Science Group - EEC Biotech - SDT - Cancer

United States Patent Application 20100130908
Kind Code A1
Wang; Xiaohuai ; et al. May 27, 2010

METHOD OF USE OF PORPHYRINS IN PREPARING A MEDICAMENT FOR SONODYNAMIC THERAPY AND A METHOD OF SONODYNAMIC THERAPY USING PORPHYRINS

Abstract
The invention provides method of use of a porphyrin compound as shown below in preparing a medicament for sonodynamic therapy, and a method of sonodynamic therapy using a porphyrin compound. Said therapy comprises administering a porphyrin compound to a patient and applying sonic wave to the patient, ##STR00001## ##STR00002## wherein each symbol has the meaning as defined in the description.

Inventors: Wang; Xiaohuai; (Guangzhou, CN) ; Su; Jiangan; (Shanghai, CN) ; Li; Qing; (Guangzhou, CN) ; Zhao; Guanglian; (Shanghai, CN) ; Luo; Yifan; (Guangdong Province, CN) ; Yu; Bo; (Shanghai, CN)

Assignee Name and Adress: Science Group Pty. Ltd.
Victoria
AU

Serial No.: 323174
Series Code: 12
Filed: November 25, 2008

[0124]III A Clinical Case

[0125]A patient, female, 69 years old, with right breast carcinoma. 10 months after surgery and chemotherapy, a tumor metastasis was detected in liver as shows by Computed Tomography-Positron Emission Tomography (CT-PET) on Nov. 9, 2007 (see FIG. 5). The lysine form of tin chlorophyllin as indicated in the above animal test B was dissolved in 0.1 mol/L phosphate buffer (pH 7.4) and given to the patient through lingual absorption every day for 2 days. Total dose of the lysine form of tin chlorophyllin was 60 mg. After 24 h, the red light light-emitting diode (LED) was irradiated to the body surface followed by local ultrasound irradiating of the tumour area at the intensities of 2.0 W/cm.sup.2 for 20 minutes in a water bathtub every day for 3 days. One week later, the treatment was repeated. After 3 cycles of SDT treatment with the lysine form of tin chlorophyllin, CT-PET scan on Jan. 10, 2008 showed the tumor shrank and the tumor metabolic activity was inhibited (see FIG. 5). Her symptom was much improved and Blood Routine and chemistry tests showed normal result.

Source

EEC BIO-TECH (GUANGZHOU) CO., LTD (EEC Biotech), a wholly-owned subsidiary of SCIENCE GROUP PTY LTD (SG) of Australia, is a limited liability company engaged in the professional research, development and medical application of modern bio-technology, particularly in the treatment of cancer.

EEC Biotech’s Head Office is located in Guangzhou, Guangdong Province, China. On the strength of the holding company SG’s rapidly expanding global information and business network, coupled with EEC Biotech’s good relations with China’s various research and development organisations, EEC Biotech is able to quickly penetrate and develop China’s and even the global medical bio-tech market.

EEC Biotech aims to be part of the cutting-edge in the fight against cancer by funding and developing break-through medical innovations through to creatively working on patient treatment delivery.

The Company’s primary focus has been on the development of Sono-Photo Dynamic Therapy (SPDT) technology, which is a new generation of anti-tumour technology developed from Photo-Dynamic Therapy (PDT).

PDT has been widely used as an anti-tumour treatment for over 100 years. It is approved for use in many countries. SPDT uses the same theory as PDT but is more advanced and effective as it contains both sound and light activation in the process. SPDT uses a chlorophyll sensitizer, which is activated by both sound and light. SPDT is a safe, non-invasive, non-toxic treatment option that allows greater flexibility in treatment and can enhance other conventional therapies such as chemotherapy and radiation.

The Company has developed a first class leadership team dealing with research and development, promotion and marketing. At the same time, it has also sought wide-ranging cooperation with various universities and professional research institutions in Australia, America and China, giving rise to an organisation with strong multi-disciplined R & D, covering areas such as bio-technology, medicine, chemistry, physics, electronics and information technology.

The Company currently has three professional clinical R & D centres in China with one anti-cancer Research Institute approved by the Chinese Government (Shaanxi EEC Cancer Research Institute). Overseas, it also has three cooperative clinical organisations in Australia, America and the United Kingdom. It is a corporate member of the Guangzhou Anti-Cancer Association, the Shaanxi Anti-Cancer Association and the American Society of Clinical Oncology.

EEC Biotech possesses several globally-leading patented technologies on cancer treatment, both within and without China.

Source

Inoperable cancers killed by new laser surgery

April 3, 2010

David Rose, Health Correspondent

Patients with inoperable head and neck cancer have seen their tumours “drop off” after treatment with a new form of laser therapy, doctors say.

The technique involves no surgery, can be carried out in a few minutes and does not harm healthy cells.

Doctors at University College Hospital in London have tested the latest form of photodynamic therapy on 11 patients with advanced head and neck cancers, all of whose tumours have shrunk or died away.

Although initial trials aimed to test only the safety of a new drug, which makes cancer cells sensitive to light and boosts the effects of chemotherapy, early results are so impressive that they have been submitted to a leading journal for publication this year.

Colin Hopper, a head and neck surgeon at the hospital, is leading the study. He said that patients with advanced or recurring cancers who had stopped responding to chemotherapy had experienced benefits.

One patient with an inoperable tumour on his tongue saw it disappear completely, while another, with advanced sarcoma on his jaw, lived for six months, far longer than doctors predicted.

