk of a nanobialy is a synthetic polymer that can accept a variety of medical, imaging or targeting components. In the July 2008 issue of the Journal of the American Chemical Society the researchers report that targeted manganese-carrying nanobialys readily attached themselves to fibrin molecules, which are found in atherosclerotic plaques and blood clots. Laboratory-made clots then glowed brightly in MRI scans. They also showed that the nanobialys could carry both water-soluble and insoluble drugs.

Pan, who is a research instructor in medicine, played a leading role in the creation of nanobialys and chose the particles' name. "When we looked at the particles with an electron microscope, we saw they are round and flat, with a dimple in the center, like red blood cells, but also a little irregular, like bagels," he says. "I came across the word bialy, which is a Polish roll like a bagel without a hole that can be made with different toppings. So I called the particles nanobialys."

Pan is one of a group of researchers headed by Gregory M. Lanza, M.D., Ph.D., and Samuel A. Wickline, M.D. Lanza is an associate professor of medicine and biomedical engineering. Wickline is a professor of medicine, physics, biomedical engineering and cell biology and physiology. Lanza and Wickline are Washington University cardiologists at Barnes-Jewish Hospital.

Nanoparticles can be a more effective way to administer medications and imaging contrast agents because they are targeted, packaged units — drugs and imaging agents stay on the nanoparticles, which can be made to concentrate at a specific site in the body.

In animal studies, the research group has shown that their original, spherical nanoparticles can carry therapeutic compounds to tumors and atherosclerotic plaques. These nanoparticles also can hold thousands of molecules of gadolinium, which allows the researchers to use standard MRI scanning equipment to see where the nanoparticles congregate. The scans can then detect the size of lesions as well as the effect of drugs delivered by the nanoparticles.

But gadolinium has recently been linked to nephrogenic systemic fibrosis (NSF). First described in 2000, NSF is an unusual progressive, incurable disease seen in about 3 percent of patients with severe kidney disease who have had MRI scans using gadolinium. In NSF, collagen accumulates in tissues causing skin hardening and thickening, joint stiffening that can lead to physical disability, and disorders of the liver, lungs, muscles and heart.

"Even though it seems that gadolinium affects only those with severe renal failure, physicians have decided not to use gadolinium even in those with moderate renal failure," Lanza says. "A lot of patients with diabetes or hypertension develop renal failure, so that decision potentially affects many people. Our goal has always been that our nanoparticle technology should be able to help everyone. And with a growing number of people having diabetes and related cardiovascular problems, we knew we needed to find a substitute for gadolinium-based particles — nanobialys are our first step in that direction."

The researchers will continue to adapt the nanobialys for a variety of medicinal applications and work to develop other types of nanoparticles so that they can supply a wide range of medical needs.

"We're not sitting in the lab generating nanoparticles and then looking for what they could be used for," Lanza says. "We see a medical problem and ask what kind of particle might overcome it and then try to create it."

---

Pan D, Caruthers SD, Hu G, Senpan A, Scott MJ, Gaffney PJ, Wickline SA, Lanza GM. Ligand-directed nanobialys as theranostic agent for drug delivery and manganese-based magnetic resonance imaging of vascular targets. Journal of the American Chemical Society 2008 Jul 23;130(29):9186-7.

Source

It's all about targeting

(WO/2008/082374) CARBON NANOTUBE NANOBOMB

WO 2008082374 20080710

Claims

What is claimed is:

1. A composition comprising bundles of carbon nanotubes and a targeting molecule bound to said nanotubes.

2. The composition of claim 1 wherein said carbon nanotubes are single wall carbon nanotubes.

3. The composition of claim 1 wherein said targeting molecule is an antibody.

4. The composition of claim 1 wherein said composition further comprises a therapeutic compound.

5. The composition of claim lwherein said therapeutic compound is a chemotherapy drug.

6. A method for killing or damaging cells comprising the steps of

(a) delivering carbon nanotubes to cells or a location near said cells, wherein said nanotubes are hydrated prior to or after delivery to said cells or location near said cells;

(b) exposing said carbon nanotubes to light of sufficient intensity and for a sufficient amount of time to cause explosion of said carbon nanotubes, whereby the explosion of said nanotubes exposes said cells to a lethal or damaging dose of heat thereby killing or damaging said cells.

