Sonnemed Patent Filing

(WO/2009/129321) COMPOUNDS AND METHODS FOR ACTIVATED THERAPY

Pub. No.:		WO/2009/129321

Publication Date: 22.10.2009
International Application No.: PCT/US2009/040688
International Filing Date: 15.04.2009

• Description
• Claims
• National Phase
• Notices
• Document

Applicants:
SONNEMED LLC [US/US]; 10 Mt. Vernon Street, #208 Winchester, MA 01890 (US) (All Except US).
LEWIS, Thomas [US/US]; (US) (US Only).
SZULWACH, Ann, M. [US/US]; (US) (US Only).

Inventors:
BURKE, Donald; .
LEWIS, Thomas; (US).

Title:
COMPOUNDS AND METHODS FOR ACTIVATED THERAPY

Abstract:
Provided herein are compounds for detection, diagnosis and treatment of target tissues or target compositions, including hyperproliferative tissues such as tumors, using sonodynamic and/or photodynamic methods. In particular, photosensitizer and/or sonosensitizer compounds that collect in hyperproliferative tissue are provided.

Description
[Snips]
The compounds of the invention are useful as sonosensitizers, photosensitizers and/or as dual acting sensitizers as therapeutic and diagnostic agents, for example for treatment of several cancer types such as, but not limited to, melanoma, prostate, brain, colon, ovarian, breast, skin, lung, esophagus and bladder cancers and other hormone-sensitive tumors, as well as for treatment of age-related macular degeneration, and for killing cells, viruses, fungi and bacteria in samples and living tissues as well known in the art of PDT and other sonosensitizer applications.
....

The invention further relates to a method of sonodynamic therapy, which comprises administering to an individual in need an effective amount of a compound of the invention, followed by local ultrasound. The compounds of the invention are also useful for photo- and sonodestruction of normal or malignant animal cells, as desired, as well as of microorganisms in culture, enabling selective photo- and sonodestruction of certain types of cells in culture or infective agents. Thus, the invention further provides the use of the compounds of the invention for in vivo, ex-vivo or in vitro killing of cells or infectious agents such as bacteria, viruses, parasites and fungi in a biological product, e.g. blood, which comprises treating the infected sample with the compound of the invention followed by ultrasound of the sample. Examples of such diseases or conditions include acne, Aids, viral hepatitis, diabetic retinopathy, infection with sars virus, coronary artery stenosis, carotid artery stenosis, intermittent claudication, or Asian (chicken) flu virus, or infections caused by intracellular infectious agents such as Clamidia, tox, ricetzia, rocky mountain spotted fever, q-fever, and others.

Source

Posted by donpatent at 2:24 PM

See also United States Patent Application 20090275548

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

11 Year Chart

IP
EPO
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

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

---

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

Combination sonodynamic therapy with immunoadjuvant may be a promising new modality for cancer treatment

doi:10.1016/j.mehy.2008.10.024

Copyright © 2008 Elsevier Ltd All rights reserved.

Combination sonodynamic therapy with immunoadjuvant may be a promising new modality for cancer treatment

References and further reading may be available for this article. To view references and further reading you must purchase this article.

Xiaopeng Ma^{a, 1}, Huixuan Pan^{b, 1} and Jilin Yi^{a, , ,}

^aDepartment of Breast and Thyroid Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

^bDepartment of Nephrology, First Affiliated Hospital, School of Medicine, Yangtze University, Jingzhou 434000, China

Received 23 September 2008;

accepted 2 October 2008.

Available online 6 January 2009.

