Nanoparticle therapy could deliver double blow to cancer

 

A new cancer therapy using nanoparticles to deliver a combination therapy direct to cancer cells could be on the horizon, thanks to research from the University of East Anglia.

The new therapy, which has been shown to make breast cancer and prostate cancer tumours more sensitive to chemotherapy, is now close to entering clinical trials.

And scientists at UEA’s Norwich Medical School have confirmed that it can be mass-produced, making it a viable treatment if proved effective in human trials.

Using nanoparticles to get drugs directly into a tumour is a growing area of cancer research. The technology developed at UEA is the first of its kind to use nanoparticles to deliver two drugs in combination to target cancer cells.

The drugs, already approved for clinical use, are an anti-cancer drug called docetaxel, and fingolimod, a multiple sclerosis drug that makes tumours more sensitive to chemotherapy.

Fingolimod cannot currently be used in cancer treatment because it also supresses the immune system, leaving patients with dangerously low levels of white blood cells.

And while docetaxel is used to treat many cancers, particularly breast, prostate, stomach, head and neck and some lung cancers, its toxicity can also lead to serious side effects for patients whose tumours are chemo-resistant.

Because the nanoparticles developed by the UEA team can deliver the drugs directly to the tumour site, these risks are vastly reduced. In addition, the targeted approach means less of the drug is needed to kill off the cancer cells.

“So far nobody has been able to find an effective way of using fingolimod in cancer patients because it’s so toxic in the blood,” explains lead researcher, Dr. Dmitry Pshezhetskiy from the Norwich Medical School at UEA.

“We’ve found a way to use it that solves the toxicity problem, enabling these two drugs to be used in a highly targeted and powerful combination.”

The UEA researchers worked with Precision NanoSystems’ Formulation Solutions Team who used their NanoAssemblr technology to investigate if it was possible to synthesise the different components of the therapy at an industrial scale.

Following successful results on industrial scale production, and a published international patent application, the UEA team is now looking for industrial partners and licensees to move the research towards a phase one clinical trial.

Also included within the nanoparticle package are molecules that will show up on an MRI scan, enabling clinicians to monitor the spread of the particles through the body.

The team has already carried out trials in mice that show the therapy is effective in reducing breast and prostate tumours. These results were published in 2017.

“Significantly, all the components used in the therapy are already cleared for clinical use in Europe and the United States,” says Dr. Pshezhetskiy. “This paves the way for the next stage of the research, where we’ll be preparing the therapy for patient trials.”

“New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth,” by Heba Alshaker, Qi Wang, Shyam Srivats, Yimin Chao, Colin Cooper and Dmitri Pchejetski was published in Breast Cancer Research and Treatment on 10 July 2017.

“Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer,” by Qi Wang, Heba Alshaker, Torsten Böhler, Shyam Srivats, Yimin Chao, Colin Cooper and Dmitri Pchejetski was published in Scientific Reports on 19 July 2017.

 Explore further: Lipid molecules can be used for cancer growth

More information: Heba Alshaker et al. New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth, Breast Cancer Research and Treatment (2017). DOI: 10.1007/s10549-017-4380-8

Qi Wang et al. Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer, Scientific Reports (2017). DOI: 10.1038/s41598-017-06142-x

Read more at: https://phys.org/news/2018-08-nanoparticle-therapy-cancer.html#jCp

“Artificial Blood” : Part I

June 10, 2013 by tildabarliya

“Artificial blood” has been the main focus of research in the past few years (1) and refers to a substance used to mimic and fulfill some functions of biological function.  Author: Tilda Barliya PhD

A number of driving forces have led to the development of artificial blood substitutes (1):

1.  The military, which requires a large volume of blood products that can be easily stored and readily shipped to the site of casualties.
2.  HIV; with the advent of this virus, the medical community and the public suddenly became aware of the significance of transfusion-transmitted diseases and became concerned about the safety of the national blood supply.
3. The growing shortage of blood donors. Approximately 60% of the population is eligible to donate blood, but fewer than 5% are regular blood donors.
4. Short shelf-life of the blood products.
5. High hospital needs: cancer patients, transplantation etc

Artificial blood products offer many important benefits:

• Readily available
• Have a long shelf life
• Can undergo filtration and pasteurization processes
• Do not require blood typing (i.e A,B AB, O)
• Do not appear to cause immunosuppression in the recipient.