Mr Hopper said: “This was a phase-one, dose-escalation study — you don’t normally expect the first patients to have a response, but with the first person we treated the tumour turned black and then dropped off, there was a quick clinical response in the targeted area. That’s been consistent in the 11 patients we have treated.”

During photodynamic therapy a drug is injected into the patient’s bloodstream that makes the cancer cells extremely sensitive to light. Those involved in the trial were injected with a new drug — known as Amphinex, a photosensitising agent — three to four days before being given standard chemotherapy. Because tumours have high metabolic activity and are surrounded by a proliferation of new blood vessels, the drug accumulates in cancer cells in preference to healthy tissue. When a low-powered red laser is shone on the tumour, directly or through the skin, the light triggers a chemical reaction that disrupts the harmful cells and boosts the action of a chemotherapy drug, bleomycin. “The results are quite impressive,” Mr Hopper said. “You can see the tumour turn black and die, not quite before your eyes, but over a matter of days.”

Although one patient died during the trial, this was not related to the therapy. No other serious side-effects have been reported.

If further trials are successful, Amphinex, made by the Norwegian company PCI Biotech, could be available on the NHS within five years.

Although the National Institute for Health and Clinical Excellence recommended photodynamic therapy as a treatment for head and neck cancer more than six years ago, it is still under-used and more commonly available to patients with skin cancer.

Out of 8,000 head and neck patients treated in 2008, only 180 received the therapy, nearly all at University College Hospital. The Department of Health commissioned a review of photodynamic therapy in 2007, but it is not expected to be published until this year.

Lesley Walker, of Cancer Research UK, said: “It is a promising treatment option which may be very useful for helping to treat some cancers, but it is unlikely that photodynamic therapy would ever be suitable for treating all types of cancer.”

Source

Radical new technology could end drilling and filling misery at the dentist

Scientists in Britain have developed a mouthwash that allows plaque-causing bacteria to be destroyed using nothing but a bright light, the light could possibly be attached to the head of a toothbrush.

The researchers say they have been experimenting with standard white light such as a conventional security light.

The new technology works in much the same way as some skin cancer treatments and may be available within three years for use at home.

According to the research team at Leeds Dental Institute a “repair solution” to help the body grow new enamel is also being developed which could do away with the need for “drilling and filling”.

The two projects are led by Professor Jennifer Kirkham, who believes they could make a big difference to dental care.

Professor Kirkham says the mouthwash which uses “photodynamic therapy” could help people who find it hard to use a toothbrush and could also be used to treat gum disease which is a major cause of tooth loss.

Antibacterial molecules in the mouthwash are absorbed only by plaque-causing bacteria, and activated when a bright light is shone into the mouth, killing them.

The technique is similar to that used in certain types of skin cancer, where the substance is painted on the target area, taken up by cancer cells, then exposed to light of a certain wavelength, which activates it to kill the cancer cell.

The researchers say though the molecule is considered to be safe for human consumption, full trials have yet to be completed.

Professor Kirkham says the team are looking for safe new ways to control plaque which do not rely on toothpaste as many who are disabled in some way or another are not able to brush effectively.

Researcher Dr Simon Wood says machines offering photodynamic therapy in dental clinics are already in use, but the aim was to find a way the mouthwash could be used at home.

The “repair solution” which is made from a protein which encourages the laying down of new enamel over microscopic holes in teeth, including those caused by acid produced by plaque bacteria.

The solution is painted on the teeth, it enters the holes and creates a scaffold, it then attracts the calcium needed to patch them.

Professor Kirkham says it could help people with early damage which could eventually lead to dental decay, or those who have tiny holes in their teeth which make consuming hot or cold food or drink painful.

The repair solution will not totally eliminate the need for the dentist’s drill as bigger cavities filled with decay would still have to be treated in the conventional manner.

It is hoped that trials will begin next year and a licence for wider use gained within five years.

November 27th, 2009

Source

Nanoparticle Self-Lighting Photodynamic Therapy For Cancer Treatment

Nanoparticle Self-Lighting Photodynamic Therapy For Cancer Treatment

Wei Chen^*

Department of Physics, University of Texas at Arlington, Arlington, TX 76019-0059

Photodynamic therapy (PDT) has been designated as a “promising new modality in the treatment of cancer” since the early 1980s. Light must be delivered in order to activate photodynamic therapy. Most photosensitizers have strong absorption in the ultraviolet (UV) – blue range, therefore, UV -blue light is needed for their activation. Unfortunately, UV-blue light has minimal penetration into tissue and its application for in vivo activation is a problem. To solve the problem and to enhance the PDT treatment for deep cancers, we introduce a new PDT system in which the light is generated by afterglow nanoparticles with attached photosensitizers. When the nanoparticle-photosensitizer conjugates are targeted to tumor, the light from afterglow nanoparticles will activate the photosensitizers for photodynamic therapy. Therefore, no external light is required for treatment. More importantly, it can be used to treat deep tumor such as breast cancer because the light source is attached to the photosensitizers and are delivered to the tumor cells all together. This new modality is refereed as Nanoparticle Self-Lighting Photodynamic Therapy (NSLPDT).

Key Words: Photodynamic Therapy, Cancer, Nanoparticles, Quantum Dots, Luminescence, Afterglow, Penetration, Radiation Therapy.

Corresponding Author: weichen@uta.edu

Source

Other articles on Wei Chen

Novel Light-Sensitive Compounds Show Promise for Cancer Therapy

July 22, 2009

by Lynn Shapiro, Writer

Chemists at the University of California, Santa Cruz, have developed novel compounds that show promise for photodynamic cancer therapy, which uses light-activated drugs to kill tumor cells.

