Organic Nanoparticle Uses Sound and Heat to Find and Treat Tumors

ScienceDaily (Mar. 20, 2011) — A team of scientists from Princess Margaret Hospital have created an organic nanoparticle* that is completely non-toxic, biodegradable and nimble in the way it uses light and heat to treat cancer and deliver drugs.

The findings, published online March 20 in Nature Materials are significant because unlike other nanoparticles, the new nanoparticle has a unique and versatile structure that could potentially change the way tumors are treated, says principal investigator Dr. Gang Zheng, Senior Scientist, Ontario Cancer Institute (OCI), Princess Margaret Hospital at University Health Network.

Dr. Zheng says: "In the lab, we combined two naturally occurring molecules (chlorophyll and lipid) to create a unique nanoparticle that shows promise for numerous diverse light-based (biophotonic) applications. The structure of the nanoparticle, which is like a miniature and colorful water balloon, means it can also be filled with drugs to treat the tumor it is targeting."

It works this way, explains first author Jonathan Lovell, a doctoral student at OCI: "Photothermal therapy uses light and heat to destroy tumors. With the nanoparticle's ability to absorb so much light and accumulate in tumors, a laser can rapidly heat the tumor to a temperature of 60 degrees and destroy it. The nanoparticle can also be used for photoacoustic imaging, which combines light and sound to produce a very high-resolution image that can be used to find and target tumors." He adds that once the nanoparticle hits its tumor target, it becomes fluorescent to signal "mission accomplished."

"There are many nanoparticles out there, but this one is the complete package, a kind of one-stop shopping for various types of cancer imaging and treatment options that can now be mixed and matched in ways previously unimaginable. The unprecedented safety of this nanoparticle in the body is the icing on the cake. We are excited by the possibilities for its use in the clinic," says Dr. Zheng.

The research was financially supported by grants and fellowships from the Ontario Institute for Cancer Research, the Canadian Cancer Society, the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, the Joey and Toby Tanenbaum/Brazilian Ball Chair in Prostate Cancer Research, and in part from the Campbell Family Institute for Cancer Research and the Ministry of Health and Long-Term Care , and The Princess Margaret Hospital Foundation..

*A nanoparticle is a minute molecule with novel properties.

Modified mRNA Is the Key to Novel Anti-Cancer Therapy, Experts Offer

ScienceDaily (Mar. 20, 2011) — Modern gene therapies raise hopes of combating many diseases until now considered terminal. Nowadays, however, the methods are expensive and carry a risk of severe complications. Modifications to ribonucleic acid mRNA introduced by scientists from the Faculty of Physics, University of Warsaw in collaboration with the Louisiana State University are blazing a trail for safer and more effective gene drugs. Clinical trials of the first new-generation anti-cancer vaccine, developed in Germany with the aid of the Polish invention, will begin later this year.

Gene therapies may be useful for the effective treatment of many diseases, including the most malignant forms of cancer. Today, such methods concentrate on changing DNA. Yet manipulating genome is a risky venture. For years, scientists from the Faculty of Physics, University of Warsaw (FUW) have been working on a safer solution: modifying messenger RNA. "In collaboration with the Louisiana State University, we have developed and patented methods for increasing mRNA stability and enhancing its productivity in the production of therapeutic proteins. We are providing biologists with a universal tool which could potentially allow to develop effective vaccines against any form of cancer," explains Jacek Jemielity, PhD (FUW).

On March 16, FUW and LSU signed a contract with the German company BioNTech, granting the licence for the production of modified mRNA. Having obtained the licence, Ribological, a subsidiary of BioNTech developing RNA-based immunotherapeutics against cancer, will begin the first phase of clinical trials of the new-generation anti-cancer vaccine this year.

Proteins perform most of the essential tasks that ensure the proper functioning of a cell. Information on protein structure is stored in the DNA contained in every cell nucleus. In order for the required protein to be produced on the basis of this data, an mRNA acid chain with a copy of the gene containing a given protein structure needs to be formed in a cell nucleus. The production of such mRNA is called transcription. The produced mRNA is transported through nucleus membrane to the cytoplasm, and it is only there, by the process of translation, that the protein can be finally synthesized.