Researchers have focused their efforts on creating artificial substitutes for 2 important functions of blood: A) oxygen transport by red blood cells and B) hemostasis by platelets (1).

A) Red Cell Substitutes:

• Hemoglobin based
• Perfluorocarbon (PFC) based

A1) Hemoglobin-based

The hemoglobin-based substitutes use hemoglobin from several different sources (1):

• Human – Human hemoglobin is obtained from donated blood that has reached its expiration date and from the small amount of red cells collected as a by-product during plasma donation.
• Animal – Animal hemoglobin is obtained from cows. This source creates some apprehension regarding the possible transmission of animal pathogens, specifically bovine spongiform encephalopathy.
• Recombinant – Recombinant hemoglobin is obtained by inserting the gene for human hemoglobin into bacteria and then isolating the hemoglobin from the culture.

Understanding hemoglobin, its transition from a monomer to a tetramer and the way it needs to be linked to the surface of the artificial blood cells is of major issue and will be discussed in more depth in part II.

A2) Perfluorocarbon (PFC) based

PFCs are synthetic hydrocarbons with halide substitutions and are about 1/100th the size of a red blood cell. These solutions have the capacity to dissolve up to 50 times more oxygen than plasma. Because PFC solutions are modified hydrocarbons, however, they do not mix well with blood and must be emulsified with lipids or oils. The PFCs are inert products. After infusion, the molecules vaporize and are then exhaled over several days (1).

B) Platelet Substitutes:

Platelets are also at very high need due to their extremely short shelf-life (5 days) and very limited supply. Several methods have been utilized to create platelet substitutes including:

• Infusible platelet membranes
• Thrombospheres
• Lyophilized human platelet product

Use and need for HLA antigen or platelet antigens, fibrinogen proteins and aggregation factors will be further discussed in part II.

In Summary:

The growing need for blood supply due to short shelf-life, limited supply and increase in disease/injured population have urged researchers to look for blood substitutes.   Although the many years of research and profound progress that have been made, there’s plenty of disadvantages having complications and  limited clinical benefits. The topic of blood substitutes will be further discussed in part II, highlighting the different substitutes that were developed, those which entered clinical trails, and the potential use of nanotechnology in this field of research.

Reference:

1. Lesley Kresie. Artificial blood: an update on current red cell and platelet substitutes. Proc (Bayl Univ Med Cent). 2001 April; 14(2): 158–161 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1291332/

2. By: Tony Rairden. Synthetic Red Blood Cells Developed. http://www.nanotech-now.com/news.cgi?story_id=35993

3. By: Abdu I. Alayash. BLOOD SUBSTITUTES: Working to Fulfill a Dream. FDA voice. http://blogs.fda.gov/fdavoice/index.php/2012/06/blood-substitutes-working-to-fulfill-a-dream/

4. Jiin-Yu Chen, Michelle Scerbo, and George Kramer. A Review of Blood Substitutes: Examining The History, Clinical Trial Results, and Ethics of Hemoglobin-Based Oxygen Carriers. Clinics (San Paulo) 2009 August; 64(8): 803-813. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728196/

Nano-Tech Sealant closes wounds and hinders bacterial infection

A new joining material for laser welding tissue during operations has the  potential to produce stronger seals and provide an alternative to sutures and  stapling in intestinal surgery, scientists report.

Their study, which involves use of a gold-based sealing material, appears in  the journal ACS Nano.

Kaushal Rege and colleagues from Arizona State University explained in a  statement that laser tissue welding (LTW) is a stitch-free surgical method for  connecting and sealing blood vessels, cartilage in joints, the liver, the  urinary tract and other tissues.

