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Home > Press > New method developed to predict response to nanotherapeutics: Taking a precision medicine approach to nanomedicine, researchers use MR imaging with magnetic nanoparticles to predict which tumors may be more responsive to therapeutic nanoparticles Abstract: Many nanotherapeutics are currently being tested in clinical trials and several have already been clinically approved to treat cancers. But the ability to predict which patients will be most responsive to these treatments has remained elusive. Now, a collaboration between investigators at Massachusetts General Hospital (MGH) and Brigham and Women's Hospital (BWH) has led to a new approach that uses an FDA-approved, magnetic nanoparticle and magnetic resonance imaging (MRI) to identify tumors most likely to respond to drugs delivered via nanoparticles. The team's preclinical results are published in Science Translational Medicine November 18. "Just as genetics is used in some cases to predict an individual's response to a drug, we wanted to develop a companion diagnostic that can predict response based on physiological differences," said Miles Miller, PhD, a postdoctoral fellow at the MGH Center for Systems Biology. "We hypothesized that ferumoxytol - a product that has been approved for the treatment of anemia - could be used to identify tumors that are more likely to respond to a nanomedicine." "Our goal is to develop new nanotherapeutics that can be safely and effectively delivered to cancer patients," said Omid Farokhzad, MD, director of the Laboratory of Nanomedicine and Biomaterials at BWH. "One of the key translational challenges has been to better match patients to new nanotherapeutics based on patients' physiology. Our work takes a precision medicine approach to nanotherapeutics: using this technique, we can predict how well drug-loaded nanoparticles will accumulate in a particular tumor." Farokhzad -- who has founded three companies, all of which have nanomedicines in the clinic or fast-approaching clinical trials -- teamed up with Ralph Weissleder, MD, PhD, Director of the MGH Center for Systems Biology and an expert in high-resolution in vivo imaging. The researchers hypothesized that the accumulation of nanoparticles may vary from patient to patient based on an individual's unique physiology. For instance, some patients may harbor tumors with more "leaky" vasculature or other physiological conditions that allow nanoparticles to accumulate faster at tumor sites. This accumulation of nanoparticles within tumors is known as the enhanced permeability and retention (EPR) effect. To determine if it would be possible to predict which tumors have high or low EPR, the investigators used ferumoxytol in mouse models of solid tumor cancers. Because it is magnetic, ferumoxytol can be imaged using MRI. "Clinical impact is the ultimate goal of our work. Therefore, we tested an imaging technology, MRI, commonly used in the clinic and a diagnostic nanoparticle, ferumoxytol, that is already FDA-approved for other indications," said Weissleder, who is also an Attending Clinician in Interventional Radiology at MGH. In addition to using MRI, the team labeled the magnetic nanoparticles with a fluorescent dye, allowing them to see the accumulation of particles on a single-cell level by microscopy.They categorized each tumor as having "low," "medium" or "high" EPR and then treated each tumor with a chemotherapeutic drug delivered via nanoparticles. The researchers report that in preclinical models, their MR imaging strategy accurately predicted how much drug would reach the tumors (with more drug being delivered to tumors with higher EPR) and therefore how well the tumors would respond to the drug-loaded nanoparticles. "This work represents a major stepping stone toward translating new discoveries of nanotherapeutics into clinical impact and selecting patients for nanotherapeutic trials," said Farokhzad. To continue moving this work closer to clinical validation, the team intends to perform similar studies in patients. Studies of different forms of cancer may also help the team to identify which cancer types will be most responsive to nanotherapeutics. ### This work was supported in part by the NIH (R01CA164448, U54-CA151884, 5P50CA086355, and HL084312, T32 CA79443) and the David H. Koch-Prostate Cancer Foundation Award in Nanotherapeutics. Farokhzad discloses his financial interest in BIND Therapeutics, Selecta Biosciences and Blend Therapeutics, which develop nanoparticle medical technologies but did not support this study. About Brigham and Women's Hospital Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 4.2 million annual patient visits, nearly 46,000 inpatient stays and employs nearly 16,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $600 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH continually pushes the boundaries of medicine, including building on its legacy in transplantation by performing a partial face transplant in 2009 and the nation's first full face transplant in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials groups. For more information, resources and to follow us on social media, please visit BWH's online newsroom. About Massachusetts General Hospital Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $800 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2015, MGH returned into the number one spot on the 2015-16 U.S. News & World Report list of "America's Best Hospitals." For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.