The new compounds, called dye-sensitized ruthenium nitrosyls, are absorbed by cancer cells and respond to specific wavelengths of light by releasing nitric oxide, which triggers cell death.

"For cancer treatment, you want localized delivery of a very high concentration of nitric oxide. We've designed these molecules to do just that," said Pradip Mascharak, professor of chemistry and biochemistry at UCSC.

Nitric oxide is a simple molecule with a wide range of biological effects. Long known for its role in regulating blood pressure, it has attracted the attention of cancer researchers in recent years. According to Mascharak, one advantage of nitric oxide for cancer treatment is that it induces an orderly type of cell death known as apoptosis. Also known as "programmed cell death," apoptosis does not lead to the inflammation, pain, and swelling normally associated with damage to cells and tissues in the body.

The drugs currently used in photodynamic therapy, called photosensitizers, produce a highly reactive form of oxygen when activated by light. The reactive oxygen kills cells in a way that tends to cause local swelling and inflammation.

Mascharak and graduate student Michael Rose have synthesized several different ruthenium nitrosyls in their lab. They described these compounds in detail in a recent paper published in Inorganic Chemistry (published online May 29, 2009). In another paper published last year in the Journal of the American Chemical Society, the researchers reported that the compounds were effective against breast cancer cells in laboratory experiments.

"We know it works in cancer cells, so now we're very confident about taking it to the next level," Mascharak said. "The idea for cancer therapy would be to embed the compounds in a matrix that you can place in the treatment site, then shine light on it to produce a high concentration of nitric oxide."

In designing the ruthenium nitrosyls, Rose and Mascharak were inspired by natural bacterial enzymes called nitrile hydratases, which release nitric oxide as a by-product when activated by light.

"We borrowed the idea from nature," Mascharak said. "Our initial goal was to understand these very unusual enzymes. Every hint that nature embedded in the behavior and structure of the enzyme we employed in designing a drug that can deliver nitric oxide in a very site-specific and controlled way."

Rose, who earned his Ph.D. this year, has been working on the project since 2004. He began by replacing the iron atom in a synthetic model of the enzyme with a different metal, ruthenium.

"Iron complexes are good in nature because they are highly reactive, but if you're trying to make a drug you want something that's more stable," Rose said. "The ruthenium complexes are much more stable when dissolved in water."

The first ruthenium nitrosyls he made released nitric oxide only under ultraviolet light, so Rose spent several years developing ways to sensitize them to specific wavelengths of visible light that could be used in photodynamic therapy. He did this by attaching dye molecules, called chromophores, to the ruthenium complex.

To test the resulting compounds as potential drugs, the chemists teamed up with breast cancer researcher Lindsay Hinck, a professor of molecular, cell, and developmental biology at UCSC. Hinck and postdoctoral researcher Rebecca Marlow worked with Rose to test the dye-sensitized ruthenium nitrosyls against breast cancer cells growing in tissue culture.

The unactivated compounds are fluorescent, which allowed the researchers to track them using a fluorescence microscope as the compounds were absorbed by the cancer cells. The release of nitric oxide after exposure to light quenched the fluorescence, and the cells showed signs of apoptosis within four to eight
hours.

Source: University of California, Santa Cruz

Source

Can a blast of light really kill breast cancer?

By David Derbyshire
Last updated at 1:46 AM on 30th June 2009

A revolutionary treatment for breast cancer which destroys tumours with a blast of laser light was unveiled by doctors today.

The technique involves no surgery, can be carried out in only a few minutes and does not harm healthy cells.

A team of British surgeons plans to start clinical trials of 'photodynamic therapy' on 20 patients this year.

A woman receiving photodynamic therapy, which can be used to treat various cancers, including skin and breast

It is the first time worldwide that doctors will test the technique on primary breast cancer. Previously, it has been used on cancers of the skin and mouth.

The procedure is being pioneered by Mo Keshtgar, a world-renowned breast cancer surgeon, at the Royal Free Hospital in North London.

During photodynamic therapy, or PDT, a drug is injected into the patient's bloodstream which makes the cancer cells extremely sensitive to light.

Photodynamic therapy uses tumour-killing drugs that are activated by light

When a low-level laser beam is shone at the cancer through the skin, the cells self-destruct. Researchers, who announced their plans to start trials at the Royal Society's Summer Science Exhibition, said it could even offer an alternative to radiotherapy for some women.

'The key appeal is that it attacks and destroys cancer cells while retaining the viability of the surrounding normal cells,' said Mr Keshtgar.

A patient undergoing a mammogram to see if she has breast cancer

'Breast cancer can be particularly traumatic, with more invasive treatments leaving physical and emotional scars.

'Our treatment will keep the structure of the connective tissue intact, meaning the breast does not become deformed or lose shape.'

The drug - called a photosensitising agent - is injected directly into patients and finds its way into the breast's epithelial cells, lining cells which can become cancerous. The drug makes these cells highly sensitive to light.

Because tumours have high metabolic activity and are surrounded by a proliferation of new blood vessels, the drug accumulates in cancer cells in preference to healthy cells.

Once the drug has been taken up by the cancer cells, surgeons point a low-powered red laser at the tumour.

The light triggers a chemical reaction which kills the harmful cells. The drug loses its potency after a few hours.

However, patients are kept in a subdued
light for 24 hours after their treatment and then told to avoid bright sunlight for another 24 hours.