Read more:  http://www.theengineer.co.uk/military-and-defence/news/sealant-closes-wounds-and-hinders-bacterial-infection/1016263.article#ixzz2TDXuCH98

Nanotechnology Facilitates More Targeted Treatments

Nanotechnology in Implantable

Medical Devices

 Topics Covered:

Introduction: What is Nanomedicine? Implantable Biosensors      Implantable Glucose Sensors Integration with Monitoring Systems      Chronic Disease Monitoring      Implantable Cardioverter-Defibrillators Implantable Drug Delivery Systems Regulatory Challenges Conclusions Sources

Introduction: What is Nanomedicine?

The term nanomedicine encompasses a broad range of technologies and materials. Types of nanomaterials that have been investigated for use as drugs, drug carriers or other nanomedicinal agents include:

• Dendrimers
• Polymers
• Liposomes
• Micelles
• Nanocapsules
• Nanoparticles
• Nanoemulsions

Around 250 nanomedicine products are being tested or used in humans, according to a new report that analyzed evolving trends in this sector. According to experts, the long-term impact of nanomedicinal products on human health and the environment is still not certain.

During the last 10 years, there has been steep growth in development of devices that integrate nanomaterials or other nanotechnology. Enhancement of in vivo imaging and testing has been a highly popular area of research, followed by bone substitutes and coatings for implanted devices.

Active and passive cell targeting will continue to be an important focus in nanomedicine. Targeted nano-enhanced solutions have been shown to often enhance existing treatments, and some nanomedicinal techniques are being developed which work as diagnosis and treatment stages simultaneously.

The unknown factor as far as nanotechnology is concerned is whether the increased production, exposure and handling of products and nanomaterials will result in serious impact on the environment and humans. It is possible that toxicity will be the restricting factor for the public acceptance and commercial success of nanotechnology-based products.

Advances in modern medicine are increasingly relying on electronic devices implanted inside the patient’s body. Nanotechnology allows us to create materials and coatings to construct these devices that are fully biocompatible. Image credit: NASA

Implantable Biosensors

Micro-electromechanical systems (MEMS) and silicon chips that are capable of implantation within the human body may permit interfacing semiconductor devices with living tissues.

Implantable Glucose Sensors

A molecular nanotechnology company Zyvex, specializing in MEMS, chose Diabetech LP as its medical device commercialization and development partner for their wireless sensor implant targeting real-time blood glucose levels in the body. Their novel portable device for patients does not only display the glucose levels from the implant to the patient but also conveys automatically in real time the information to GlucoDynamix, the clinical management system of Diabetech.

Likewise Digital Angel received a patent in October 2006 for their embedded biosensor system. A glucose-sensing RFID microchip is implanted in the patient. The chip can measure glucose levels precisely and can convey the same back to a digital scanner.

This will pave the way for implantable biosensors that can evaluate disease indicators or symptoms and regulate drug release to help in disease treatment.

For example, an implanted glucose sensor can be coupled with an insulin release system and help sufferers of diabetes control their sugar levels without the need for insulin injection or pin-prick tests.

While biocompatibility and long-term stability are being addressed, a number of prototypes have begun to emerge for the management of patients having acute diabetes or to treat epilepsy and other debilitating neurological disorders, and to monitor patients suffering from heart disease.

Integration with Monitoring Systems

Virtual Medical World published an article in November 2005 that stated that a research project financed by the Academy of Finland was underway to develop of minute subcutaneous sensors that can be used for active monitoring of the heart or prosthetic joint function even over long time periods.

For instance, a subcutaneous EKG monitor can detect cardiac arrhythmia, and this data can be wirelessly transmitted to the PC or mobile phone of the physician.

Chronic Disease Monitoring

Guidant is a specialist in treating vascular and cardiac disease and has invested in CardioMEMS based on an article published in Virtual Medical Worlds in November, 2005. CardioMEMS develops novel devices based on MEMS technology to help physicians monitor remotely the progress of chronic diseases like heart failure.

The University of Texas received a grant in 2006 to fund the research and development of an implantable intravascular biosensor that will monitor disease and health progression.

The nano pressure sensor can monitor pressure within the cardiovascular system while the data is transmitted to a wristwatch-like data collection device. The data is transmitted by this external device to a central remote monitoring station where it can be seen by health care providers in real time.

Implantable Cardioverter-Defibrillators

The implantable cardioverter-defibrillator (ICD) has transformed treatment of patients at risk for sudden cardiac death because of ventricular tachyarrhythmias.

