Man who co-discovered HIV accused of stealing rights to Aids cure

A Nobel prize-winning French researcher who co-discovered the virus that leads to Aids but sparked controversy after his colleague said he had claimed all the glory, has now been accused of stealing the rights to a revolutionary invention that may provide a cure to the disease, it emerged yesterday.

By Henry Samuel in Paris

Last Updated: 3:58PM GMT 09 Mar 2009

Prof Luc Montagnier is locked in a legal battle with inventor Bruno Robert over the intellectual property rights to a technique whereby the Aids virus and other serious ailments, including Parkinson's and Alzheimer's disease, can be pinpointed by their electromagnetic "signatures".

The hope is that once identified, the diseases can be blocked or neutralised with an opposite electromagnetic signal.

Mr Robert, 47, approached Mr Montagnier in May 2005 with his work on electromagnetic waves. In November of that year, Mr Bruno registered a patent for the process of homing in on a "biochemical element presenting a biological activity through the analysis of low-frequency electromagnetic signals." A month later, France's patents body, Inpi, was surprised to a request for the very same patent from Prof Montagnier.

Last Tuesday, Prof Montaignier took Mr Bruno to court, claiming the intellectual property rights over the discovery. The verdict is due on 20 May.

Mr Bruno's lawyer alleged in Le Journal du Dimanche that Prof Montagnier had already admitted that he had not come up with the discovery, as he had signed a contract to use Mr Bruno's technique in 2005 in exchange for 100,000 euros per year over a five-year period. Mr Bruno never received any payment. Prof Montagnier's lawyer said the pair had only signed a "protocol agreement" which was not legally binding.

Prof Montagnier was awarded a Nobel prize last year for discovering the virus that leads to Aids along with Françoise Barré-Sinoussi. A third researcher, Jean-Claude Chermann received no award despite being hailed by peers as a key driving force in the lab.

Prof Chermann accused his former colleague of squeezing him out by intense lobbying. "Frankly, Montagnier, everyone laughs about him," he told Le Monde. "He followed communication lessons, cut his moustache, put on a little waistcoat...He played the mandarin like hell. I, for one am not a (re)searcher, I'm a finder," he said.

Source

Ref:
Montagnier patent filing
Robert patent filing

Sonodynamic Therapy (SDT)

The photodynamic agent we use is also sensitive to ultrasound frequencies. This approach allows deeper penetration into the body. Sonodynamic therpay is carried out using a simple therapeutic ultrasound machine with especially designed treatment head known as maniple, which is applied over the affected area with some ultrasound gel placed on the skin. This is done after the light bed exposure.

We are combining Photodynamic therapy with Sonodynamic therapy. This uses low-level ultrasound, which kills cancer cells using a non-thermal effect, especially cavitation. The agent we use is sensitive to the ultrasound frequency we use, which is 1 Mhz. Following the light bed exposure (Photodynamic Therapy), the ultrasonic probe, covered with ultra sound gel, is moved over the skin on the area nearest to the main tumour mass. The use of ultrasound enables us to penetrate significantly deeper into the body than we would otherwise be able to do. (see a review of research into the uses of low level ultra sound in cancer therapy, Uyu, Wang & Mason in Ultra Sonics Sonochermistry, Vol 11, issue 2, April 2004, pages 95-130).

Most photosensitizers come from a class of naturally occuring compounds called porphorins. Natural porphorins are breakdown products from recycled haemoglobin and are inherently light sensitive. These accumulate in tumours and cause cancer cells to auto-fluoresce. The first generation of photosensitizer approved for use in cancer treatment - Photofrin, - is derived from haemoglobin, whilst some of the more advanced agents are chlorophyll derivatives.

PDT has several advantages over surgery and radiotherapy; it is comparatively non-invasive, it can be targeted accurately and repeated dosages can be given without the total dose limitations associated with radiotherapy, and the healing process results in little or no scarring. PDT can always be done on an out-patient or day case setting, and it has no side serious effects.

The next generation of Photodynamic Therapy is a significant advance on previous PDT. This uses a specific extract of Chlorophyll A (trade name Ausclorin) which does not have to be given intravenously and can be given orally. It accumulates selectively in tumour sites and it does not persist in the skin. Photofrin does persist, so long term photosensitivity can develop lasting as long as 90 days. With the new preparation, the agent is cleared from the skin within 24 to 48 hours, so no photosensitivity occurs. Ausclorin and previous photosensitizers can use the laser, or a specialised light consisting of light emitting diodes, emitting in the red light region and the infra-red region of the spectrum or with light beds using fluorescent tubes in the red light region for whole body treatment.. Because the breakdown wave lengths of Ausclorin also occur in the infra-red region, this means that with the infra-red lights, penetration can occur as deep as twelve inches into the body, so deep tumours can be treated from the surface. This therefore makes it a non-invasive whole body treatment. The treatment programme can be repeated as often as is necessary, and for advanced tumours it is best to treat slowly so as to avoid too rapid a tumour break down in too short a period of time.

METHOD OF TREATMENT USING SONODYNAMIC THERAPY (SDT) AND AUSCLORIN PHOTODYNAMIC THERAPY (PDT):

The patient is assessed clinically. Then a dose of Ausclorin is calculated based on the patient's weight and stage of the tumour. This is taken orally each morning before breakfast whilst the Ausclorin clears from the skin and accumulates selectively in tumour sites. Following this the patient is exposed to the appropriate lights. The time of exposure is important, and can vary from up to 60 minutes for patients with less advanced tumours, to only a few minutes with patients with more advanced tumours (the more advanced the tumour, the slower the treatment programme).

Further light bed exposure is then calculated on an on-going clinical basis. The patient is given enough Ausclorin for treatment at the clinic and three months treatment at home.

Anecdotally there has been success using PDT with breast cancer and prostate cancer. There have been encouraging results with several types of brain tumour including glioblastoma multiforme, and many brain tumours significantly regressed during photodynamic therapy. One case of glioblastoma multiforma showed a total dissappearance of tumour.

We often combine ozone autohaemotherapy with PDT. PDT relies on the production of singlet oxygen (O). This is derived from oxygen (O2). Tumours are characteristically hypoxic (showing low oxygen lavels). Ozone autohaemotherapy is an effective way of increasing oxygenation just before light bed exposure, therefore increasing the effectiveness of PDT.

SCIENTIFIC INFORMATION REGARDING NEXT GENERATION PHOTODYNAMIC THERAPY

The fluorescent camera can display tumours near the surface of the body. This is often as good as, if not better than the latest scans known as PET scans (position emission tomography).