Mr Keshtgar said the technique could be available within six years, once it has been properly tested on volunteers.

The initial small-scale trial will be on breast cancer patients due to have mastectomies. They will have PDT just before their surgery, after which the tissue will be examined to determine the effects.

If the trials are promising, the team will recruit women to take part in a larger trial. They will be monitored for five years after their treatment.

Traditional treatment: Chemotherapy

Mr Keshtgar said the technique could help patients anxious about surgery or who are not well enough for invasive operations.

Dr Alexis Willett, head of policy at Breakthrough Breast Cancer, said: 'We welcome research into new therapies that may reduce the need for invasive treatment.

'It will be interesting to see how trials progress.'

PDT trials are already underway for cancers of the prostate, bile duct and pancreas.

Around 46,000 women are diagnosed with breast cancer each year in the UK. It is the most commonly diagnosed cancer and accounts for nearly a third of cancers in women.

One in nine women will develop the disease at some point in their lives, while more than 1,000 die of it each month.

Source

Novel light-sensitive compounds show promise for cancer therapy

June 16, 2009

Contact: Tim Stephens (831) 459-2495; stephens@ucsc.edu

Fluorescence microscopy shows breast cancer cells treated with a dye-sensitized ruthenium nitrosyl before (top) and after (bottom) exposure to light, which triggers the release of nitric oxide, leading to cell death. (Image from Rose et al., 2008, JACS.)

Chemists at the University of California, Santa Cruz, have developed novel compounds that show promise for photodynamic cancer therapy, which uses light-activated drugs to kill tumor cells.

The new compounds, called dye-sensitized ruthenium nitrosyls, are absorbed by cancer cells and respond to specific wavelengths of light by releasing nitric oxide, which triggers cell death.

"For cancer treatment, you want localized delivery of a very high concentration of nitric oxide. We've designed these molecules to do just that," said Pradip Mascharak, professor of chemistry and biochemistry at UCSC.

Nitric oxide is a simple molecule with a wide range of biological effects. Long known for its role in regulating blood pressure, it has attracted the attention of cancer researchers in recent years. According to Mascharak, one advantage of nitric oxide for cancer treatment is that it induces an orderly type of cell death known as apoptosis. Also known as "programmed cell death," apoptosis does not lead to the inflammation, pain, and swelling normally associated with damage to cells and tissues in the body.

The drugs currently used in photodynamic therapy, called photosensitizers, produce a highly reactive form of oxygen when activated by light. The reactive oxygen kills cells in a way that tends to cause local swelling and inflammation.

Mascharak and graduate student Michael Rose have synthesized several different ruthenium nitrosyls in their lab. They described these compounds in detail in a recent paper published in Inorganic Chemistry (published online May 29, 2009). In another paper published last year in the Journal of the American Chemical Society, the researchers reported that the compounds were effective against breast cancer cells in laboratory experiments.

"We know it works in cancer cells, so now we're very confident about taking it to the next level," Mascharak said. "The idea for cancer therapy would be to embed the compounds in a matrix that you can place in the treatment site, then shine light on it to produce a high concentration of nitric oxide."

In designing the ruthenium nitrosyls, Rose and Mascharak were inspired by natural bacterial enzymes called nitrile hydratases, which release nitric oxide as a by-product when activated by light.

"We borrowed the idea from nature," Mascharak said. "Our initial goal was to understand these very unusual enzymes. Every hint that nature embedded in the behavior and structure of the enzyme we employed in designing a drug that can deliver nitric oxide in a very site-specific and controlled way."

Rose, who earned his Ph.D. this year, has been working on the project since 2004. He began by replacing the iron atom in a synthetic model of the enzyme with a different metal, ruthenium.

"Iron complexes are good in nature because they are highly reactive, but if you're trying to make a drug you want something that's more stable," Rose said. "The ruthenium complexes are much more stable when dissolved in water."

The first ruthenium nitrosyls he made released nitric oxide only under ultraviolet light, so Rose spent several years developing ways to sensitize them to specific wavelengths of visible light that could be used in photodynamic therapy. He did this by attaching dye molecules, called chromophores, to the ruthenium complex.

To test the resulting compounds as potential drugs, the chemists teamed up with breast cancer researcher Lindsay Hinck, a professor of molecular, cell, and developmental biology at UCSC. Hinck and postdoctoral researcher Rebecca Marlow worked with Rose to test the dye-sensitized ruthenium nitrosyls against breast cancer cells growing in tissue culture.

The unactivated compounds are fluorescent, which allowed the researchers to track them using a fluorescence microscope as the compounds were absorbed by the cancer cells. The release of nitric oxide after exposure to light quenched the fluorescence, and the cells showed signs of apoptosis within four to eight hours.

"That was probably the most exciting day of my grad school career, when I looked through the microscope and saw the fluorescent compounds in the cells," Rose said.

Rose used a commercially available dye initially, then synthesized new dyes so that he could customize their properties. "In the end, the whole molecule was built from scratch in our lab," he said. "That's the fun of synthetic chemistry: It's like building with Legos, but you get to make your own Legos, so it's even better."

Mascharak said he now plans to collaborate with medical researchers at UCLA to conduct additional tests of the compounds in a tumor model. Meanwhile, he and Rose have continued to investigate the unusual chemistry of nitrile hydratases. They have just published their findings in the Journal of the American Chemical Society (published online May 27, 2009).

"We have now clearly shown the mechanism for how the enzyme nitrile hydratase is photoregulated by nitric oxide. This process gave us the idea of making light-sensitive metal nitrosyls as antitumor drugs," Mascharak said.