The main focus of traditional medicine is on combating diseases by regulating protein activity in cells through pharmacological agents introduced from outside. Starting from the 1970s, there have been constant attempts to develop different therapies -- gene therapies. Their interference in the transcription or translation is such that proteins with given therapeutic properties are produced directly in cells.

The lifetime of mRNA chains is short: it is usually a matter of hours, not infrequently of minutes. Therapeutic mRNA injected into the organism would be decomposed by enzymes before it could reach the cells and produce the life-saving protein. This is why the main focus of attention has until now been on the modifications of DNA. Yet the interference in the DNA buried in the recesses of a cell nucleus is difficult, expensive and dangerous. "Introduced for therapeutic purposes, a change is permanently recorded in the genome, and its consequences can be hard to predict. We may as well cure one disease and another one will develop. Therefore, already years ago, we turned our attention to mRNA, especially to what may be found at one of the ends of its chain," says Prof. Edward Darżynkiewicz (FUW).

For a chemist, mRNA is a long and monotonous polymer, containing some 2000 nucleosides -- building blocks that come in four varieties only. An atypical structure, however, may be found at one of the ends of mRNA: a specific chemical compound, attached to the rest of the chain by means of a triphosphate bridge. This structure, called a cap, protects the mRNA chain from destructive enzymes. It is also recognized by the eIF4e protein, which initiates protein production in the cytoplasm.

It was due to their own chemical methods that the scientists from FUW have developed and investigated many artificial varieties of cap structure. Several groups of structures discovered in this manner have been submitted for a patent. Compounds in which an oxygen atom in the triphosphate bridge was substituted with a sulphur atom have proven to be particularly significant. "An average mRNA particle consists of eighty thousand atoms; we have changed only one. This slight modification has had some fascinating consequences," says Joanna Kowalska, PhD (FUW). Conducted by the group led by Prof. Roberta E. Rhoads (LSU), investigations of mRNA chains with a new endpoint have proven it is possible to achieve a threefold increase in the lifetime of mRNA in a cell and a fivefold increase in its productivity in protein production. Tests on mice, in turn, conducted in Mainz by the BioNTech company and the local university, have revealed that the mice's immune system response to the given protein was three times stronger than in the case of unmodified mRNA. "These are very exciting results. The improvement obtained by using the modified cap analogs as developed at the University of Warsaw might turn out to be the key for an efficacious RNA-based immunotherapy," states Ugur Sahin, CEO of BioNTech and Professor at the University Medical Center Mainz.

The invention of the Polish scientists is paving the way for using the translation mechanism occurring in the cytoplasm for medical purposes. The new-generation drugs will have many merits. The compound introduced into the organism does not have to penetrate the cell nucleus. The lack of interference in the genome eliminates the risk of mutation, and the limited lifetime of mRNA chains allows a physician to trigger a particular response of the organism only when necessary. What is more, the defense reaction of the organism to foreign mRNA is considerably more specific than in the case of DNA. "Our methods for modifying and developing cap structures work perfectly well in test tubes, which is essential for anyone setting his or her mind on the industrial production of drugs," observes Jacek Jemielity, PhD.

The licence for the use of the methods related to the modifications of mRNA endpoints has just been bought by the German company BioNTech from Mainz. This year they intend to begin the first phase of the clinical trials of a new anti-cancer drug, in which the therapeutic sequences of nucleotides in the mRNA end with a cap modified according to the guidelines laid down by the Polish scientists. The drug will be injected into the lymph nodes. There it will reach the dendritic cells, where the key elements of our immune system, T lymphocytes, will be able to specialize in destroying a protein singled out by the scientists.

Under the terms of the contract, the Faculty of Physics, University of Warsaw has also undertaken to produce modified mRNA endpoints in quantities sufficient to conduct the clinical trials.

Depression Drugs -- SSRIs -- May Reorganize Brain Plasticity, New Research Suggests

ScienceDaily (Mar. 18, 2011) — Selective serotonin reuptake inhibitors (SSRI) such as Prozac are regularly used to treat severe anxiety and depression. They work by immediately increasing the amount of serotonin in the brain and by causing long term changes in brain function. However it can take weeks of treatment before a patient feels any effect and both beneficial effects and side effects can persist after treatment is stopped.