News Article | October 23, 2015
Site: news.mit.edu

More than half of all cancer patients who receive chemotherapy are treated with drugs containing platinum. These drugs are very powerful, but like many other chemotherapy agents, they can have side effects and may provoke resistance in tumor cells. Although platinum-based drugs have been used since the late 1970s, it has taken scientists decades to fully understand how they work. “It’s a very simple question but it has a complicated answer,” Stephen Lippard, the Arthur Amos Noyes Professor of Chemistry at MIT, said during yesterday’s James R. Killian Jr. Faculty Achievement Award Lecture. For his contributions to unraveling the mechanism of how platinum drugs kill cancer cells, Lippard, one of the founders of the field of bioinorganic chemistry, was awarded this year’s Killian Award. “His groundbreaking work has pushed back the frontiers of inorganic chemistry, while simultaneously paving the way for improvements in human health and the conquering of disease,” reads the award citation. “It’s a great honor for me to be here,” Lippard said after receiving the award from Steven Hall, chair of the MIT faculty and a professor of aeronautics and astronautics. “It’s very humbling to be selected by one’s peers for this honor.” When Lippard began his scientific career in the 1960s, the biological activity of the first platinum drug, cisplatin, had just been identified. The discovery was serendipitous: Michigan State chemist Barnett Rosenberg was investigating the effects of electric fields on the growth of E. coli bacteria, which stopped dividing and grew into long filaments. He eventually realized that platinum leaching from the electrodes used in the experiment was reacting with ammonium chloride in the bacteria’s environment to produce cisplatin, which induced the filamentous growth without the electric field. Subsequently Rosenberg showed that cisplatin could shrink tumors in mice, and the National Cancer Institute began running clinical trials; the Food and Drug Administration approved the drug for treatment of cancer in 1978. Since then, two related platinum drugs, carboplatin and oxaliplatin, have also been approved to treat cancer. Cisplatin, the simplest of the three, consists of an atom of platinum bound to two molecules of ammonia and two chloride ions. In carboplatin, the two chloride ions are replaced by a more complicated structure, a cyclobutane dicarboxylate. Oxaliplatin has an even more complex architecture, with the central platinum atom bound to two separate ring structures. After receiving his PhD from MIT in 1965, Lippard joined the faculty at Columbia University and began investigating how these drugs worked, with a focus on their impact on DNA. He continued this pursuit after returning to MIT in 1983, eventually building up evidence that platinum drugs bind to DNA at specific locations, forming cross-links. These linkages prevent the cell from transcribing the genes necessary to initiate cell division, so the cells become unable to divide and undergo programmed cell death, or apoptosis. “From that understanding, our ultimate goal was to see if we could make improved drug candidates,” said Lippard, who is a member of MIT’s Koch Institute for Integrative Cancer Research. Although platinum drugs have been used successfully to treat many types of cancer — especially testicular cancer — they also have limitations: The drugs can have significant side effects, and cancer cells can become resistant to them, allowing tumors to recur. “That has led us, and others around the world, to look at nonclassical platinum compounds,” Lippard said. In one approach Lippard described, he and others are modifying cisplatin by adding two more chemical groups that have their own anti-cancer activity. After entering a cancer cell, the two components are released, generating cisplatin in the process, and together they attack the cell on multiple fronts. In one early example, Lippard attached cisplatin to a drug known as DCA, which interferes with cancer cell metabolism, forcing them to undergo apoptosis. Although the DCA-platinum compound proved powerful against cancer cells, Lippard said he doesn’t believe it will be developed as a cancer drug. However, this work demonstrated that such an approach is viable: “It shows that we can alter two different types of processes in cancer cells, which I think would make it much more difficult for them to become resistant and hopefully would lead to clinical success,” he said. He also described efforts to package cisplatin into targeted nanoparticles, which could help minimize the drug’s side effects and also deliver it directly to cancer cells. He is one of the founders of a company called Blend Therapeutics that is developing this and other approaches to treat cancer. Another way to improve platinum drugs, Lippard said, is to replace one chloride ion with a large chemical group to form a complex that impedes the transcription of DNA in tumors but without forming cross-links. Earlier research had suggested that neutral platinum compounds with two DNA-binding sites that form cross-links are required to kill cancer cells, but more recent studies have shown that some positively charged “monofunctional” platinum compounds with only one DNA-binding site also have anti-cancer activity. In a study published in 2012, Lippard showed that a compound called phenanthriplatin, in which one chloride ion is replaced by a bulky three-ring structure, was four to 40 times more potent than cisplatin in a screen of many types of cancer cells. The next step is to test the compound’s effectiveness in animals, he said, which, with additional improvements, may lead to a clinical trial. “We’re pretty excited about it and we think that phenanthriplatin and compounds like it could be developed and go forward,” Lippard said. “I would like to cure at least one person of cancer before I leave the planet.”