The Medtronic CareLink Monitor is a small, convenient device that allows patients to gather information by holding an antenna over the implanted cardiac device. The data is automatically downloaded by the monitor and sent through an internet connection directly to the secure Medtronic CareLink Network. The patient’s data is accessed by clinicians by logging onto a website from any internet-connected computer in their home or office or through the laptop while travelling.

The ICD systems also include portable computer systems that program the implantable cardioverter defibrillators or pacemakers. This interactive system has an LCD touch screen with a user-friendly interface that helps clinicians retrieve and study patient information during routine follow-up visits and easily makes programming changes to the implanted devices.

http://youtu.be/dlert3zh8fo

This video demonstrates how an Implantable Cardioverter Defibrillator or ICD is used to treat dangerously fast or irregular heart beats. Run time: 0:58s.

 

Implantable Drug Delivery Systems

More and more advances in modern medicine are relying on electronic devices implanted inside the patient’s body, to minimize the need for regular examinations, surgery, or in-patient time. Nanotechnology allows us to create materials and coatings to construct these devices that are fully biocompatible, so that they integrate seamlessly with the body’s systems.

Implantable drug delivery systems can deliver small amounts of drugs on a regular basis, so that the patient does not need to be injected. Implantable drug delivery systems give a more consistent drug level in the blood compared to injections, which often makes the treatment more effective and reduces side effects.

By using active monitoring capabilities built into the device, the dosage can be adjusted to suit changes in physical activity, temperature changes and other variables.

In treatments such as chemotherapy, which are usually aimed at a specific area of the body, the device can be implanted near the target area, keeping drug concentration much lower in the rest of the body.

Smart implantable insulin pumps are designed so as to offer relief for people with Type I diabetes. These are implantable, active drug delivery devices that build on and go beyond the capabilities offered by passive glucose biosensors.

Regulatory Challenges

Nanomaterials and nanotechnology offer significant promise in the medical device community, as well as many other industry sectors. They also pose a number of regulatory challenges, which as time goes by will become more pressing than the technical challenges. Some of the difficulaties in regulating nanomedical devices are as follows:

• It is important to determine the intended use of the product, but it can be difficult to define uses among several stakeholders.
• The indicated patient population must be understood, and there should be clarity about the claimed benefits of a product.
• Throughout the submission process of products for market approval, it is important to communicate with the FDA or other relevant authority. Manufacturing processes are highly critical for a successful submission. Marketing, sales, labeling and international issues, training and education are all part of this effort.

Conclusions

Nanomedicine will transform healthcare in the coming years, changing the day-to-day business practices of health care organizations and improving how patient care is provided.

Health care organizations must monitor innovations continually, perform clinical trials and developments related to this area and also other evolving health IT solutions.

There is a lot of research going on in this area; however not many products have reached the commercialization stage. There is still a long way to go before all these promising devices become a part of our daily lives.

Sources

• Nanotechnology: Observing the regulatory frontier – Packaging World
• Nanomedicine: Big Potential for Small Products – Huff Post Tech
• Medical Benefits of Molecular Manufacturing – CRN
• Implantable Medical Devices and EHR Systems – Virtual Medical World
• MEMS for implantable Medical Devices – AZoNano

Nanoparticles Enable Earlier Cancer Diagnosis

From Science Daily, Dec. 17, 2012 — Finding ways to diagnose cancer earlier could greatly improve the chances of survival for many patients. One way to do this is to look for specific proteins secreted by cancer cells, which circulate in the bloodstream. However, the quantity of these biomarkers is so low that detecting them has proven difficult.

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 A new technology developed at MIT may help to make biomarker detection much easier. The researchers, led by Sangeeta Bhatia, have developed nanoparticles that can home to a tumor and interact with cancer proteins to produce thousands of biomarkers, which can then be easily detected in the patient’s urine.

This biomarker amplification system could also be used to monitor disease progression and track how tumors respond to treatment, says Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at MIT.