BRIEF SUMMARY OF RESULTS FOR TEN RECENT CONSECUTIVE PATIENTS IN A COLLEAGUES CLINIC WHO HAS USED SDT OVER THE PAST 12 MONTHS:

1. Stage III breast cancer. Primary breast tumour plus metastases in the axillary lymph node, the other breast and the liver. After PDT and lumpectomy: no evidence of cancer in all four sites.

2. Stage IV breast cancer with rampant body metastases. Very low energy, not enough to work in the garden. In bed by 7:30pm. After PDT (ongoing) weight increased 3kg and now normal. Normal sleeping time and energy levels. Resumed gardening. Scan shows that the tumours have stopped spreading.

3. Metastatic melanoma grade IV. ABout 80 metastases visible. Oncologist predicted 2 more months of life. After PDT (ongoing), Alive and well 4 months after prediction. Metastases down to about 20. Energy, appetite and weight improved. Physician estimates that about 80% of the cancer is gone. Further treatment needed.

4. Prostate cancer (large tumolur mass), grade IV, urinary infections, bowel infections, Inability to urinate without catheter, impotent. After SDT/PDT (ongoing) Prostate shrinking and softening, urination better, impotence easing. Needs further treatment but improving.

5. Ovarian cancer Grade IV. Had hysterectomy and other surgery. No symptoms other than elevated cancer marker. After pDT cancer marker now normal. No evidence of cancer.

6. Squamous cell carcinoma grade 1. Lump on upperlip removed surgically. PDD showed 6 metastases on upper lip. After SDT all metastases have disappeared..

7. Prostate grade IV. Hard prostate with 2 nodules, metastasized outside the gland. After SDT (ongoing) Prostate shrunk, softened, one nodule disappeared. Better urination. Clear or almost clear of cancer.

8. Mesothelioma lung cancer. Symptoms include coughing at night, disturbed sleep. Painful breathing, not allowing deep inhalations. Photodynamic diagnosis showed over 12 metastases in the thorax. No noticable benefits from chemotherapy. After SDT (ongoing): Coughing at night has stopped, giving much better sleep. Breathing not as painful, allowing deeper inhilation. "I have an amazing increase in energy". Visible metastases have dropped from 12 or more to one.

9. Breast cancer grade IV. Lumpectomy. PDD showed metastases in the breast and the axillary lymph nodes. After SDT (ongoing) Cleared metastases from the breast. Those in the lymph glands remain. Next treatment will be PDT/SDT.

10. Breast cancer grade IV with extensive liver metastases. PDT failed to hault the progress of the illness. SDT was not available at the time and she has chosen other treatment.

Source

Ausclorin

Effect of Chlorin Structure on Theoretical Electronic Absorption Spectra and on the Energy Released by Porphyrin-Based Photosensitizers

Abstract

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Marcela Palma^†, Gloria I. Crdenas-Jirn*^† and M. Isabel Menndez Rodrguez*^‡

Laboratorio de Qumica Terica, Departamento de Ciencias del Ambiente, Facultad de Qumica y Biologa, Universidad de Santiago de Chile, USACH Casilla 40, Correo 33, Santiago, Chile, and Departamento de Qumica Fsica y Analtica, Facultad de Qumica. Universidad de Oviedo, C/Julin Clavera 8, 33006 Oviedo, Asturias, Spain

J. Phys. Chem. A, 2008, 112 (51), pp 13574–13583

DOI: 10.1021/jp804350n

Publication Date (Web): November 24, 2008

Copyright © 2008 American Chemical Society

†

Universidad de Santiago de Chile.

,

* Authors to whom correspondence should be addressed: e-mail gloria.cardenas@usach.cl (G.I.C.-J.) or isabel@uniovi.es (M.I.M.R.).

,

‡

Universidad de Oviedo.

Abstract

In this work eight porphyrins (p) and eight chlorins (c) are theoretically characterized [BLYP/6-31G(d)] in their singlet and triplet states. Nine of them (1_p, 1_c, 2_p, 3_p, 4_p, 5_p, 6_c, 7_c, and 8_c) have already been synthesized and are in trial use in photodynamic therapy (PDT). The seven remaining were built up as chlorins analogous to porphyrins 2_p−5_p and porphyrins analogous to chlorins 6_c−8_c. The aim is to investigate the effect of the chlorin structure on the Q-band of electronic spectra at BLYP/6-31G(d) (gas phase, methanol solution) and at BHANDHLYP/6-31+G(d) (methanol solution), and on the triplet → singlet energy emission, as these two factors determine the quality of a good photosensitizer. It is found that meso substituents lead to greater geometry distortions than β-substituents in both porphyrins and chlorins and in both singlet and triplet states. In methanol solution, chlorin-like structures with β substitution present significantly red-shifted Q-bands in comparison with their porphyrin analogues, so they would be better photosensitizers than porphyrins. Concerning to the triplet → singlet energy emission calculated in methanol solution, three porphyrins (4_p, 6_p, and 8_p) and all the studied substituted chlorins could be useful to generate active ¹O₂. 4_c would be the best photosensitizer, as it absorbs the largest wavelength in the therapeutic window (approximately 690 nm) and releases the amount of energy closest to the required one (1.22 eV).

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New Target Against Flu Virus May Extend Vaccine Potency

Antibody Uncovers Vulnerability of Protein Stem

HMS researchers have found an Achilles heel in the influenza virus that may someday make annual flu shots a thing of the past. By targeting a hidden pocket in the microbe with a newly discovered antibody, they disabled a wide range of viruses, including those that cause the avian flu and the virulent 1918 Spanish flu.

While this research could lead to clinical trials of a new antiviral as soon as 2012 and may eventually lead to a more durable influenza vaccine, its influence may extend even further. The work, described in the March Nature Structural and Molecular Biology, validates a novel approach to finding such viral vulnerabilities and reveals what may be a more general principle for defeating a variety of pathogens.

Photo by Graham Ramsay

Wayne Marasco and Jianhua Sui have discovered influenza’s Achilles heel and devised a method to attack it.

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Striking Gold
The story begins in the lab of Wayne Marasco, HMS associate professor of medicine at the Dana–Farber Cancer Institute. Twelve years ago, Marasco collected blood from 57 healthy Bostonians and used the samples to create a library of 27 billion different human antibodies.

Researchers “pan” the library by presenting it with an antigen, such as a whole virus or a protein on the viral surface. Panning unearths antibodies that bind to that antigen. Marasco used his library to isolate an antibody against SARS in 2004.
When the avian flu appeared, Marasco and first author Jianhua Sui put the library to work again. But instead of panning with the whole H5N1 influenza virus, they focused on a single protein. They isolated the H5 version of hemagglutinin, a surface protein on influenza that allows the virus to invade a cell and replicate. (The N portion is a different surface protein called neuraminidase, which allows the virus to exit the cell.) The effort uncovered 10 potential antibodies.