Patent
Blend Therapeutics | Date: 2013-12-19

The present teachings relate to compounds and compositions for treatment of cancers. In some embodiments, the composition comprises a platinum (IV) complex having at least one carboxylate or carbamate ligand.


Patent
Blend Therapeutics | Date: 2014-03-17

The present teachings relate to compounds and compositions for treatment of cancers. In some embodiments, the composition comprises a platinum compound having a heterocycle ligand. Cabazitaxel-platinum nanoparticles are disclosed herein, as well as methods of making and using the same.


Patent
Blend Therapeutics | Date: 2013-12-30

Particles, including nanoparticles and microparticles, and pharmaceutical formulations thereof, containing conjugates of an active agent such as a therapeutic, prophylactic, or diagnostic agent attached to a targeting moiety via a linker have been designed which can provide improved temporospatial delivery of the active agent and/or improved biodistribution. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer or infectious diseases.


The present disclosure relates to novel pharmaceutical compositions comprising a nanoparticle associated with, tether to, or encapsulating a platinum-based active pharmaceutical agent. The platinum-based drug is released from the nanoparticles in a controlled fashion. Also contemplated are methods of making the nanoparticles, as well as methods for using them in the treatment or prevention of diseases or conditions. One embodiment relates to phenanthriplatin nanoparticles and methods of using and making the same.


Patent
Blend Therapeutics | Date: 2015-11-18

The present teachings relate to compounds and compositions for treatment of cancers. In some embodiments, the composition comprises a platinum (IV) complex having at least one reacting group for reacting with a functional group on a protein, engineered protein, antibody, antibody fragment, peptide, agonist, antagonist, aptamer or ligand which may be capable of recognizing a selected target cell population, and/or derivatives/analogs/mimics thereof.


Particles, including nanoparticles and microparticles, and pharmaceutical formulations thereof, containing conjugates of an active agent such as a therapeutic, prophylactic, or diagnostic agent attached to a targeting moiety via a linker have been designed which can provide improved temporospatial delivery of the active agent and/or improved biodistribution. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer or infectious diseases.