New research investigates physiological changes within the brain that may be caused by selective serotonin reuptake inhibitors.

New research published by BioMed Central's open access journalMolecular Brain investigates physiological changes within the brain that may be caused by SSRI treatment.

The hippocampus is an area of the brain involved in long term memory and spatial awareness, and is involved in symptoms afflicting people with Alzheimer's disease, such as loss of memory and disorientation. Neuronal cells in the hippocampus can change their activity and strength of connections throughout life, a process known as plasticity, which thought to be one of the ways new memories are formed. Altered plasticity is often associated with depression and stress.

Researchers from the Department of Pharmacology, Nippon Medical School, showed that chronic treatment of adult mice with fluoxetine (Prozac) caused changes to granule cells, one of the main types of neuronal cells inside the hippocampus, and to their connections with other neuronal cells. The granule cells appeared to undergo serotonin-dependent 'dematuration', which increased their activity and reversed adult-type plasticity into an immature state. These changes to the cell's plasticity were associated with increased anxiety and in alternating between periods of hyper or hypo activity.

Katsunori Kobayashi explained, "Some of the side effects associated with Prozac in humans, such as anxiety and behavioral switching patterns, may be due to excessive dematuration of granule cells in the hippocampus."

Personlized Dendritic Cell Vaccine Increases Survival in Patients With Deadly Brain Cancer

ScienceDaily (Mar. 18, 2011) — A dendritic cell vaccine personalized for each individual based on the patient's own tumor may increase median survival time in those with a deadly form of brain cancer called glioblastoma, an early phase study at UCLA's Jonsson Comprehensive Cancer Center has found.

Published in the peer-reviewed journal Clinical Cancer Research, the study also identified a subset of patients more likely to respond to the vaccine, those with a subtype of glioblastoma known as mesenchymal, which accounts for about one-third of all cases. This is the first time in brain cancer that a subset of patients more likely to respond to an immunotherapy has been identified, said Dr. Linda Liau, a Jonsson Cancer Center researcher, professor of neurosurgery and senior author of the study.

The study found that the vaccine, administered after the conventional treatments of surgery and radio-chemotherapy, was associated with a median survival of 31.4 months, double the 15 months of historical controls in the published literature. In all, 23 patients were enrolled in the Phase I study that was launched in 2003. Of those, about one third of participants are still alive, some more than eight years after their diagnosis.

The study also found that the vaccine was safe and that side effects were minimal, limited mostly to flu-like symptoms and rashes near the vaccine injection site.

"This is quite an encouraging result, especially in an early phase study like this," Liau said. "It's promising to see patients with this type of brain cancer experience such long survivals."

However, Liau cautioned that the findings need to be confirmed in larger, randomized studies. She currently is leading a Phase II, randomized study at UCLA testing the vaccine in newly diagnosed glioblastoma patients. The patients will receive either the standard of care (surgery, radiation and chemotherapy) or the standard of care plus the vaccine. The study is a multi-center trial, and UCLA is the only site offering it in California.

It has recently been discovered that there are at least three subtypes of glioblastoma: proneural, proliferative and mesenchymal. During the course of her study, Liau and her colleagues saw that one group of patients seemed to be responding very well to the vaccine and examined their tumors using a microarray analysis of their DNA. They found that those with a gene expression profile identifying their cancers as mesenchymal responded better to the vaccine.

The finding was surprising, Liau said, because patients with the mesenchymal subtype generally have more aggressive disease and shorter survival than those with the other subtypes. In patients with this type of glioblastoma, several genes that modulate the immune system are dysregulated, meaning they don't work properly. Liau speculates that the vaccine helped replenish the immune system, allowing that subset of patients to more easily fight the brain cancer.

"Glioblastoma remains one of the diseases for which there is no curative therapy … and the prognosis for patients with primary malignant brain tumors remains dismal," the study states. "Our results suggest that the mesenchymal gene expression profile may identify an immunogenic sub-group of glioblastoma that may be more responsive to immune-based therapies."