Sui and Marasco, in partnership with co-author Rubin Donis, chief of the molecular virology and vaccines branch of the Centers for Disease Control and Prevention, tested three of these antibodies in mice infected with a lethal dose of avian flu. The antibodies neutralized between 80 and 100 percent of the infections.

Unexpectedly, the antibodies also neutralized other strains. They knocked down H1N1 (the 1918 Spanish flu), H2N2, H6N1 and more. “It became apparent very quickly that the target they were recognizing was highly conserved,” said Marasco.

Not only were these antibodies more broadly effective than expected, they also worked differently. Most antibodies stick to the round top of the lollipop-shaped hemagglutinin protein and interfere with the protein’s ability to bind to the cell membrane. But Marasco and Sui’s antibodies were not blocking the membrane binding. “That told us right there that the antibody wasn’t working against the globular head,” said Marasco.

Stemming the flu. Each year, scientists develop new influenza vaccines to target the ever-mutating globular heads (light red) of the hemagglutinin proteins that coat the virus. A newly discovered antibody binds to the much less variable and much less accessible stem of the protein (red). Work is under way to turn this antibody into an antiviral that can be used to contain a pandemic and to protect immunosuppressed individuals during flu season. Since the machinery of the stem evolves more slowly than the head, the discovery may lead to a broadly effective influenza vaccine that lasts for longer than a single season.

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At this point, a third part of the team became critically important. Robert Liddington and his team at the Burnham Institute for Medical Research crystallized one of the antibodies bound together with hemagglutinin. “That’s when the revelations started coming,” said Marasco.

The crystal confirmed that the antibody was not bound to the enticing top of the protein, but rather to a pocket in the stem. That pocket contains complex machinery. It houses three entangled moving parts that allow the virus to infect the cell (see video). The crystal revealed that the antibody grabs onto all three and prevents that machinery from working. “In the past, people didn’t even know to look in that pocket,” said Sui.

Sui took this information and used it to search a database of more than 6,000 (and growing) known genetic variants of the flu. She found that only two versions of this complex stem-based machinery have evolved. An examination by Liddington’s team of crystal structures of known variants found the same. The antibodies Sui and Marasco found work against one version. They are now running the other version of the stem through the same panning process to find an antibody against it.

Enduring Weakness
The contrast between the slow evolution of the stem and the impossible-to-keep-up-with evolution of the head is stunning. But it is not surprising. The part of the headpiece that binds to the cell membrane is very small, said Sui. So the rest of the headpiece can change dramatically without compromising the function.

But in the stem, “the delicate and complex machinery is highly conserved,” said Donis. “The virus cannot mutate it because by doing so, it would commit suicide.” Indeed, Donis’s team attempted to force mutations in the stem, but none emerged.

In discovering this new, hidden vulnerability, the researchers have realized that the virus has been fooling them, and our bodies, all along. “The virus has very cleverly developed an area on the top of its coat protein that creates a molecular decoy,” said Marasco. He speculates that the immune system mounts a full-scale attack against the easy-to-spot decoy while it simultaneously suppresses any efforts to target the elusive stem. Similarly, new vaccines chase the decoy each season hoping to hit it just right.

DOUBLE CLICK PIC FOR VIDEO

Courtesy Dana–Farber Cancer Institute

HMS researchers are targeting a common weakness to tackle influenza.

Courtesy Dana–Farber Cancer Institute

HMS researchers are targeting a common weakness to tackle influenza.

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But now, with the new insights from this work, “a pan-therapy for all kinds of influenza may be within our grasp,” said Liddington. Further, Marasco suspects that the influenza virus’s means of protecting its most vulnerable machinery may be a more general strategy. He has observed almost the exact same system in corona viruses, such as SARS.

Assuming that approval for human testing proceeds without a hitch, the new influenza antibody will likely be used as an antiviral first. Since it is unlikely that a mutant will evolve to defeat it, the hope is that this antiviral can be stockpiled and stored for years. Marasco also speculates that it may be possible to develop a vaccine that both masks the decoy and allows the immune system to attack the less flexible stem.

In the future, Marasco plans to apply these same methods to other viruses. The team’s approach not only allows them to find novel antibodies and hidden targets, it also helps researchers respond nimbly as resistant strains evolve.

—Elizabeth Dougherty

Students may contact Wayne Marasco at wayne_marasco@dfci.harvard.edu for more information.

Conflict Disclosure: The authors report no conflicts of interest.

Funding Sources: National Institutes of Health

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Quest PharmaTech reports encouraging results from study of cancer therapy

Fri. March 06, 2009; Posted: 07:04 AM

Mar 06, 2009 (Datamonitor via COMTEX) -- QPTFF | Quote | Chart | News | PowerRating -- Quest PharmaTech, a drug development company, has announced promising results from a study designed to investigate the effectiveness of its proprietary SL052 for photodynamic therapy used in combination with immunotherapeutic agents in solid tumor animal models.

The study, conducted by Mladen Korbelik at the BC Cancer Agency in Vancouver, has demonstrated that SL052 increased the potency and effectiveness of immunotherapeutic agents when used in combination with SL052 photodynamic therapy (PDT).

According to the company, the results also confirmed that SL052 was an effective and well tolerated photosensitizer for PDT ablation of two highly tumorigenic, solid murine tumors. Further, the results demonstrated that photodynamic therapy generated direct local cytotoxicity and induced a systemic immune response, which could enhance its therapeutic effect on both primary tumors and metastases at distant sites.

The study tested several applications of SL052 and evaluated host recognition and immunological destruction of solid tumors. The results indicate the potential of SL052 PDT for use in combination with cancer vaccines to generate a superior immune response compared with vaccines alone.

The study also revealed that SL052 PDT may be effectively combined with either single or multiple-complementary effectors of the host's immune response to substantially boost the frequency of permanent cures, the company added.

Madi Madiyalakan, CEO of Quest, said: "These results further define the therapeutic profile of SL052. While its activation through either photodynamic or sonodynamic therapy was already established, we now have a clear indication of its potential to act as either an immune response stimulator or as a cancer vaccine. Taken together, these characteristics of SL052 provide a new potential treatment modality for cancer therapy."

For full details for QPTFF click here.