This research was funded by the National Science Foundation.

Source

Cancer campaign man's £50m target

David Longman wants to raise £50m to fund research into the treatment

A Cambridgeshire man is hoping to raise £50m to develop a cancer treatment which saved his daughter's life.

David Longman, from Hemingford Abbots, wants to help fund research trials for Photodynamic Therapy (PDT).

He came across PDT five years ago when his eldest daughter had a tumour which was destroyed by the treatment.

PDT uses laser, or other light sources, combined with a light-sensitive drug (sometimes called a photosensitising agent) to destroy cancer cells.

Simple treatment

Mr Longman, who is starting the campaign Killing Cancer in the autumn, said: "PDT is a very quick and simple treatment without the side-effects patients experience with chemotherapy and radiotherapy.

"For patients who might otherwise have devastating surgery, PDT represents a very positive set of benefits to the patients.

"But for years funding for its development has been ignored by the major charitable funders."

PDT is currently approved for use to treat head and neck cancer, skin cancer, cancer in the lungs and the oesophagus.

Mr Longman wants PDT to be tested on brain tumours, throat cancer, lung cancer, bladder and colon cancer, Crohn's disease and liver tumours, cervical and vulval cancer, penile and prostate cancer.

'Changing cancer world'

He also wants PDT to be used to treat MRSA and as an alternative to a hysterectomy.

Mr Longman gave up his career in a bid to achieve "international recognition" for the treatment.

He said: "When we launch the campaign... I know we are going to completely change the cancer world.

"We are going to put the power of choice into the hands of the public, and we will raise the funds we need to develop the trials."

He added that hospitals in the UK and the USA were lined up to start the research, starting with PDT for breast cancer in London and Boston, US.

Source

NovoCure

(WO/2009/044289) TREATING CANCER USING ELECTROMAGNETIC FIELDS IN COMBINATION WITH PHOTODYNAMIC THERAPY

• Biblio. Data
• Description
• Claims
• National Phase
• Notices
• Documents

Latest bibliographic data on file with the International Bureau Permanent Link Bookmark this page
Pub. No.: WO/2009/044289 International Application No.: PCT/IB2008/003361 Publication Date: 09.04.2009 International Filing Date: 05.03.2008
IPC:	A61N 5/06 (2006.01), A61N 1/40 (2006.01)
Applicants:	NOVOCURE LTD. [IL/IL]; Po Box 15022, Matam Center, 319805 Haifa (IL) (All Except US). PALTI, YORAM [IL/IL]; (IL) (US Only).
Inventor:	PALTI, YORAM; (IL).
Priority Data:	60/893,173 06.03.2007 US

Title:

TREATING CANCER USING ELECTROMAGNETIC FIELDS IN COMBINATION WITH PHOTODYNAMIC THERAPY

Abstract:

A light generating circuit is implanted in a subject's body and aimed at a target region such as a tumor. A photosensitizer is introduced into the target region, and an AC electric field is induced in the region. The field causes the light generating circuit to generate light, which activates the photosensitizer; and at certain field strengths and frequencies, the field itself has a beneficial effect. The beneficial effects of the field and the activated photosensitizer are thereby obtained simultaneously.

I CLAIM:

1. A method of simultaneously exposing a target region within a subject's body to light and an electric field, the method comprising the steps of: embedding, within the subject, a light-emitting circuit having a first terminal and a second terminal, wherein the light-emitting circuit is positioned so as to illuminate the target region, and wherein the first terminal and the second terminal are spaced apart by a distance D; administering, to the subject, a photosensitizer that accumulates in tissue at the target region, wherein the photosensitizer is activated by a wavelength of light that is emitted by the light-emitting circuit; and imposing, into the target region, an AC electric field having an amplitude and orientation that causes an AC voltage gradient large enough to drive the light-emitting circuit to appear between the first terminal and the second terminal.

2. The method of claim 1, wherein the imposing step comprises the step of capacitively coupling the AC electric field into the target region.

3. The method of claim 1, wherein the light-emitting circuit comprises a light- emitting diode.

Source


Disruption of Cancer Cell Replication by Alternating Electric Fields
[CANCER RESEARCH 64, 3288–3295, May 1, 2004]
Eilon D. Kirson,1 Zoya Gurvich,2 Rosa Schneiderman,2 Erez Dekel,3 Aviran Itzhaki,4 Yoram Wasserman,1,4
Rachel Schatzberger,2 and Yoram Palti2
1Department of Biomedical Engineering, NovoCure Ltd., Haifa, Israel; 2B. Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa, Israel; 3Department
of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel; and 4Elisha Medical Centre, Haifa, Israel

ABSTRACT
Low-intensity, intermediate-frequency (100–300 kHz), alternating electric
fields, delivered by means of insulated electrodes, were found to have
a profound inhibitory effect on the growth rate of a variety of human and
rodent tumor cell lines (Patricia C, U-118, U-87, H-1299, MDA231, PC3,
B16F1, F-98, C-6, RG2, and CT-26) and malignant tumors in animals.
This effect, shown to be nonthermal, selectively affects dividing cells while
quiescent cells are left intact. These fields act in two modes: arrest of cell
proliferation and destruction of cells while undergoing division. Both
effects are demonstrated when such fields are applied for 24 h to cells
undergoing mitosis that is oriented roughly along the field direction. The
first mode of action is manifested by interference with the proper formation
of the mitotic spindle, whereas the second results in rapid disintegration
of the dividing cells. Both effects, which are frequency dependent, are
consistent with the computed directional forces exerted by these specific
fields on charges and dipoles within the dividing cells. In vivo treatment of
tumors in C57BL/6 and BALB/c mice (B16F1 and CT-26 syngeneic tumor
models, respectively), resulted in significant slowing of tumor growth and
extensive destruction of tumor cells within 3–6 days. These findings
demonstrate the potential applicability of the described electric fields as a
novel therapeutic modality for malignant tumors.