Summary

Sonodynamic therapy (SDT) is a new cancer therapy basing on photodynamic therapy (PDT). Some chemicals produce free radicals on irradiation with laser (photosensitizers) or ultrasound (sonosensitizers). These active molecules destroy biological tissues, thus producing therapeutic effects. Although PDT has been adopted in clinical cancer therapy especially for superficial cancers, this modality is under continued investigation for improved efficacy and expanded use. For example, PDT-generated tumor cell lysates are effective cancer vaccines; treatment of PDT in conjunction with immunoadjuvant, called “PDT-immunoadjuvant therapy” (PIT), “photoimmunotherapy” or “laser immunotherapy”, is considered to be a promising therapeutic interventions for the treatment of cancers. Ultrasound, especially focused ultrasound, can penetrate deeply into tissues and can be focused into a small region of a tumor to activate the cytotoxicity of sonosensitizers. This is a unique advantage in the non-invasive treatment of nonsuperficial tumors when compared to laser light used for PDT. For the similar mechanism of PDT and SDT, we hypothesize that SDT may be exploited for the generation of effective therapeutic cancer vaccines like PDT; and combination SDT with Immunoadjuvant may be a promising systemic treatment modality, not only for superficial cancers but also for deep-seated tumors, which would surpass PIT.

Article Outline

Introduction

The similar principle, process, drugs and mechanism of PDT and SDT

PDT-generated tumor cell lysates (in vitro) are effective cancer vaccines

‘‘PDT-immunoadjuvant therapy” forms an in situ autovaccine

The unique advantage of ultrasound

Hypotheses

Future perspectives

Acknowledgements

References

Corresponding author. Tel.: +86 27 83663818; fax: +86 27 83662851.
¹ These authors contributed equally to this study.

Source

Primary clinical use of sonodynamic therapy (SDT) for advanced breast cancer

Sub-category: New Systemic Agents – Cytotoxics

Category: Treatment Meeting:

2008 Breast Cancer Symposium


Abstract No: 194

Author(s): T. J. Lewis, X. Wang

Abstract:

Background: Sonodynamic therapy (SDT), the synergistic effect of drugs and ultrasound, is promising for cancer treatment. A new sonosensitizing agent has been developed that is derived from chlorophyll, is sensitive to red light, and is extremely sensitive to ultrasound. This agent is specifically absorbed in tumor cells and produces cytotoxic moities upon interaction with 'diagnostic' ultrasound. Animal studies show that SDT inhibits growth of mouse S-180 sarcoma. Here we report clinical data for SDT for advanced breast cancer on 20 patients. Patients were considered late stage with metastasized carcinomas. Prior to SDT treatment, all patients had undergone convention therapies but received no benefit. Methods: All patients had pathologically proven breast carcinomas. The SDT agent was given to patients sublingually with a total dose of 30 to 60mg. After 24h, ultrasound was used to irradiate the general area of the tumors. Sound application was repeated one and two weeks later. Results: ~90% of patients treated experienced a positive response to SDT therapy. 35% experienced "excellent" responses with marked tumor elimination and alleviation of symptoms that was tracked for >1 year, eg. "Case 1." 30% experienced "good" responses also with tumor diminution and symptom relief, eg. "Case 2." Case 1 had left breast carcinoma with multi-organ metastases including auxiliary lymph nodes, bones, liver and abdomen lymph nodes. After 2 treatments PET/CT scan showed good PR. The latest PET/CT taken 28 months after the treatment showed no signs of tumor in any cavity of the body. Case 2 had breast carcinoma which spread broadly. The patient had surgery, chemo, RT, hormone, trastuzumab, zoledronic acid, etc, but all failed. The tumor kept growing until the patient had high-level paraplegia, breath failure, and heart failure. After 3 SDT treatments the patient's symptom improved significantly. Windpipe spile, gastric and urine catheter were all taken off. PET/CT scan showed a partial response. The patient died 7 months later. Conclusions: Primary clinical data shows that SDT is well tolerated and has a significant therapeutic effect for patients with advanced breast cancer. Terminally ill patient can be treated safely and effectively. Sonodynamic therapy has significant merit for further investigation.