7. The method of claim 6 wherein said cells are mammalian cells.

8. The method of claim 6 wherein said cells are cancer cells.

9. The method of claim 6 wherein said cells are on the surface of the body of a mammal.

10. The method of claim 6 wherein said cells are inside the body of a mammal.

11. The method of claim 6 wherein said nanotubes are single wall carbon nanotubes.

12. The method of claim 6 wherein said nanotubes further comprise a targeting molecule.

13. The method of claim 12 wherein said targeting molecule is an antibody.

14. The method of claim 1 wherein said nanotubes further comprise a therapeutic compound.

15. The method of claim 9 wherein said therapeutic compound is a chemotherapy drug.

16. The method of claim 6 wherein said light is near infra-red light.

17. The method of claim 7 wherein said mammalian cells are human cells.

18. The method of claim 9 wherein said cells are human cells.

19. The method of claim 10 wherein said cells are human cells.

WO/2008/082374

http://medicalphysicsweb.org/cws/article/industry/35088

Researchers Target Tumors With Tiny 'Nanoworms'

ScienceDaily (May 7, 2008) — Scientists at UC San Diego, UC Santa Barbara and MIT have developed nanometer-sized “nanoworms” that can cruise through the bloodstream without significant interference from the body’s immune defense system and—like tiny anti-cancer missiles—home in on tumors.

Their discovery, detailed in this week’s issue of the journal Advanced Materials, is reminiscent of the 1966 science fiction movie, the Fantastic Voyage, in which a submarine is shrunken to microscopic dimensions, then injected into the bloodstream to remove a blood clot from a diplomat’s brain.

Using nanoworms, doctors should eventually be able to target and reveal the location of developing tumors that are too small to detect by conventional methods. Carrying payloads targeted to specific features on tumors, these microscopic vehicles could also one day provide the means to more effectively deliver toxic anti-cancer drugs to these tumors in high concentrations without negatively impacting other parts of the body.

“Most nanoparticles are recognized by the body's protective mechanisms, which capture and remove them from the bloodstream within a few minutes,” said Michael Sailor, a professor of chemistry and biochemistry at UC San Diego who headed the research team. “The reason these worms work so well is due to a combination of their shape and to a polymer coating on their surfaces that allows the nanoworms to evade these natural elimination processes. As a result, our nanoworms can circulate in the body of a mouse for many hours.”

“When attached to drugs, these nanoworms could offer physicians the ability to increase the efficacy of drugs by allowing them to deliver them directly to the tumors,” said Sangeeta Bhatia, a physician, bioengineer and a professor of Health Sciences and Technology at MIT who was part of the team. “They could decrease the side effects of toxic anti-cancer drugs by limiting their exposure of normal tissues and provide a better diagnosis of tumors and abnormal lymph nodes.”

The scientists constructed their nanoworms from spherical iron oxide nanoparticles that join together, like segments of an earthworm, to produce tiny gummy worm-like structures about 30 nanometers long—or about 3 million times smaller than an earthworm. Their iron-oxide composition allows the nanoworms to show up brightly in diagnostic devices, specifically the MRI, or magnetic resonance imaging, machines that are used to find tumors.

“The iron oxide used in the nanoworms has a property of superparamagnetism, which makes them show up very brightly in MRI,” said Sailor. “The magnetism of the individual iron oxide segments, typically eight per nanoworm, combine to provide a much larger signal than can be observed if the segments are separated. This translates to a better ability to see smaller tumors, hopefully enabling physicians to make their diagnosis of cancer at earlier stages of development.”

In addition to the polymer coating, which is derived from the biopolymer dextran, the scientists coated their nanoworms with a tumor-specific targeting molecule, a peptide called F3, developed in the laboratory of Erkki Ruoslahti, a cell biologist and professor at the Burnham Institute for Medical Research at UC Santa Barbara. This peptide allows the nanoworms to target and home in on tumors.

“Because of its elongated shape, the nanoworm can carry many F3 molecules that can simultaneously bind to the tumor surface,” said Sailor. “And this cooperative effect significantly improves the ability of the nanoworm to attach to a tumor.”

The scientists were able to verify in their experiments that their nanoworms homed in on tumor sites by injecting them into the bloodstream of mice with tumors and following the aggregation of the nanoworms on the tumors. They found that the nanoworms, unlike the spherical nanoparticles of similar size that were shuttled out of the blood by the immune system, remained in the bloodstream for hours.

“This is an important property because the longer these nanoworms can stay in the bloodstream, the more chances they have to hit their targets, the tumors,” said Ji-Ho Park, a UC San Diego graduate student in materials science and engineering working in Sailor’s laboratory.

Park was the motivating force behind the discovery when he found by accident that the gummy worm aggregates of nanoparticles stayed for hours in the bloodstream despite their relatively large size.

While it’s not clear yet to the researchers why, Park notes that “the nanoworm’s flexibly moving, one dimensional structure may be one the reasons for its long life in the bloodstream.”

The researchers are now working on developing ways to attach drugs to the nanoworms and chemically treating their exteriors with specific chemical “zip codes,” that will allow them to be delivered to specific tumors, organs and other sites in the body.