Source

Watching cells die

Published: 26 March 2009 10:15 AM

Source: The Engineer Online

The viscosity of different parts of cancer cells increases dramatically when they are blasted with light-activated cancer drugs, according to new images that provide fundamental insights into how cancer cells die.

The images, taken by researchers from Imperial College London, reveal the physical changes that occur inside cancer cells while they are dying as a result of Photodynamic Therapy (PDT). This cancer treatment uses light to activate a drug that creates a short-lived toxic type of oxygen, called singlet oxygen, which kills cancerous cells.

The research team behind the study says that revealing what happens to viscosity within a dying cancer cell is important because it helps give a better understanding of how cells function and which factors are important for controlling reactions inside cells. Ultimately, this could help scientists design more efficient drugs for Photodynamic Therapy and other treatments.

The research is also of wider significance because these are the first ever real-time maps showing viscosity changing over a period of time inside a cell during a biologically important process such as cell death.

Previous studies have shown that the viscosity of human cells and organs also changes in patients with diseases such as diabetes and atherosclerosis, said Dr Marina Kuimova from Imperial College London's Department of Chemistry, who carried out the research.

'We're still not quite sure exactly what the relationship is between increased stickiness inside cells and disease, but we expect that the two are related,' added Kuimova.

'Knowing more about these changes, and being able to map them when they occur in all kinds of different scenarios, from dying cancer cells, to diseased blood cells, could help us to better understand how some diseases and their treatments affect cell and organ function.'

Dr Kuimova and her colleagues were able to track viscosity as it changed inside live cancer cells thanks to a newly developed Photodynamic Therapy drug, with unusual fluorescent properties. The drug, which is made of a molecule with a spinning component like a rotor, emits different wavelengths of light depending on the viscosity of its surroundings.

The changing wavelengths of light emitted during experiments, and captured over a period of 10 minutes, showed that once the PDT drug was activated, the level of viscosity inside the cell increased dramatically. The researchers suggest that this increasing viscosity is caused by the toxic oxygen molecules released into the cell.

They think that increased levels of viscosity might even contribute directly to the cancer cell's further deterioration by slowing down vital communication and transport processes inside the cell.

Dr Stanley Botchway from the Science and Technology Facilities Council, which worked in collaboration with Imperial College London on the research, said: 'The huge viscosity we measured was surprising and it certainly gives a new insight into the change in cellular environment during cell death.'

However, the researchers noted that as viscosity in the cancerous cell increases, the toxic oxygen molecule's mission to kill the cell is slowed down too.

Dr Kuimova explained: 'It looks like while the increasing viscosity contributes to the cell's demise, these new "sticky" cell conditions can slow the drug down, so it’s not as straightforward a relationship as it might first appear.

'More work is needed to better understand the complex interplay between viscosity and cell death. We hope to use our imaging technique to track changes in viscosity in other kinds of cells as they occur in real time, to unlock some of the secrets of what goes on inside cells when they're functioning, malfunctioning or dying.'

The research was led by Imperial College London in collaboration with the Science and Technology Facilities Council's Rutherford Appleton Laboratory (RAL), Oxford University, King's College London, and the University of Aarhus in Denmark.

The work was funded by the Engineering and Physical Sciences Research Council, with support from the Science and Technology Facilities Council, and the Danish Foundation for Basic Research.

Source

Photodynamic therapy with meta-tetrahydroxyphenylchlorin

Photodynamic therapy with meta-tetrahydroxyphenylchlorin (Foscan®) in the management of squamous cell carcinoma of the head and neck: experience with 35 patients

Kai Johannes Lorenz¹ and Heinz Maier¹

(1)	Department of Otolaryngology/Head and Neck Surgery, German Armed Forces Hospital of Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany

Received: 27 October 2008 Accepted: 26 February 2009 Published online: 17 March 2009

Abstract Photodynamic therapy (PDT) is a relatively new method of treating superficial tumours of the skin and mucosa. After the injection of a photosensitising agent, the tumour area is exposed to non-thermal laser light. This causes a phototoxic reaction, producing oxygen radicals that destroy tumour cells. From November 2003 to July 2007, a total of 35 patients with recurrent squamous cell carcinoma or secondary tumours of the head and neck region were treated with PDT at the German Armed Forces Hospital in Ulm. These patients had failed or found unsuitable for other treatments. Meta-tetrahydroxyphenylchlorin (mTHPC), known under the trade name of Foscan^®, was used as the photosensitising agent. Local control was achieved in 21 patients (60%) and partial remission in 10 patients (28.5%). Four patients (11.5%) did not respond to PDT treatment. The mean duration of overall survival was 401.45 (±321.2) days, median was 356 after the completion of treatment. The mean duration of recurrence-free survival was 327.7 (±131.1) days, median was 181 for patients with complete remission. None of the patient developed serious complications. Photodynamic therapy is an important treatment option for patients who present with recurrent carcinoma or secondary tumours of the upper aerodigestive tract and who have failed or unsuitable for other treatments. Due to the excellent treatment results that have been achieved so far, PDT may in the future also play a role in the primary treatment of superficial tumours of the oral cavity, pharynx and larynx.