Source

194 - SonneMed, LLC
Source

Mechanism of Porphyrin-Induced Sonodynamic Effect: Possible Role of Hyperthermia

Radiation Research

Published by: Radiation Research SocietyRadiation Research 165(3):299-306. 2006

doi: 10.1667/RR3510.1

Mechanism of Porphyrin-Induced Sonodynamic Effect: Possible Role of Hyperthermia

Manabu Kinoshita¹ and Kullervo Hynynen

Department of Radiology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115

¹Corresponding author: Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115; mkinosit@bwh.harvard.edu

Abstract

Kinoshita, M. and Hynynen, K. Mechanism of Porphyrin-Induced Sonodynamic Effect: Possible Role of Hyperthermia. Radiat. Res. 165, 299–306 (2006).

The biological effects of ultrasound have been investigated vigorously for various applications including the thermal coagulation of tissues, the opening of tight junctions, and localized gene or drug introduction. The synergistic cell killing effect of ultrasound and porphyrin derivatives, the so-called sonodynamic effect, holds promise for cancer treatment. Although several models to explain the sonodynamic effect have been proposed, its exact mechanism, especially in vivo, remains unknown. We examined the effect of a porphyrin derivative, protoporphyrin IX, on ultrasound-induced killing of HeLa cells. In some experiments, the intracellular protoporphyrin IX concentration was increased by 5-aminolevulinic acid treatment of the cells. Although extracellular protoporphyrin IX showed an enhanced cell killing effect by microbubble-enhanced ultrasound, intracellular protoporphyrin IX did not. On the other hand, intracellular protoporphyrin IX enhanced the cell killing effect of hyperthermia, which can be produced by ultrasound exposure, in a moderately acidic environment (pH 6.6). Because porphyrin derivatives are generally imported into the intracellular component in vivo, our results suggest that hyperthermia caused by ultrasound may play an important role in the sonodynamic effect induced by porphyrin derivatives.

Received: March 29, 2005; Accepted: June 10, 2005

Source

Sonodynamic Antitumor Effect of Protoporphyrin IX

Vol. 53, No. 6, 2007 View or print article as PDF (277 KB) Experimental Chemotherapy Sonodynamic Antitumor Effect of Protoporphyrin IX Disodium Salt on S180 Solid Tumor Quanhong Liu, Xiaobing Wang, Pan Wang, Lina Xiao College of Life Science, Shaanxi Normal University, Xi'an, China Address of Corresponding Author Chemotherapy 2007;53:429-436 (DOI: 10.1159/000110008) Key Words Sonodynamic therapy Antitumor effect Protoporphyrin IX Sarcoma 180 solid tumor Abstract Background: The sonodynamically induced antitumor effect of protoporphyrin IX (PPIX) disodium salt was studied in mice bearing sarcoma 180 solid tumors. Methods: In order to determine the optimum timing of ultrasound exposure after administration of PPIX, the PPIX concentrations in plasma, skin, muscle and tumor were estimated by measuring the fluorescence intensity of tissue extractions with a fluorescence photometer based on the standard curve. Antitumor effects were estimated by measuring tumor size and calculating the average survival time of tumor-bearing mice after sonodynamic therapy; additionally, the morphological changes of sarcoma 180 cells were evaluated by transmission electron microscope observation in vivo. Results: Our experiments suggested a time of 24 h after the administration of PPIX to be best for ultrasound exposure. At an ultrasound intensity 5 W/cm2 and a PPIX dose 5 mg/kg, a significant synergistic effect of ultrasound combined with PPIX was observed, reducing tumor volume and increasing average animal survival time; this synergistic effect was obviously stronger than ultrasound treatment alone, while PPIX alone showed no significant effect. Transmission electron microscope observation indicated that changes in cell ultrastructure, such as cell membrane destruction, mitochondria swelling and chromatin condensation, were important factors that inhibited tumor growth and even induced cell death. Conclusion: The results implied that the antitumor effect of ultrasound could be enhanced in the presence of PPIX which might be involved in a sonochemical mechanism. Copyright © 2007 S. Karger AG, Basel Source