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(WO/2009/026724) SYSTEM AND APPARATUS FOR SONODYNAMIC THERAPY

Biblio. Data

• Description
• Claims
• National Phase
• Notices
• Documents

Pub. No.: WO/2009/026724 International Application No.: PCT/CA2008/001548 Publication Date: 05.03.2009 International Filing Date: 29.08.2008
IPC:	A61N 7/00 (2006.01)
Applicants:	ANGEL SCIENCE & TECHNOLOGY (CANADA), INC. [CA/CA]; 4936 Yonge Street, Suite 260, Toronto, ON M2N 6S3 (CA) (All Except US). CHEN, Rixin [CA/CA]; (CA) (US Only).
Inventor:	CHEN, Rixin; (CA).
Agent:	DEETH WILLIAMS WALL LLP; 400-150 York Street, Toronto, Ontario M5H 3S5 (CA).
Priority Data:	11/849,179 31.08.2007 US

Title:

SYSTEM AND APPARATUS FOR SONODYNAMIC THERAPY >>>>>>>>>>>>>>>>>>>>>>>>>>>>>Click pic to enlarge

Abstract:

The present invention relates to diffuse ultrasound along with chemical agents to treat tissue, called sonodynamic therapy (SDT), and a system for treatment using SDT that comprises a whole body ensonification apparatus and control system. The whole body ensonification may reduce the chances of missing desired tissue that may not be easily detectable or may be found throughout the body. The apparatus has a plurality of diffuse ultrasound transducers for ensonifying at least part of a chamber filled with fluid and designed to accommodate a body for treatment. The person may be treated with sono-sensitive chemical agents, which may be activated when ensonified by the apparatus.

Source

US Filing

United States Patent Application	20090062724
Kind Code	A1
Chen; Rixen	March 5, 2009

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SYSTEM AND APPARATUS FOR SONODYNAMIC THERAPY

Abstract

The present invention relates to diffuse ultrasound along with chemical agents to treat tissue, called sonodynamic therapy (SDT), and a system for treatment using SDT that comprises a whole body ensonification apparatus and control system. The whole body ensonification may reduce the chances of missing desired tissue that may not be easily detectable or may be found throughout the body. The apparatus has a plurality of diffuse ultrasound transducers for ensonifying at least part of a chamber filled with fluid and designed to accommodate a body for treatment. The person may be treated with sono-sensitive chemical agents, which may be activated when ensonified by the apparatus.

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Inventors:

Chen; Rixen; (Vancouver, CA)

NOTES:
ANGEL SCIENCE & TECHNOLOGY (CANADA), INC.

Angel’s HIFU technology has been developed in conjunction with the China National Ultrasound Research Laboratory and the technology continues to be expanded and improved by its researchers and scientists today. Angel began first stage clinical trials in China in 2002. Successful and positive third stage clinical trials were completed at the end of 2005.
Source

Studies Show Combination Laser Therapy Effective At Clearing Acne, Reducing Oil Production

Posted : Thu, 05 Mar 2009 22:00:23 GMT

SAN FRANCISCO, March 5

AAD-lasertherapy-acne

Dermatologist evaluates the latest laser and light sources approved for treating acne

SAN FRANCISCO, March 5 /PRNewswire-USNewswire/ -- From the removal of childhood birthmarks to skin rejuvenation, laser technology has become a mainstay in dermatology. Now, dermatologists are fine-tuning this technology to safely and effectively treat one of the most common skin conditions that plagues teenagers and adults alike: acne.

Speaking today at the 67th Annual Meeting of the American Academy of Dermatology [AAD] (Academy), dermatologist Macrene Alexiades-Armenakas, MD, PhD, FAAD, assistant clinical professor of dermatology at Yale University School of Medicine in New Haven, Conn., presented scientific data illustrating how photodynamic therapy combined with a long-pulse, pulsed-dye laser and topical 5-aminolevulinic acid provides long-lasting clearance of acne lesions.

"Laser technology has made great inroads in the treatment of acne, which until recently has been treated almost exclusively - and with varying degrees of success - with topical, systemic and hormonal medications," said Dr. Alexiades-Armenakas. "Now, we have solid evidence-based medicine supporting the effectiveness of certain laser therapies as a long-term solution for treating active acne. The key is to distinguish the benefits and limitations of these available technologies and select the most effective treatments for each acne patient."

Photodynamic Therapy with a Photosensitizer
In a preliminary study, Dr. Alexiades-Armenakas examined whether a combination of photodynamic therapy (PDT) with a photosensitizer known as topical 5-aminolevulinic acid (ALA) and activated by long-pulse, pulsed dye laser could safely and effectively clear mild to severe cases of acne. PDT works by using laser or light energy - in this case a pulsed dye laser was used - to activate the ALA, which is a solution that penetrates into the oil glands and is applied to the skin one hour prior to treatment. As it penetrates, ALA binds to the oil glands and sensitizes the cells to light.

The 14 patients treated with ALA PDT received one to six treatments depending on the severity of their acne and continued to use topical medications during and after the study. The control group consisted of four patients who were either treated with conventional therapy (such as systemic or topical medications) or with laser energy but without ALA PDT.

Upon analyzing the data, Dr. Alexiades-Armenakas found that all (100 percent) of the 14 patients in the ALA PDT treatment group experienced complete clearance of their acne. She reported that an average of 2.9 ALA PDT treatments was administered to this patient group and improvement in the acne lesions was visible within one to two weeks after the first treatment. By comparison, none of the four patients in the control group who were treated with either laser energy alone or conventional therapy achieved complete clearance of their acne.

"The first-of-a-kind study found this particular form of photodynamic therapy used in conjunction with topical therapy to be the first such treatment to achieve complete clearance of acne up to 13 months post treatment and a 77 percent clearance rate per treatment. Four subsequent studies conducted by other investigators involving an additional 75 patients demonstrated similar results," said Dr. Alexiades-Armenakas. "Patients also experienced an added benefit of significant improvement in their acne scars, as the pulsed dye laser offers superior penetration to the deeper layers of the skin where scars form."
.....

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COMPOSITION AND METHOD FOR CANCER TREATMENT USING TARGETED SINGLE-WALLED CARBON NANOTUBES

United States Patent Application	20080227687
Kind Code	A1
Harrison; Roger G. ; et al.	September 18, 2008

Abstract

The present invention is a method for detecting and destroying cancer tumors. The method is based on the concept of associating a linking protein or linking peptide such as, but not limited to, annexin V or other annexins to single-walled carbon nanotubes (SWNT) to form a protein-SWNT complex. Said linking protein or peptide can selectively bind to cancerous cells, especially tumor vasculature endothelial cells, rather than to healthy ones by binding to cancer-specific external receptors such as anionic phospholipids including phosphatidylserine expressed on the outer surfaces of cancer cells only. Irradiation of bound SWNTs with specific wavelength is then used to detect and destroy those cells to which the SWNTs are bound via the linking protein or peptide thereby destroying the tumor or cancer cells.