Keywords Photodynamic therapy - Foscan - mTHPC - Head and neck tumours - Squamous cell carcinoma

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Kai Johannes Lorenz Email: kai.lorenz@extern.uni-ulm.de

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Cancer drug delivery research at Case Western Reserve University cuts time from days to hours

7/22/2008 4:46:05 PM

Researchers at Case Western Reserve University have developed a technique that has the potential to deliver cancer-fighting drugs to diseased areas within hours, as opposed to the two days it currently takes for existing delivery systems.

Using laboratory mice, drug delivery time from injection to the cancer cells was reduced from two days to mere hours. Using this as a model for potential human use, cancer patients may someday soon receive the benefits of cancer-fighting drugs within hours of injection.

Findings are discussed in a paper, co-authored by Clemens Burda, associate professor of chemistry and director of the Center for Chemical Dynamics and Nanomaterials Research at Case Western Reserve University and graduate student Yu Cheng, appearing in the current edition of the Journal of the American Chemical Society.

The system uses gold nanoparticle vectors to deliver photodynamic therapy (PDT) drugs through the bloodstream to cancerous sites.

"Gold nanoparticles are usually not used for the PDT drug vector," said Cheng. "However, gold is chemically inert and nontoxic."

Photodynamic therapy utilizes light-sensitive drugs that, when exposed to light of a certain wavelength, will energize and burn away cancer cells.

Because exposure to light activates these drugs, PDT patients must keep out of bright lights for days while the drugs make their way through the bloodstream to the cancer site. At that time, they are activated by a light focused on the specific area of the body.

"By shortening the waiting time from drug injection to activation, PDT patients are much less inconvenienced and tend to have a more normal lifestyle," said Burda.

Looks like a "Hairy Ball"

The drug delivery system uses a gold nanoparticle (Au NP) as its hub. Gold is non-toxic to the human body, and has a versatile surface chemistry, large surface-to-volume ratio and variable size and shape.

Each Au NP is coated with polyethylene glycol (PEG) ligands, giving it the appearance of a hairy ball, said Burda. These PEG molecules offer several advantages over other materials: they are soluble in fats and water, don't interact with proteins in the bloodstream and help protect the drug, keeping it safe and stable until delivery to the cancer site.

Between each PEG ligand, molecules of a photodynamic chemotherapy drug (Pc 4) are attached to the Au NP. The Pc 4 drug (a phthalocyanine compound) was developed at Case Western Reserve by Malcolm Kenney, professor of chemistry.

When the nanoparticle reaches the cancerous tissue the drug molecules are released and uploaded to the diseased area. Focused red light is used to energize the drug in the patient once it has been delivered to the tumor.

Burda says that a potential future research project would look at providing a time-release administration of the drug rather than a more all-at-once release. In the long term, Burda hopes to make the Au NP delivery system applicable to a broad range of diseases.

The Au NP has a diameter of 5 nm. The addition of PEG ligands expands the total diameter to 32 nm, larger than some other nanoparticles currently in use, but still small enough to pass unencumbered through the bloodstream.

A single 1/4-mL injection holds approximately 100 million Au NPs, each carrying approximately 100 drug molecules.

Tail to Tumor in Two Minutes

In the laboratory of Baowei Fei, assistant professor of radiology and biomedical engineering at Case Western Reserve, these Au NPs have been used to treat mice with cancerous tumors. Once the Au NPs have been injected into the tail, the Pc 4 is uploading into the diseased area within minutes. The accelerated speed of drug administration in mice is due in part to the much more efficient dispersion of the NP delivered drug.

When tested on human cells called HeLa – a line of laboratory-grown human cells used in testing – most of the drug is uploaded within one hour.

Testing on human beings may not begin for some time. Commercialization will take even longer due to Food and Drug Administration (FDA) testing and approval. However, all of the components – Au Nps, PEG ligands and Pc 4 – have already received FDA approval.

What's Next

Burda says that as Au NP testing continues, short-term goals include minimizing the amount of material and drug load needed for effective interaction with cancer cells; optimizing potential targeting systems on the PEG ligands for faster, even more specific placement in diseased areas; and increasing the overall effectiveness of nanoparticle enhanced therapy.

"The system is very modular," says Burda. "We can change the size and shape of the Au core NPs and we can change the functionality of the PEG ligands. This should lead to optimization of the drug targeting and therapy. If our research is successful, other researchers might adapt this drug delivery system to other diseases and applications."

Funding support came from the National Science Foundation, National Institute of Health/National Cancer Institute and the Biomedical Research Technology Transfer Center under the leadership of Pamela Davis, dean of the Case Western Reserve School of Medicine and vice president for medical affairs.

Case Western Reserve University is among the nation's leading research institutions. Founded in 1826 and shaped by the unique merger of the Case Institute of Technology and Western Reserve University, Case is distinguished by its strengths in education, research, service, and experiential learning. Located in Cleveland, Case offers nationally recognized programs in the Arts and Sciences, Dental Medicine, Engineering, Law, Management, Medicine, Nursing, and Social Work. http://www.case.edu.