News Article | October 27, 2015
Site: www.pehub.com

TARIS Biomedical, which focuses on developing new treatments for urologic diseases, has secured $32 million in funding. Flagship Ventures led the round with participation from Polaris Venture Partners and RA Capital Management. Also, TARIS has appointed Dr. Christopher Cutie as vice president of clinical development. And, the company has named Kevin Finney, most recently Allergan’s vice president and corporate development head, and Mark Iwicki, most recently president and CEO of Civitas Therapeutics, to its board of directors. LEXINGTON, Mass.–(BUSINESS WIRE)–TARIS Biomedical LLC, a company using proprietary delivery technology and deep expertise in bladder biology to develop novel treatments for urologic diseases, announced today it has relaunched with a $32 million financing led by Flagship Ventures with participation from return investor Polaris Venture Partners and new investor RA Capital Management. Last year, the company sold its lead clinical program to Allergan Inc. in a transaction worth up to $587.5 million, including up-front payment, development and commercial milestones. TARIS will use the proceeds from this current financing to advance an exciting new pipeline that targets a range of high unmet need bladder diseases, initially focusing on bladder cancer and overactive bladder segments. “The sale to Allergan of our clinical-stage treatment for interstitial cystitis in 2014 was an important validation of our revolutionary approach to treating bladder diseases,” said Purnanand Sarma, Ph.D., President and Chief Executive Officer of TARIS. “Since then we have been working hard to build a high value therapeutically-focused urology company on this foundation. This new funding will enable us to launch multiple clinical trials over the next 12 months and further expand our team.” Ed Kania, Managing Partner of Flagship Ventures and board member of TARIS said, “TARIS combines the experience and success of an established company with the agility and sense of mission of a startup. We are pleased to join existing and new finance partners as we help TARIS advance its technology to help millions of patients who suffer from bladder diseases.” Flagship and Polaris have been investors in TARIS since its inception and, with this financing, RA Capital has joined as a new member of the syndicate. Unlike existing bladder disease treatments, TARIS’ drug-device combination approach localizes drug treatment to the bladder and enables continuous drug exposure over weeks to months, with the potential to markedly increase efficacy and minimize systemic side effects. TARIS’ co-founders include famed MIT scientist and serial entrepreneur Robert Langer Sc.D. and MIT scientist Michael Cima Ph.D., both of whom continue to serve on the company’s board. To support its rapid growth, TARIS has added Christopher Cutie, M.D., to its senior leadership team as Vice President of Clinical Development, adding to the company’s strong expertise in bladder diseases and drug-device combinations. Dr. Cutie, in addition to over 10 years of experience at Massachusetts General Hospital as a urologic oncologist, also serves as a Global Medical Advisor for Tokai Pharmaceuticals, Inc. and before that, as a physician in residence at Algeta ASA (now Bayer AG). He is a graduate of the University of Pennsylvania and holds an MD degree from Yale University School of Medicine and a Master of Business Administration from Harvard Business School. TARIS has also strengthened its board of directors, adding two senior executives who each bring more than 20 years of commercial and management experience in the life sciences industry to the