“There’s a desperate search for biomarkers, for early detection or disease prognosis, or looking at how the body responds to therapy,” says Bhatia, who is also a member of MIT’s David H. Koch Institute for Integrative Cancer Research. She adds that the search has been complicated because genomic studies have revealed that many cancers, such as breast cancer, are actually groups of several diseases with different genetic signatures.

The MIT team, working with researchers from Beth Israel Deaconess Medical Center, described the new technology in a paper appearing in Nature Biotechnology on Dec. 16. Lead author of the paper is Gabriel Kwong, a postdoc in MIT’s Institute for Medical Engineering and Science and the Koch Institute.

Amplifying cancer signals

Cancer cells produce many proteins not found in healthy cells. However, these proteins are often so diluted in the bloodstream that they are nearly impossible to identify. A recent study from Stanford University researchers found that even using the best existing biomarkers for ovarian cancer, and the best technology to detect them, an ovarian tumor would not be found until eight to 10 years after it formed.

“The cell is making biomarkers, but it has limited production capacity,” Bhatia says. “That’s when we had this ‘aha’ moment: What if you could deliver something that could amplify that signal?”

Serendipitously, Bhatia’s lab was already working on nanoparticles that could be put to use detecting cancer biomarkers. Originally intended as imaging agents for tumors, the particles interact with enzymes known as proteases, which cleave proteins into smaller fragments.

Cancer cells often produce large quantities of proteases known as MMPs. These proteases help cancer cells escape their original locations and spread uncontrollably by cutting through proteins of the extracellular matrix, which normally holds cells in place.

The researchers coated their nanoparticles with peptides (short protein fragments) targeted by several of the MMP proteases. The treated nanoparticles accumulate at tumor sites, making their way through the leaky blood vessels that typically surround tumors. There, the proteases cleave hundreds of peptides from the nanoparticles, releasing them into the bloodstream.

The peptides rapidly accumulate in the kidneys and are excreted in the urine, where they can be detected using mass spectrometry.

This new system is an exciting approach to overcoming the problem of biomarker scarcity in the body, says Sanjiv Gambhir, chairman of the Department of Radiology at Stanford University School of Medicine. “Instead of being dependent on the body to naturally shed biomarkers, you’re sampling the site of interest and causing biomarkers that you engineered to be released,” says Gambhir, who was not part of the research team.

Distinctive signatures

To make the biomarker readings as precise as possible, the researchers designed their particles to express 10 different peptides, each of which is cleaved by a different one of the dozens of MMP proteases. Each of these peptides is a different size, making it possible to distinguish them with mass spectrometry. This should allow researchers to identify distinct signatures associated with different types of tumors.

In this study, the researchers tested their nanoparticles’ ability to detect the early stages of colorectal cancer in mice, and to monitor the progression of liver fibrosis.

Liver fibrosis is an accumulation of scarring in response to liver injury or chronic liver disease. Patients with this condition have to be regularly monitored by biopsy, which is expensive and invasive, to make sure they are getting the right treatment. In mice, the researchers found that the nanoparticles could offer much more rapid feedback than biopsies.

They also found that the nanoparticles could accurately reveal the early formation of colorectal tumors. In ongoing studies, the team is studying the particles’ ability to measure tumor response to chemotherapy and to detect metastasis.

The research was funded by the National Institutes of Health and the Kathy and Curt Marble Cancer Research Fund.

Breakthrough nanoparticle halts multiple sclerosis

Posted: Nov 18th, 2012

(Nanowerk News) In a breakthrough for nanotechnology and multiple sclerosis, a biodegradable nanoparticle turns out to be the perfect vehicle to stealthily deliver an antigen that tricks the immune system into stopping its attack on myelin and halt a model of relapsing remitting multiple sclerosis (MS) in mice, according to new Northwestern Medicine research.

The new nanotechnology also can be applied to a variety of immune-mediated diseases including Type 1 diabetes, food allergies and airway allergies such as asthma.

In MS, the immune system attacks the myelin membrane that insulates nerves cells in the brain, spinal cord and optic nerve. When the insulation is destroyed, electrical signals can’t be effectively conducted, resulting in symptoms that range from mild limb numbness to paralysis or blindness. About 80 percent of MS patients are diagnosed with the relapsing remitting form of the disease.