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Inventors:	Harrison; Roger G.; (Norman, OK) ; Resasco; Daniel E.; (Norman, OK)
Correspondence Name and Address:	DUNLAP CODDING, P.C. PO BOX 16370 OKLAHOMA CITY OK 73113 US
Serial No.:	033857
Series Code:	12
Filed:	February 19, 2008

U.S. Current Class:	514/2; 606/3
U.S. Class at Publication:	514/2; 606/3
Intern'l Class:	A61K 38/00 20060101 A61K038/00; A61B 18/18 20060101 A61B018/18

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Claims

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1. A method of treating a cancer tumor or cancer cells in a patient, comprising:

providing a composition comprising a protein-carbon nanotube complex comprising a protein or peptide operatively attached to a carbon nanotube, wherein the protein or peptide of the protein-carbon nanotube complex comprises a binding protein or peptide that has binding specific for an external receptor or binding site on a tumor vasculature endothelial cell or on a cancer cell;

administering the composition comprising the protein-carbon nanotube complex to the patient wherein the protein-carbon nanotube complex preferentially binds via the binding protein or peptide to the external receptor or binding site on an outer surface of the endothelial cell of the tumor vasculature of the cancer tumor or on an outer surface of the cancer cell in the patient; and

exposing the patient to electromagnetic radiation comprising a wavelength absorbable by the carbon nanotube causing elevation of the temperature of the carbon nanotube of the protein-carbon nanotube complex to a temperature which induces damage or death of the endothelial cell of the tumor vasculature or of the cancer cell to which the protein-carbon nanotube complex is bound.

[Snip from Description]
[0023]After treatment with the protein-SWNT complex or peptide-SWNT complex of the present invention, the tumor having the SWNTs bound thereto is then selectively exposed to electromagnetic radiation, for example, near-infrared (NIR) radiation. NIR radiation causes excessive local heating of SWNTs but does not otherwise affect biological systems which are not associated to the SWNTs (12). This excessive local heating of the SWNTs bound to the surface of endothelial cells of the tumor vasculature or to surfaces of the cancer cells leads to the destruction of the tumor vasculature or of the cancer cells and thus to the death or inhibition of growth of the tumor or cancer cells. Without wishing to be held to theory, it is believed that the killing of the tumor is by a combination of heating and cutting off the tumor's blood supply. In order to avoid damage to normal blood vessels, it is advantageous to delay the NIR treatment (or treatment with other wavelengths) until there is clearing of free SWNTs from the bloodstream such that substantially the only SWNTs in the body are those bound to the tumor vasculature or cancerous cells. The free SWNTs should clear within a matter of hours after administration. For example, in a recent study (30) with rabbits, SWNTs were injected into the bloodstream, and the SWNT concentration decreased exponentially with a half-life of 1.0.+-.0.1 hour. No adverse effects from low-level SWNT exposure could be detected from behavior or pathological examination.

Source

Note:
No --administering to the patient an immunostimulant to enhance the patient's immune response to antigens released from the cancer cells or tumor vasculature endothelial cells-- in this application. (See United States Patent Application 20090062785 below, for that.)

PAIR (to follow the USPTO prosecution history) - After the entry page - Insert '20080227687' in the box and select 'Publication Number'.

COMPOSITIONS AND METHODS FOR CANCER TREATMENT USING TARGETED SINGLE-WALLED CARBON NANOTUBES

United States Patent Application	20090062785
Kind Code	A1
Harrison, JR.; Roger G. ; et al.	March 5, 2009

Abstract

The present invention is a method for detecting and destroying cancer tumors. The method is based on the concept of associating a linking protein or linking peptide such as, but not limited to, annexin V or other annexins to single-walled carbon nanotubes (SWNT) to form a protein-SWNT complex. Said linking protein or peptide can selectively bind to cancerous cells, especially tumor vasculature endothelial cells, rather than to healthy ones by binding to cancer-specific external receptors such as anionic phospholipids including phosphatidylserine expressed on the outer surfaces of cancer cells only. Irradiation of bound SWNTs with one or more specific electromagnetic wavelengths is then used to detect and destroy those cells to which the SWNTs are bound via the linking protein or peptide thereby destroying the tumor or cancer cells and preferably an immunostimulant is provided to the patient to enhance the immune response against antigens released from the tumor or cancer cells.

---

Inventors:

Harrison, JR.; Roger G.; (Norman, OK) ; Resasco; Daniel E.; (Norman, OK)

Claims1. A method of treating a cancer tumor or cancer cells in a patient, comprising:providing a composition comprising a protein-carbon nanotube complex comprising a protein or peptide operatively attached to a carbon nanotube, wherein the protein or peptide of the protein-carbon nanotube complex comprises a binding protein or peptide that has binding specific for an external receptor or binding site on a tumor vasculature endothelial cell or on a cancer cell;

administering the composition comprising the protein-carbon nanotube complex to the patient wherein the protein-carbon nanotube complex preferentially binds via the binding protein or peptide to the external receptor or binding site on an outer surface of the endothelial cell of the tumor vasculature of the cancer tumor or on an outer surface of the cancer cell in the patient;

exposing the patient to electromagnetic radiation comprising a wavelength absorbable by the carbon nanotube causing elevation of the temperature of the carbon nanotube of the protein-carbon nanotube complex to a temperature which induces damage or death of the endothelial cell of the tumor vasculature or of the cancer cell to which the protein-carbon nanotube complex is bound; and

administering to the patient an immunostimulant to enhance the patient's immune response to antigens released from the cancer cells or tumor vasculature endothelial cells.

[Snip from Description]
[0027]After treatment with the protein-SWNT complex or peptide-SWNT complex of the present invention, the tumor having the SWNTs bound thereto is then selectively exposed to electromagnetic radiation, for example, radio frequency radiation, near-infrared (NIR) radiation, visible light, or UV radiation. The energy level of NIR radiation can be adjusted to give excessive local heating of SWNTs but not otherwise affect biological systems which are not associated to the SWNTs (12). This excessive local heating of the SWNTs bound to the surface of endothelial cells of the tumor vasculature or to surfaces of the cancer cells leads to the destruction of the tumor vasculature or of the cancer cells and thus to the death or inhibition of growth of the tumor or cancer cells. Without wishing to be held to theory, it is believed that the killing of the tumor is by a combination of heating and cutting off the tumor's blood supply. In order to avoid damage to normal blood vessels, it is advantageous to delay the NIR treatment (or treatment with other wavelengths) until there is clearing of free SWNTs from the bloodstream such that substantially the only SWNTs in the body are those bound to the tumor vasculature or cancerous cells. The free SWNTs should clear within a matter of hours after administration. For example, in a recent study (30) with rabbits, SWNTs were injected into the bloodstream, and the SWNT concentration decreased exponentially with a half-life of 1.0.+-.0.1 hour. No adverse effects from low-level SWNT exposure could be detected from behavior or pathological examination.