company. Kevin Finney was most recently Vice President and head of Corporate Development at Allergan Inc. He previously held executive management roles at Prometheus Laboratories Inc. (acquired by Nestle Health Science in 2011), Amylin Pharmaceuticals Inc. (acquired by Bristol-Meyers Squibb in 2012) and Parke-Davis division of Warner-Lambert (acquired by Pfizer). Mark Iwicki served most recently as President and Chief Executive Officer at Civitas Therapeutics (acquired by Acorda). Prior to Civitas, he served as President and Chief Executive Officer at Blend Therapeutics and was President and Chief Executive Officer of Sunovion Pharmaceuticals Inc. (formerly Sepracor Inc.). Earlier in his career, Mr. Iwicki was a Senior Vice President and business unit head for multiple therapeutic areas at Novartis Pharmaceuticals. Other TARIS board members include Purnanand Sarma, Ph.D; Ed Kania of Flagship Ventures; Dennis Ausiello, M.D., of Massachusetts General Hospital, and Kevin Bitterman, of Polaris Venture Partners. Rajeev Shah of RA Capital joined as a board observer. About Bladder Diseases, Overactive Bladder and Bladder Cancer Bladder diseases, including bladder cancer, overactive bladder, urinary tract infections, affect nearly 60 million people in the US and hundreds of millions worldwide. The incidence of bladder diseases is expected to continue increasing, given the correlation of many of these diseases with aging as well as a growing aging population. Bladder cancer projected statistics for 2015, according to the National Cancer Institute, include 74,000 new cases and 16,000 deaths, representing 4.5% of all new cancer cases and 2.7% of all deaths. This ranks bladder cancer as the 5th most common malignancy, and the most expensive cancer to treat on a per patient lifetime basis. The prevalence of the disease in the US was estimated to be nearly 600,000 in 2012. Current bladder cancer treatments include surgical tumor resection and instillation-based therapy. In severe cases, patients that are medically fit and willing, undergo radical cystectomy (bladder removal). There has been little innovation in bladder cancer over the past 20 years and new therapies are needed that have better efficacy and are well tolerated. Overactive bladder (OAB) is a symptom complex that is characterized by urinary urgency with or without urinary incontinence. Two large epidemiological studies, one in the US and the other in Europe, showed this disorder affects approximately 16% of the population (over 33 million in the US alone). OAB can have devastating effects on quality of life and remains one of the most common indications for admission to nursing homes. Pharmacological treatment of OAB primarily includes oral therapies, which often demonstrate poor efficacy and side effects including dry mouth, constipation, and cognitive impairment. Despite oral therapies, patients often seek more aggressive treatment options. The need for new, well-tolerated and efficacious new therapies is significant. About TARIS Biomedical® TARIS Biomedical® is building a unique therapeutically-focused urology company developing powerful new treatments for millions of patients suffering from difficult-to-treat bladder diseases. We are advancing therapies for debilitating conditions, including bladder cancer and overactive bladder, enabled by continuous local dosing where it is needed. www.tarisbiomedical.com TARIS Biomedical LLC was formed as part of the transaction between TARIS Biomedical, Inc., and Allergan in August 2014. This new entity retained the management team, pipeline programs and intellectual property related to TARIS’ platform technology, other than those acquired by Allergan.