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Nanoparticle self-lighting photodynamic therapy for deep cancer treatment

Posted: February 11, 2008

Nanoparticle self-lighting photodynamic therapy for deep cancer treatment

(Nanowerk Spotlight) Photodynamic therapy (PDT) is a cancer treatment that combines a chemical compound, called a photosensitizer, with a particular type of light to kill cancer cells. The treatment works like this: the photosensitizing agent is injected into the bloodstream. The agent is absorbed by cells all over the body, but stays in cancer cells longer than it does in normal cells. One to three days after injection, when most of the agent has left normal cells but remains in cancer cells, the tumor is exposed to light. The photosensitizer in the tumor absorbs the light and produces an active form of oxygen (singlet oxygen) that destroys nearby cancer cells. PDT has been used for the past 30 years and is a treatment that works. PDT takes very little time, is often done as an outpatient, can be accurately targeted to the affected area, can be repeated, and has no long-term side effects. It also isn't as expensive or invasive as some other cancer treatment options. The limitation of this form of cancer treatment is that the light needed to activate most photosensitizers cannot pass through more than one centimeter of tissue. For this reason, PDT is usually used to treat tumors on or just under the skin or on the lining of internal organs or cavities. PDT is also less effective in treating large or deep tumors, because the light cannot pass far into these tumors. Researchers have now proposed a new PDT system in which the light is generated by x-ray scintillation nanoparticles with attached photosensitizers. When the nanoparticle-photosensitizer conjugates are targeted to tumors and stimulated by x-rays during radiotherapy, the particles generate visible light that can activate the photosensitizers for photodynamic therapy. Therefore, the radiation and photodynamic therapies are combined and occur simultaneously, and the tumor destruction can be more efficient. More importantly, it can be used for deep tumor treatment as x-rays can penetrate through tissue.

"I have been working on nanotechnologies for 15 years" Dr. Wei Chen tells Nanowerk. "My original work was trying to use quantum dots for in vivo imaging. I was facing the challenge of light penetration. I also have experience with the design and synthesis scintillation nanoparticles. I knew light delivery was also a challenging issue for PDT, just like in vivo optical imaging. Then, I came up with the idea to combine photodynamic therapy with radiation therapy through scintillation nanoparticles for deep cancer treatment."

Chen, an assistant professor of Nano-Bio Physics at the University of Texas at Arlington, points out that photodynamic therapy is not new, and radiation therapy is not new; but the combination of both through scintillation nanoparticles is new and potentially important for deep cancer treatment. He introduced the concept in a paper in the Journal of Nanoscience and Nanotechnology in April 2006 ("Using Nanoparticles to Enable Simultaneous Radiation and Photodynamic Therapies for Cancer Treatment").

A schematic illustration of nanoparticle–porphyrin conjugates for X-ray stimulated photodynamic therapy for cancer treatment. Annexin V is a molecule that can target some specific antigens at tumor cells. (Image: Dr. Chen, University of Texas at Arlington)

Although PDT has been widely used for skin cancer treatment, its application for deep cancer treatment is still a challenging issue because the light for PDT activation cannot penetrate deep into the tissue. To solve this problem, Chen and his collaborators propose a new PDT system in which the light is generated by scintillation luminescence nanoparticles (such as X-ray luminescence nanoparticles) with the attached photosensitizers.

Chen explains that, when the nanoparticle-photosensitizer conjugates are targeted to a tumor and stimulated by X-ray or other radiation sources during radiation therapy, the particles will generate light (energy) to activate the photosensitizers. With this novel therapeutic approach, no external light is necessary to activate the photosensitizing agent within tumors. Tissue thickness therefore would no longer be a limiting issue for PDT.

"Effectively, the radiation and photodynamic therapies are combined and occur simultaneously, and the tumor destruction will be more effective" he says. "More importantly, it can be used for deep tumor treatment as X-ray can penetrate deep into the tissue. No external light is necessary to deliver to the tumor and only an extremely low dose of radiation is needed for the treatment. Therefore, this provides a simple but more efficient modality for cancer treatment. We called this new modality Nanoparticle Self-Lighting Photodynamic Therapy."

Working with Chen's group are Dr. Shaopeng Wang and Dr. Yuanfang Liu, senior research scientists at ICx/Nomadics Inc.; Dr. Alan G. Joly, an optical physicist and a senior scientist at Pacific Northwest National Laboratory; and Dr. Carey Pope, Regents Professor And Head Sitlington Chair In Toxicology at the Center for Veterinary Health Sciences, Oklahoma State University.

The researchers reported their findings in a recent paper published in the January 29, 2008 online edition of Applied Physics Letters ("Investigation of water-soluble x-ray luminescence nanoparticles for photodynamic activation").

Their pilot studies indicate that water-soluble scintillation nanoparticles (the particle size in the study was about 15 nm) can potentially be used to activate photodynamic therapy as a promising deep cancer treatment modality.

For practical applications, the nanoparticle-porphyrin conjugates must be delivered to the tumor cells in vehicles such as antibodies, peptides, liposomes or other functional molecules. In designing the delivery vehicles one needs to consider how they will affect the quantum yield of singlet oxygen. Chen and his team used folic acid to target folate receptors at tumor cells. Their results indicate that folic acid has no effect on the quantum yield of singlet oxygen production in the nanoparticle conjugates, making this system practical for photodynamic activation applications.

Initial results of the studies have been promising. But before Nanoparticle Self-Lighting Photodynamic Therapy becomes a clinical reality, the researchers must overcome two main challenges: 1) they need to develop a class of water-soluble scintillation nanoparticles with very high quantum efficiencies of X-ray luminescence, and 2) they need to improve the targeting capabilities of the nanoparticle- photosensitizer compound – but this is a challenge for all drug-based cancer treatments.

By Michael Berger. Copyright 2008 Nanowerk LLC http://www.nanowerk.com/spotlight/spotid=4466.php