Source

Notes:
Resasco; Daniel E. is Chief Scientist and Founder of SouthWest NanoTechnologies, Inc. (SWeNT)

IP for Harrison; Roger G
US Patent filings
US Patents

Quest PharmaTech - Photosensitizer SL052

Quest PharmaTech Announces Results Showing its Photosensitizer, SL052, is an Effective Immuno-Stimulant when combined with Immunotherapy for the Removal of Solid Tumors

Wednesday, March 4, 2009, 12:36 pm EST

TSX Venture: QPT - QUEST PHARMATECH INC. (Tier2) (QPT.V) QUOTES

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IP
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WIPO WO/2008/011707 WO/2007/016762

EDMONTON, March 4 /CNW/ - Quest PharmaTech Inc. (TSX-V: QPT - News), ("Quest" or the "Company") a pharmaceutical company developing and commercializing products for the treatment of cancer and dermatological conditions, today announced results from a study designed to investigate the effectiveness of its proprietary SL052 for photodynamic therapy (PDT) used in combination with immunotherapeutic agents in solid tumor animal models. The study, conducted by Dr. Mladen Korbelik at the BC Cancer Agency in Vancouver, demonstrated that SL052 increased the potency and effectiveness of immunotherapeutic agents when used in combination with SL052 PDT.

The results also confirmed that SL052 was an effective and well tolerated photosensitizer for PDT ablation of two highly tumorigenic, solid murine tumors. Further, the results demonstrated that photodynamic therapy generated direct local cytotoxicity and induced a systemic immune response, which could enhance its therapeutic effect on both primary tumors and metastases at distant sites.

The study tested several applications of SL052 and evaluated host recognition and immunological destruction of solid tumors. The results indicate the potential of SL052 PDT for use in combination with cancer vaccines to generate a superior immune response compared with vaccines alone. The study also revealed that SL052 PDT may be effectively combined with either single or multiple-complementary effectors of the host's immune response to substantially boost the frequency of permanent cures.

"The effects of immunotherapy can be amplified when combined with photodynamic therapy, potentially making immunophotodynamic therapy a superior systemic cancer treatment modality," said Thomas Woo, Vice President of Product Development at Quest.

SL052 is a non-toxic agent with broad potential to treat a variety of solid tumors using photodynamic (light activation) therapy or sonodynamic (ultrasound activation) therapy. Photodynamic therapy is applicable for superficial level solid tumors and sonodynamic therapy targets more deeply seated solid tumors.

"These results further define the therapeutic profile of SL052," stated Dr. Madi R. Madiyalakan, Chief Executive Officer at Quest. "While its activation through either photodynamic or sonodynamic therapy was already established, we now have a clear indication of its potential to act as either an immune response stimulator or as a cancer vaccine. Taken together, these characteristics of SL052 provide a new potential treatment modality for cancer therapy."

About SL052

SL052 is a member of Quest PharmaTech's SonoLight Portfolio with the potential to reduce or eliminate the side effects associated with currently available cancer treatment modalities: surgery, chemotherapy and radiotherapy. Its properties of activation with harmless physical agents (light and ultrasound), combined with its ability to generate cancer vaccines and stimulate an anti-cancer immune response warrant further development in a broad-spectrum oncology arena. With these results, the next development stage for SL052 is a Phase I clinical trial for the treatment of Prostate Cancer. Quest is presently awaiting approval from Health Canada that will allow it to initiate a Phase I clinical trial for SL052.

About Quest PharmaTech Inc.

Quest is a publicly traded, Alberta-based pharmaceutical company committed to the development and commercialization of new pharmaceutical products. It is developing a series of products for the treatment of cancer and dermatological conditions based on its unique photodynamic and sonodynamic therapy platforms.

     Neither TSX Venture Exchange nor its Regulation Services Provider (as
that term is defined in the policies of the TSX Venture Exchange) accepts
responsibility for the adequacy or accuracy of this release.

For further information

Dr. Madi R. Madiyalakan, Chief Executive Officer, Quest PharmaTech Inc., Tel: (780) 448-1400 Ext. 204, Email: madi@questpharmatech.com, Internet: www.questpharmatech.com
Media and Investor Relations, Adam Peeler, The Equicom Group Inc., Tel: (416) 815-0700 Ext. 225, Email: apeeler@equicomgroup.com

Source

New Type Of Vaccination Provides Instant Immunity To Two Types Of Cancer In Animal Model

ScienceDaily (Mar. 4, 2009) — The experiments, thus far performed only in mice, appear to overcome a major drawback of vaccinations – the lag time of days, or even weeks, that it normally takes for immunity to build against a pathogen. This new method of vaccination could potentially be used to provide instantaneous protection against diseases caused by viruses and bacteria, cancers, and even virulent toxins.

The team, led by Scripps Professor Carlos Barbas, III, Ph.D., tested the vaccination method – called covalent immunization – on mice with either melanoma or colon cancer.

The scientists injected these mice with chemicals specifically designed to trigger a programmable and "universal" immune reaction. They developed other chemicals, "adapter" molecules," that recognized the specific cancer cells. Once injected into the animal, the adapter molecules self-assembled with the antibodies to create covalent antibody-adapter complexes.

"The antibodies in our vaccine are designed to circulate inertly until they receive instructions from tailor-made small molecules to become active against a specific target," Barbas says. "The advantage of this method is that it opens up the possibility of having antibodies primed and ready to go in the time it takes to receive an injection or swallow a pill. This would apply whether the target is a cancer cell, flu virus, or a toxin like anthrax that soldiers or even civilian populations might have to face during a bioterrorism attack."

Only those mice that received both the vaccine and the adapter compound generated an immediate immune attack on the cancer cells that led to significant inhibition of tumor growth. This is the first time that such a covalent vaccine has been successfully designed and tested – typically, antibodies do not bind to chemicals in this covalent fashion.

The current breakthrough builds on work the Barbas laboratory has been engaged in for the past few years on chemically programmed monoclonal antibodies, a new class of therapeutics that the group invented. In this type of therapy, small, cell-targeting molecules and non-targeting catalytic monoclonal antibodies self-assemble to target pathogens. Monoclonal antibodies are produced in the laboratory from a single cloned B-cell – the immune system cell that makes antibodies – to bind to a specific substance. Three clinical trials are now under way by Pfizer to test the therapeutic effectiveness of this new type of therapy in cancer and diabetes. The antibodies in the antibody-adapter complex are monoclonal antibodies engineered to link themselves to adapter molecules.