The Northwestern nanotechnology does not suppress the entire immune system as do current therapies for MS, which make patients more susceptible to everyday infections and higher rates of cancer. Rather, when the nanoparticles are attached to myelin antigens and injected into the mice, the immune system is reset to normal. The immune system stops recognizing myelin as an alien invader and halts its attack on it.

“This is a highly significant breakthrough in translational immunotherapy,” said Stephen Miller, a corresponding author of the study and the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. “The beauty of this new technology is it can be used in many immune-related diseases. We simply change the antigen that’s delivered.”

“The holy grail is to develop a therapy that is specific to the pathological immune response, in this case the body attacking myelin,” Miller added. “Our approach resets the immune system so it no longer attacks myelin but leaves the function of the normal immune system intact.”

The nanoparticle, made from an easily produced and already FDA-approved substance, was developed by Lonnie Shea, professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and Applied Science.

“This is a major breakthrough in nanotechnology, showing you can use it to regulate the immune system,” said Shea, also a corresponding author. The paper will be published Nov. 18 in the journal Nature Biotechnology.

Miller and Shea are also members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. In addition, Shea is a member of the Institute for BioNanotechnology in Medicine and the Chemistry of Life Processes Institute.

CLINICAL TRIAL FOR MS TESTS SAME APPROACH — WITH KEY DIFFERENCE

The study’s method is the same approach now being tested in multiple sclerosis patients in a phase I/II clinical trial — with one key difference. The trial uses a patient’s own white blood cells — a costly and labor intensive procedure — to deliver the antigen. The purpose of the new study was to see if nanoparticles could be as effective as the white blood cells as delivery vehicles. They were.

THE BIG NANOPARTICLE ADVANTAGE FOR IMMUNOTHERAPY

Nanoparticles have many advantages; they can be readily produced in a laboratory and standardized for manufacturing. They would make the potential therapy cheaper and more accessible to a general population. In addition, these nanoparticles are made of a polymer called Poly(lactide-co-glycolide) (PLG), which consists of lactic acid and glycolic acid, both natural metabolites in the human body. PLG is most commonly used for biodegradable sutures.

The fact that PLG is already FDA approved for other applications should facilitate translating the research to patients, Shea noted. Miller and Shea tested nanoparticles of various sizes and discovered that 500 nanometers was most effective at modulating the immune response.

“We administered these particles to animals who have a disease very similar to relapsing remitting multiple sclerosis and stopped it in its tracks,” Miller said. “We prevented any future relapses for up to 100 days, which is the equivalent of several years in the life of an MS patient.”

Shea and Miller also are currently testing the nanoparticles to treat Type one diabetes and airway diseases such as asthma.

NANOPARTICLES FOOL IMMUNE SYSTEM

In the study, researchers attached myelin antigens to the nanoparticles and injected them intravenously into the mice. The particles entered the spleen, which filters the blood and helps the body dispose of aging and dying blood cells. There, the particles were engulfed by macrophages, a type of immune cell, which then displayed the antigens on their cell surface. The immune system viewed the nanoparticles as ordinary dying blood cells and nothing to be concerned about. This created immune tolerance to the antigen by directly inhibiting the activity of myelin responsive T cells and by increasing the numbers of regulatory T cells which further calmed the autoimmune response.

“The key here is that this antigen/particle-based approach to induction of tolerance is selective and targeted. Unlike generalized immunosuppression, which is the current therapy used for autoimmune diseases, this new process does not shut down the whole immune system,” said Christine Kelley, National Institute of Biomedical Imaging and Bioengineering director of the division of Discovery Science and Technology at the National Institutes of Health, which supported the research. “This collaborative effort between expertise in immunology and bioengineering is a terrific example of the tremendous advances that can be made with scientifically convergent approaches to biomedical problems.”