“We are now using nanoworms to construct the next generation of smart tumor-targeting nanodevices,” said Ruoslahti. We hope that these devices will improve the diagnostic imaging of cancer and allow pinpoint targeting of treatments into cancerous tumors.”

Other researchers involved in the development were Michael Schwartz of UC San Diego, Geoffrey von Maltzahn of MIT, and Lianglin Zhang of UC Santa Barbara. The project was funded by grants from the National Cancer Institute of the National Institutes of Health.

Adapted from materials provided by University of California, San Diego. Original article written by Kim McDonald.

Magnet guided cancer treatment

Friday April 18 2008

Cancer cells under the microscope

“Magnets can guide anti-cancer drugs to tumours” reported The Guardian today. They go on to discuss research on a new drug delivery method that suggests that cancer treatments can be delivered straight to tumour cells using tiny magnets. This, the paper said, will save healthy cells from the toxic effects of these drugs.

At present, the use of this technology in man is speculative and further research is required. The study will be of interest to the scientific community and represents a step forward in the search for ways of treating cancer that are more targeted and therefore less toxic for patients.

Where did the story come from?

Dr M Muthana and colleagues from the University of Sheffield Medical School, the University of Kent, and Keele University School of Medicine carried out the research. The study was funded by the Biotechnology and Biological Sciences Research Council. The study was published in the peer-reviewed medical journal: Gene Therapy.

What kind of scientific study was this?

In this laboratory study, the researchers used models and live mice to explore a new method of delivering therapeutic genes to diseased tissues such as tumours.

The researchers were particularly interested in developing a technology that takes advantage of the properties of cells called monocytes. Monocytes, a type of white blood cell, can migrate from the blood into body tissues. Here, they become macrophages, which operate as part of the immune system by taking up foreign matter and helping to destroy bacteria, protozoa and tumour cells. Monocytes are known to enter malignant tumours in large numbers, becoming macrophages, and to accumulate in areas of tumours where there is no blood supply (the most inaccessible parts of tumours). This property makes them potential vehicles to deliver therapy deep within tumours.

Magnetic nanoparticles (MNPs) have been bound to chemotherapy drugs in the past and a magnetic field used to direct and concentrate the drug in the target tissue. Though there is some success with this approach, relatively little of the drug is able to penetrate tumours beyond their surface tissues. The researchers were exploring whether monocytes loaded with magnetic nanoparticles could be attracted to tumour cells using a magnetic field.

The findings represent a step forward in the search for better, more targeted and therefore less toxic treatments for human cancers.

There were a number of different parts to the experiment. To begin with, the researchers cultured monocytes with magnetic nanoparticles to see whether they would take them up (absorb them). They then determined whether these “magnetic” monocytes would be attracted to a magnetic field.

To see whether these magnetised monocytes would still be able to penetrate into tumours, the researchers set up an experimental model. The model was set up in a chamber, at the bottom of which were “tumour spheroids” (balls of human tumour cells). The middle of the chamber constituted a layer of endothelial cells (the type of cells that line the interior of blood vessels) and the upper part of the chamber contained the magnetic monocytes. A magnet was then applied to the bottom of the chamber. The researchers were interested in whether the magnet would attract more cells to the tumours and how the monocytes behaved when they were genetically modified to carry a gene.

The researchers repeated their experiments in live mice injected with human prostate cancer cells that had grown tumours on their legs. The mice were injected with monocytes loaded with magnetic nanoparticles and a marker gene that would later indicate where the monocytes had penetrated. A magnet was applied near the tumour site. When the mice were dissected, the researchers assessed the concentration of magnetic monocytes in their tumours and other tissues, and compared these concentrations to what happened when a magnet was not applied or when the mice were injected with normal (i.e. non-magnetic) monocytes.

What were the results of the study?The researchers found that the monocytes quickly and effectively absorbed the magnetic nanoparticles and were not negatively affected by them.

In the experimental model, the monocytes containing the magnetic nanoparticles were attracted to the magnetic field, and they concentrated towards the side of the culturing vessel to which a magnet was being held. The monocytes were able to cross the endothelial layer in the model and penetrate the tumour spheroids, suggesting that being magnetised did not affect this ability of the cells. Applying a magnet to the bottom of the chamber near the tumour-like balls increased the infiltration of the monocytes into the tumours.

The use of the magnet significantly increased the amount of monocytes penetrating the mouse tumours and large numbers of these were detected in the deep parts of the tumour (that have little circulation and are usually hard to target with drugs).

What interpretations did the researchers draw from these results?

The researchers conclude that they have described a new “magnetic” approach to enhancing the uptake of genetically modified cells by the target tissue.