The Search for the Ideal Vaccination

The practice of vaccination has been extraordinarily successful in controlling certain diseases, but there are drawbacks. Vaccine development can be an educated guessing game – in the case of the flu, for example, scientists must study worldwide outbreak patterns to anticipate which type of flu might strike a particular area. In addition, the most common vaccination strategies use whole proteins, viruses, or other complex immunogens – not just the specific part of the macromolecule that is recognized by the immune system – to elicit an immune response, which makes for wasted immune activity. Then there is the body's own kinetics – the time it takes to mount a disease-relevant immune response to immunogens limits the speed with which immunity can be achieved. Finally, age-related declines in the ability to mount strong immune responses to biological-based vaccines present another challenge to the effectiveness of such vaccines.

Barbas's chemical-based – rather than biological based – approach to vaccine development addresses many of these challenges.

"Our approach differs from the traditional vaccine approach in the sense that when we design an antibody-adapter compound we know exactly what that compound will react with," Barbas says. "The importance of this is best exemplified with HIV. In current vaccines, many antibodies are generated against HIV, but most are not able to target the active part of the virus."

In the near term, Barbas will apply his covalent vaccination approach to HIV, cancer, and infectious diseases for which no vaccines currently exist. A particular focus will be creating adapter molecules specific to these diseases.

"We believe that chemistry-based vaccine approaches have been underexplored and may provide opportunities to make inroads into intractable areas of vaccinology," Barbas says.

The study was funded by the Skaggs Institute for Chemical Biology and the National Institutes of Health.

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Journal reference:

1. Mikhail Popkov et al. Instant immunity through chemically programmable vaccination and covalent self-assembly. Proceedings of the National Academy of Sciences, March 2, 2009

Adapted from materials provided by Scripps Research Institute.

Source

Preying On a Tumor's Weakness With Nanotechnology to Fight Cancer

Winner of this year's $30,000 Lemelson-MIT Student Prize uses gold nanoparticles to kill malignancies but spare healthy tissue

By Larry Greenemeier

GEOFFREY VON MALTZAHN: The 28-year-old Ph.D. candidate has won this year's $30,000 Lemelson-MIT Student Prize for his work developing ways to use nanotechnology to fight cancer.
COURTESY OF HARVARD-MIT DIVISION OF HEALTH SCIENCES AND TECHNOLOGY

The Harvard-MIT Division of Health Sciences and Technology (HST) today named Geoffrey von Maltzahn this year's recipient of the $30,000 Lemelson-MIT Student Prize for developing a technique that utilizes nano-sized gold particles to target malignant tumors and kill cancer cells while leaving healthy tissue unscathed. Established in 1994, the award is given out annually to an MIT senior or graduate student who has contributed significantly to the fields of science or technology.

The approach capitalizes on "tumors behaving like tumors," says von Maltzahn, a 28-year-old Ph.D. candidate, and so, triggering the growth of as many new blood vessels as quickly as possible to nourish and help them thrive. But instead of feeding these tumors, von Maltzahn relies on these ultra-porous nascent blood vessels to transport rod-shaped gold nanoparticles injected into cancer patients to the tumor, where they latch onto malignant tissue.

Although other researchers have tested the use of nanoparticles to fight cancer (read about another MIT/Harvard effort here), Von Maltzahn has developed two ways to attack tumors once the nanoparticles have set up shop there. The first is to shine a near-infrared laser on the patient's skin above the malignancies; the light heats the gold to high enough temps to interrupt and destroy cancer cells with minimal if any damage to surrounding healthy cells. In pre-clinical mouse trials a single nanoparticle injection (which includes trillions of nanoparticles) eradicated 100 percent of tumors when combined with near-infrared light. The problem with current radiation therapy is that in most cases it is not confined to malignant growths and healthy tissue gets caught in the crossfire, according to von Maltzahn.

His other award-winning technique involves two injections: the first batch are sent out as scouts to identify and attach to tumors, where they serve as markers for a second battalion of nanoparticles covered with cancer-fighting agents that home in on and destroy the tumors but ignore healthy tissue. In mouse trials, von Maltzahn and his colleagues found that this "scout-assassin" system successfully delivered doses of medicine in mice that were more than 40-times more potent and much more successful at killing tumors than were medicine-coated particles injected sans the ability to communicate with nanoparticle advance teams. The major benefit of von Maltzahn's methods is that the medication could be injected anywhere in the body but would only latch onto the cancerous tissue. "If we were injecting this directly into the tumor, it wouldn't be a transformative technology," he says. "It's essential to be able to inject it intravenously anywhere in the body and have it …. home in on the tumor." Once the medicine has been delivered, the nanoparticles would be stripped bare and could safely pass out of the body after being filtered from the blood by the spleen or liver, von Maltzahn says, noting that gold has a very low toxicity profile.

According Catherine Murphy, a chemistry professor at the University of South Carolina in Columbia, the shape of a metal determines how much light it absorbs. "If you want to shine near-infrared light, which is really good for tissue penetration, and burn something up," she says, "a rod shape works really well." Murphy developed the process for transforming spherical bits of gold into the nanorods that von Maltzahn used in his research.

Von Maltzahn, who has worked with his advisor Sangeeta Bhatia, a Harvard-MIT HST electrical engineering and computer science professor, on this research for the past five years, is co-founder of a pair of companies that he hopes will help commercialize his technique: In July 2007, he helped form Salt Lake City, Utah, -based Nanopartz Inc., a worldwide supplier of gold nanoparticles, and in September 2008, he helped create Boston-based Resonance Therapeutics, which will further develop his cancer-fighting techniques. Eugene Zubarev, an assistant chemistry professor at Rice University in Houston, developed the method for mass producing nanoparticles that Nanopartz relies on to make the nanoparticles it sells.

Von Maltzahn two years ago developed another nanotech-based approach to stopping cancer that relied on polymer-coated iron oxide nanoparticles held together by DNA tethers that together help create a visual image of a tumor through magnetic resonance imaging (MRI), as Scientific American.com reported in November, 2007. To test the particles, he and his team implanted mice with a tumor-like gel saturated with nanoparticles and placed those mice into the wells of cup-shaped electrical coils, which activated the nanoparticles via magnetic pulses.

Von Maltzahn says he's currently conducting clinical trials of his near-infrared laser technology (to ablate cancerous tumors), but it is still years away from becoming a routine treatment. The scout-assassin model is even farther from becoming a cancer-fighting staple, says Maltzahn, noting that it could take him and his colleagues another two decades to make it safe and effective enough to use in humans.

Von Maltzahn plans to keep close tabs on his companies but to continue to pursue an academic career as a professor of biomedical or chemical engineering. Neither the business nor the academic aspects of research can be overlooked if medicine is to make its way from the lab to the patient, he says. "One of the things that appeals to me," von Maltzahn says, "is developing therapeutics such as these in a way that they can be commercialized."