LEXINGTON, Mass.--(BUSINESS WIRE)--TARIS Biomedical LLC, a company using proprietary delivery technology and deep expertise in bladder biology to develop novel treatments for urologic diseases, announced today it has relaunched with a $32 million financing led by Flagship Ventures with participation from return investor Polaris Venture Partners and new investor RA Capital Management. Last year, the company sold its lead clinical program to Allergan Inc. in a transaction worth up to $587.5 million, including up-front payment, development and commercial milestones. TARIS will use the proceeds from this current financing to advance an exciting new pipeline that targets a range of high unmet need bladder diseases, initially focusing on bladder cancer and overactive bladder segments. “The sale to Allergan of our clinical-stage treatment for interstitial cystitis in 2014 was an important validation of our revolutionary approach to treating bladder diseases,” said Purnanand Sarma, Ph.D., President and Chief Executive Officer of TARIS. “Since then we have been working hard to build a high value therapeutically-focused urology company on this foundation. This new funding will enable us to launch multiple clinical trials over the next 12 months and further expand our team.” Ed Kania, Managing Partner of Flagship Ventures and board member of TARIS said, “TARIS combines the experience and success of an established company with the agility and sense of mission of a startup. We are pleased to join existing and new finance partners as we help TARIS advance its technology to help millions of patients who suffer from bladder diseases.” Flagship and Polaris have been investors in TARIS since its inception and, with this financing, RA Capital has joined as a new member of the syndicate. Unlike existing bladder disease treatments, TARIS’ drug-device combination approach localizes drug treatment to the bladder and enables continuous drug exposure over weeks to months, with the potential to markedly increase efficacy and minimize systemic side effects. TARIS’ co-founders include famed MIT scientist and serial entrepreneur Robert Langer Sc.D. and MIT scientist Michael Cima Ph.D., both of whom continue to serve on the company’s board. To support its rapid growth, TARIS has added Christopher Cutie, M.D., to its senior leadership team as Vice President of Clinical Development, adding to the company’s strong expertise in bladder diseases and drug-device combinations. Dr. Cutie, in addition to over 10 years of experience at Massachusetts General Hospital as a urologic oncologist, also serves as a Global Medical Advisor for Tokai Pharmaceuticals, Inc. and before that, as a physician in residence at Algeta ASA (now Bayer AG). He is a graduate of the University of Pennsylvania and holds an MD degree from Yale University School of Medicine and a Master of Business Administration from Harvard Business School. TARIS has also strengthened its board of directors, adding two senior executives who each bring more than 20 years of commercial and management experience in the life sciences industry to the company. Kevin Finney was most recently Vice President and head of Corporate Development at Allergan Inc. He previously held executive management roles at Prometheus Laboratories Inc. (acquired by Nestle Health Science in 2011), Amylin Pharmaceuticals Inc. (acquired by Bristol-Meyers Squibb in 2012) and Parke-Davis division of Warner-Lambert (acquired by Pfizer). Mark Iwicki served most recently as President and Chief Executive Officer at Civitas Therapeutics (acquired by Acorda). Prior to Civitas, he served as President and Chief Executive Officer at Blend Therapeutics and was President and Chief Executive Officer of Sunovion Pharmaceuticals Inc. (formerly Sepracor Inc.). Earlier in his career, Mr. Iwicki was a Senior Vice President and business unit head for multiple therapeutic areas at Novartis Pharmaceuticals. Other TARIS board members include Purnanand Sarma, Ph.D; Ed Kania of Flagship Ventures; Dennis Ausiello, M.D., of Massachusetts General Hospital, and Kevin Bitterman, of Polaris Venture Partners. Rajeev Shah of RA Capital joined as a board observer. About Bladder Diseases, Overactive Bladder and Bladder Cancer Bladder diseases, including bladder cancer, overactive bladder, urinary tract infections, affect nearly 60 million people in the US and hundreds of millions worldwide. The incidence of bladder diseases is expected to continue increasing, given the correlation of many of these diseases with aging as well as a growing aging population. Bladder cancer projected statistics for 2015, according to the National Cancer Institute, include 74,000 new cases and 16,000 deaths, representing 4.5% of all new cancer cases and 2.7% of all deaths. This ranks bladder cancer as the 5th most common malignancy, and the most expensive cancer to treat on a per patient lifetime basis. The prevalence of the disease in the US was estimated to be nearly 600,000 in 2012. Current bladder cancer treatments include surgical tumor resection and instillation-based therapy. In severe cases, patients that are medically fit and willing, undergo radical cystectomy (bladder removal). There has been little innovation in bladder cancer over the past 20 years and new therapies are needed that have better efficacy and are well tolerated. Overactive bladder (OAB) is a symptom complex that is characterized by urinary urgency with or without urinary incontinence. Two large epidemiological studies, one in the US and the other in Europe, showed this disorder affects approximately 16% of the population (over 33 million in the US alone). OAB can have devastating effects on quality of life and remains one of the most common indications for admission to nursing homes. Pharmacological treatment of OAB primarily includes oral therapies, which often demonstrate poor efficacy and side effects including dry mouth, constipation, and cognitive impairment. Despite oral therapies, patients often seek more aggressive treatment options. The need for new, well-tolerated and efficacious new therapies is significant. About TARIS Biomedical® TARIS Biomedical® is building a unique therapeutically-focused urology company developing powerful new treatments for millions of patients suffering from difficult-to-treat bladder diseases. We are advancing therapies for debilitating conditions, including bladder cancer and overactive bladder, enabled by continuous local dosing where it is needed. www.tarisbiomedical.com TARIS Biomedical LLC was formed as part of the transaction between TARIS Biomedical, Inc., and Allergan in August 2014. This new entity retained the management team, pipeline programs and intellectual property related to TARIS’ platform technology, other than those acquired by Allergan.

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