Brad Silver, 41, who grew up in Southern California and now lives in a Cleveland suburb, was diagnosed with glioblastoma in 2003 and was told that he had, at best, two months to live. He was stunned.

"I was 33 years and my wife was seven months pregnant with my son," said Silver, a college water polo instructor. 'I didn't think I was going to live to see my son born, let alone grow up."

Silver sought a second opinion at UCLA and the golf-ball sized tumor in his left lateral lobe was removed. He underwent radiation and chemotherapy and enrolled in the vaccine clinical trial. Today, eight years later, he remains cancer free. His son, named Brad Silver II and a miniature version of his dad, will celebrate his eighth birthday in April.

"If I had listened to that first doctor, I would not be here today. If not for Dr. Liau, I would not be here today," Silver said. "I'm 100 percent back to being me because of this vaccine and that clinical trial. It's almost unbelievable."

The vaccine preparation is personalized for each individual. After the tumor is removed, Liau and her team extract the proteins, which provide the antigens for the vaccine to target. After radiation and chemotherapy, the white blood cells are taken from the patient and grown into dendritic cells, a type of white blood cell that is an antigen-presenting cell. The vaccine preparation from this point takes about two weeks, as the dendritic cells are grown together with the patient's own tumor antigens. The tumor-pulsed dendritic cells are then injected back in to the body, prompting the T cells to go after the tumor proteins and fight the malignant cells.

"The body may have trouble fighting cancer because the immune system doesn't recognize it as a foreign invader," Liau said. "The dendritic cells activate the patient's T cells to attack the tumor, basically teaching the immune system to respond to the tumor."

The individualized vaccine is injected into the patient in three shots given every two weeks for a total of six weeks. Booster shots are given once every three months until the cancer recurs. Patients are scanned every two months to monitor for disease recurrence, Liau said.

This study was funded in part by the National Institutes of Health, the Philip R. and Kenneth A. Jonsson Foundation, the Neidorf Family Foundation, STOP Cancer, the Ben & Catherine Ivy Foundation and Northwest Biotherapeutics, Inc.

World First: Localized Delivery of an Anti-Cancer Drug by Remote-Controlled Microcarriers

ScienceDaily (Mar. 18, 2011) — Soon, drug delivery that precisely targets cancerous cells without exposing the healthy surrounding tissue to the medication's toxic effects will no longer be an oncologist's dream but a medical reality, thanks to the work of Professor Sylvain Martel, Director of the Nanorobotics Laboratory at Polytechnique Montréal.

Left: Navigation using magnetic resonance in the hepatic artery. Right: Image of liver using magnetic resonance. Key: Blue dots represent therapeutic magnetic microcarriers (TMMC); + represent anticancer agents; Red oval is part of the liver; Red bar is the catheter.

Known for being the world's first researcher to have guided a magnetic sphere through a living artery, Professor Martel is announcing a new breakthrough in the field of nanomedicine. Using a magnetic resonance imaging (MRI) system, his team successfully guided microcarriers loaded with a dose of anti-cancer drug through the bloodstream of a living rabbit, right up to a targeted area in the liver, where the drug was successfully administered. This is a medical first that will help improve chemoembolization, a current treatment for liver cancer.

Microcarriers on a mission

The therapeutic magnetic microcarriers (TMMCs) were developed by Pierre Pouponneau, a PhD candidate under the joint direction of Professors Jean-Christophe Leroux and Martel. These tiny drug-delivery agents, made from biodegradable polymer and measuring 50 micrometers in diameter -- just under the breadth of a hair -- encapsulate a dose of a therapeutic agent (in this case, doxorubicin) as well as magnetic nanoparticles.

Essentially tiny magnets, the nanoparticles are what allow the upgraded MRI system to guide the microcarriers through the blood vessels to the targeted organ. During the experiments, the TMMCs injected into the bloodstream were guided through the hepatic artery to the targeted part of the liver where the drug was progressively released.

The results of these in-vivo experiments have recently been published in the journal Biomaterials and the patent describing this technology has just been issued in the United States.