Source

Newly discovered gene plays vital role in cancer

[PRESS RELEASE, 27 February 2009] Gene p53 protects against cancer and is usually described as the most important gene in cancer research. However, scientists at Karolinska Institutet have now shown that a previously unknown gene, Wrap53, controls the activity of p53. As the regulation mechanism is relatively unexplored, the study opens up new routes to solving the mystery of cancer.

Marianne Farnebo Photo: private

The p53 gene makes sure that cells with damaged DNA either repair themselves or commit suicide. If p53 itself is damaged, which is the case in roughly half of all cancer tumours, cells that are on their way to becoming cancerous are allowed to survive. Much cancer research revolves around the cell processes that p53 induces.

A group of researchers at Karolinska Institutet have now identified a new gene, called Wrap53, that regulates the activity of p53. The study, which is published in the journal Molecular Cell, demonstrates that Wrap53 gives rise to a molecule, called antisense RNA, the presence of which is necessary for the production of sufficient quantities of p53 protein in the event of DNA damage.

According to Marianne Farnebo, one of the scientists involved in the study, the results indicate that damage to Wrap53 can indirectly cause cancer. Wrap53 is therefore a new potential target for future cancer therapies.

"Mutations in the p53 gene contribute to about half of all cancer cases," she says. "In the remaining half, p53 is probably inactivated in other ways, such as damage to Wrap53 knocking out the production of the p53 protein."

The study is also one of the first to show how antisense RNA regulates genes in the human body. It is already a well-known fact that genes often control each other through the influence of their end products - usually proteins - on gene expression. With antisense regulation, control is effected instead through the production of mutually stabilising or destructive RNA molecules by genes with overlapping sequences, which determines whether or not the RNA molecules form proteins.

"At least 20 per cent of all genes can be regulated by antisense RNA, making it a potentially very common control mechanism," says Dr Farnebo. "But it's been difficult to show that antisense RNA really does serve important functions in the body, as we've managed to do in this study."

Publication:
Salah Mahmoudi, Sofia Henriksson, Martin Corcoran, Cristina Méndez-Vidal, Klas G. Wiman & Marianne Farnebo
Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage

For more information, please contact:
PhD Marianne Farnebo

Work:
+46 (0)8-517 703 67
Mobile:
+46 (0)70-217 42 04

E-mail:

* Marianne.Farnebo@ki.se

* Department of Oncology-Pathology

Source

Re 636 nm spectral poperties

Absorption Spectra of Formylchlorins

The absorption spectra of the formylchlorins (in toluene at room temperature) are summarized in Table 2. Three classes are noted: zinc chlorins bearing a 10-mesityl group (ZnC-M¹⁰ series); zinc chlorins bearing a 5-p-tolyl group and a 10-mesityl group (ZnC-T⁵M¹⁰ series); and various free base chlorins (FbC series). Selected absorption spectra of the ZnC-M¹⁰ series are shown in Figure 1 (see Supporting Information for additional spectra).

Table 2 Spectral Properties of Chlorins.a

Figure 1 Absorption spectra (normalized) in toluene at room temperature of ZnC-M10 (trace a, λQy 606 nm),17ZnC-M10F13 (trace b, λQy 634 nm), ZnC-F5P10 (trace c, λQy 650 nm), and ZnC-F3M10F13 (trace d, λQy 667 nm).

The long-wavelength absorption band can now be tuned over the range of 606 – 667 nm.

Source

Comparison between sonodynamic effect with protoporphyrin IX and hematoporphyrin on sarcoma 180

Journal	Cancer Chemotherapy and Pharmacology
Publisher	Springer Berlin / Heidelberg
ISSN	0344-5704 (Print) 1432-0843 (Online)
Issue	Volume 60, Number 5 / October, 2007
Category	Original Article
DOI	10.1007/s00280-006-0413-4
Pages	671-680
Subject Collection	Biomedical and Life Sciences
SpringerLink Date	Friday, January 12, 2007

PDF (608.2 KB)HTMLFree Preview

QuanHong Liu¹ , XiaoBing Wang¹, Pan Wang¹, LiNa Xiao¹ and Qiao Hao¹

(1)	College of Life Sciences, Shaanxi Normal University, Xi’an, 710062, China

Received: 14 October 2006 Accepted: 21 December 2006 Published online: 12 January 2007

Abstract

Purpose
The comparison between sonodynamic antitumor effect with protoporphyrin IX (PPIX) and hematoporphyrin (Hp) at a concentration of 5 mg/kg on Sarcoma 180 (S180) cells was studied in vivo, and the potential cell damage mechanism was also investigated.

Methods
The sonodynamically induced anti-tumor effect of PPIX was studied in mice bearing S180 solid tumors. In order to determine the optimum timing of ultrasound exposure after administration of PPIX, the PPIX concentrations in plasma, skin, muscle and tumor were determined by the fluorescence intensity of tissue extractions with a fluorescence spectrophotometer based on the standard curve. Anti-tumor effects were estimated by measuring the tumor size and the tumor weight. Additionally, the morphological changes of S180 cells were evaluated by transmission electron microscope (TEM) observation immediately after sonodynamic therapy (SDT) treatment.

Results
A time of 24 h after the intravenous administration of PPIX was chosen as the best time for ultrasound exposure. The antitumor effect induced by PPIX mediated sonodynamic therapy (PPIX-SDT) was in a dose dependent manner when ultrasound intensity was at or above the inertial cavitation threshold (5 W/cm²). A significant tumor growth delay was observed both in PPIX mediated sonodynamic therapy and in Hp mediated sonodynamic therapy treatments (Hp-SDT), and the tumor weight inhibition ratios after the synergistic treatments were 42.82 ± 0.03 and 35.22 ± 0.03%, respectively, this difference was significant at P <>2) showed a slight tumor growth inhibitory effect compared with the control group, and PPIX or Hp alone showed almost no significant effect. Furthermore, TEM observation indicated cell damage was more serious in PPIX-SDT treatment group than in Hp-SDT treatment group. After sonication, the cell ultra-structure such as cell membrane destruction, mitochondria swelling, chromatin condensation might be important factors that inhibited the tumor growth and even induced cell death.

Conclusions
The comparative results suggested that PPIX as a sonosensitizer might have more potential cytotoxicity than Hp when irradiated with ultrasound, and the ultra-structural changes may account for cell destruction induced by sonodynamic therapy in our experiment mode.

Keywords Sonodynamic therapy - Anti-tumor effect - Protoporphyrin IX - Hematoporphyrin - Sarcoma 180

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QuanHong Liu Email: lshaof@snnu.edu.cn Source