They say that their new technology could be used to overcome the problem of “poor uptake of cell-based forms of gene therapy by diseased tissues like malignant tumours”.

What does the NHS Knowledge Service make of this study?

This study in mice will be of interest to the scientific community as it represents a potential new use for magnetic nanoparticles, i.e. to help deliver gene therapies to diseased tissues. However, until the findings are repeated in humans, it is difficult to say how relevant and how imminent such treatments may be.

The researchers say that the technology “could markedly improve the efficacy of cell-based gene delivery protocols”. The fact that human tumour cells were used may increase the relevance of the study’s findings and the chances of a practical application, but more will need to be done to see whether human monocytes behave in a similar way in the human body. As it stands, treatments using this method are a long way off.

The potential of this technology should not be underestimated and will no doubt be the subject of future research. The findings represent a step forward in the search for better, more targeted and therefore less toxic treatments for human cancers.

Links to the headlines

Magnet cure. Daily Mirror, April 18 2008

Magnets can guide anti-cancer drugs to tumours, say scientists. The Guardian, April 18 2008

Links to the science

Muthana M, Scott SD, Farrow N, et al. A novel magnetic approach to enhance the efficacy of cell-based gene therapies. Gene Therapy 2008; Apr 17 [Epub ahead of print]

Source

Kanzius' next step

Inventor, researchers find device can target cancer cells

BY DAVID BRUCE
david.bruce@timesnews.com [more details]

Published: April 15. 2008 6:00AM

John Kanzius as he is being interviewed in an overhead walkway to the M D Anderson Cancer Center Feb. 28. (Rob Engelhardt / Erie Times-News)

John Kanzius couldn't believe what he was hearing in his earpiece.

Kanzius, a Millcreek Township inventor, was being interviewed live Monday on CBS' "Early Show" about his radio-frequency generator. Researchers at two prestigious cancer centers are testing the device to see if it can treat cancer in humans.

One of those researchers, Steven Curley, M.D., of M.D. Anderson Cancer Center in Houston, was telling "Early Show" co-host Harry Smith that his team has successfully targeted cancer cells with tiny pieces of metal -- an important step in the process.

"I just about fell out of my chair," Kanzius said after being interviewed by the "Early Show" from his winter home in Sanibel, Fla. "I knew the news, but I had no idea that Steve was going to talk about it on national television."

Kanzius was featured Sunday night on CBS' "60 Minutes," which broadcast a segment on Kanzius' device.

Since the broadcast, Kanzius said he has been bombarded with e-mails and telephone calls.

"It started almost immediately after '60 Minutes' ended," Kanzius said. "I've received more than 100 e-mails."

Both Kanzius and Curley said the "60 Minutes" piece told their story accurately. The 12-minute segment focused on Kanzius, who invented the device in 2003 after he was diagnosed with a rare form of leukemia.

Media

More stories, photos and videos on the CBS Web site at htt://www.goerie.com/extra/kanziusCBS

Reporter Lesley Stahl also interviewed Curley and David Geller, M.D., the lead researcher on the Kanzius project at the University of Pittsburgh Medical Center.

They told Stahl that Kanzius' device is designed to beam high-frequency radio waves into the body, after cancer cells are targeted with microscopic pieces of metal, called nanoparticles.


Radio waves are harmless to the body, but heat metal. Cancer cells containing the nanoparticles would be destroyed, but healthy cells would be left unharmed.

Earlier tests had shown the device completely kills cancerous tumors in living animals.

Since those tests, Curley and his team have been trying to target cancer cells with nanoparticles, without placing them in healthy cells. His comment on the "Early Show" indicates they have been successful.

"We are preparing a manuscript on targeting in four different lines of human cancer cells, and animal work is starting next month," Curley said in an e-mail Monday.

The CBS broadcasts have had a dramatic effect on the John Kanzius Cancer Research Foundation and its new Web site. The foundation is a nonprofit dedicated to raising money for research on Kanzius' device.


The new site went up just days before the broadcasts and is already being visited by computer users across the country.

"We have received between 20,000 and 30,000 visits since 7 p.m. Sunday," said Brian Barnes, owner of High Recall Advertising, the Missouri-based agency that built and operates the site for the foundation. "We're getting one to two donations a minute, for a total of about $10,000 so far."

The next step for Kanzius is to return to Erie in May and begin working at Industrial Sales and Manufacturing Inc., in Millcreek, to build a larger generator to use in human trials.

"Those are my orders from Steve," Kanzius said with a laugh.


@ Foundation's site: www.johnkanziuscancerresearchfoundation.org.

DAVID BRUCE can be reached at 870-1736 or by e-mail.

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