“We are proud to share our expertise in therapeutics development with Dr. Stephen Miller’s stellar team of academic scientists,” said Scott Johnson, CEO, president and founder of the Myelin Repair Foundation. “The idea to couple antigens to nanoparticles was conceived in discussions between Dr. Miller’s laboratory, the Myelin Repair Foundation’s drug discovery advisory board and Dr. Michael Pleiss, a member of the Myelin Repair Foundation’s internal research team, and we combined our efforts to focus on patient-oriented, clinically relevant research with broad implications for all autoimmune diseases. Our unique research model is designed to foster and extract the innovation from the academic science that we fund and transition these technologies to commercialization. The overarching goal is to ensure this important therapeutic pathway has its best chance to reach patients, with MS and all autoimmune diseases.”

Source: Northwestern University

Read more: http://www.nanowerk.com/news2/newsid=27513.php#ixzz2CfJ05yyZ

Nanotechnology and MRI imaging

October 17, 2012 by tildabarliya

Author: Tilda Barliya PhD via Pharmaceutical Intelligence: http://pharmaceuticalintelligence.com/2012/10/17/nanotechnology-and-mri-imaging/

The recent advances of “molecular and medical imaging” as an integrated discipline in academic medical centers has set the stage for an evolutionary leap in diagnostic imaging and therapy. Molecular imaging is not a substitute for the traditional process of image formation and interpretation, but is intended to improve diagnostic accuracy and sensitivity.

Medical imaging technologies allow for the rapid diagnosis and evaluation of a wide range of pathologies. In order to increase their sensitivity and utility, many imaging technologies such as CT and MRI rely on intravenously administered contrast agents. While the current generation of contrast agents has enabled rapid diagnosis, they still suffer from many undesirable drawbacks including a lack of tissue specificity and systemic toxicity issues. Through advances made in nanotechnology and materials science, researchers are now creating a new generation of contrast agents that overcome many of these challenges, and are capable of providing more sensitive and specific information (1)

Magnetic resonance imaging (MRI) contrast enhancement for molecular imaging takes advantage of superb and tunable magnetic properties of engineered magnetic nanoparticles, while a range of surface chemistry offered by nanoparticles provides multifunctional capabilities for image-directed drug delivery. In parallel with the fast growing research in nanotechnology and nanomedicine, the continuous advance of MRI technology and the rapid expansion of MRI applications in the clinical environment further promote the research in this area.

It is well known that magnetic nanoparticles, distributed in a magnetic field, create extremely large microscopic field gradients. These microscopic field gradients cause substantial diphase and shortening of longitudinal relaxation time (T1) and transverse relaxation time (T2 and T2*) of nearby nuclei, e.g., proton in the case of most MRI applications. The magnitudes of MRI contrast enhancement over clinically approved conventional gadolinium chelate contrast agents combined with functionalities of biomarker specific targeting enable the early detection of diseases at the molecular and cellular levels with engineered magnetic nanoparticles. While the effort in developing new engineered magnetic nanoparticles and constructs with new chemistry, synthesis, and functionalization approaches continues to grow, the importance of specific material designs and proper selection of imaging methods have been increasingly recognized (2)

Earlier investigations have shown that the MRI contrast enhancement by magnetic nanoparticles is highly related to their composition, size, surface properties, and the degree of aggregation in the biological environment.

Therefore, understanding the relationships between these intrinsic parameters and relaxivities of nuclei under influence of magnetic nanoparticles can provide critical information for predicting the properties of engineered magnetic nanoparticles and enhancing their performance in the MRI based theranostic applications. On the other hand, new contrast mechanisms and imaging strategies can be applied based on the novel properties of engineered magnetic nanoparticles. The most common MRI sequences, such as the spin echo (SE) or fast spin echo (FSE) imaging and gradient echo (GRE), have been widely used for imaging of magnetic nanoparticles due to their common availabilities on commercial MRI scanners. In order to minimize the artificial effect of contrast agents and provide a promising tool to quantify the amount of imaging probe and drug delivery vehicles in specific sites, some special MRI methods, such as  have been developed recently to take maximum advantage of engineered magnetic NPs

• off-resonance saturation (ORS) imaging
• ultrashort echo time (UTE) imaging

Because one of the major limitations of MRI is its relative low sensitivity, the strategies of combining MRI with other highly sensitive, but less anatomically informative imaging modalities such as positron emission tomography (PET) and NIRF imaging, are extensively investigated. The complementary strengths from different imaging methods can be realized by using engineered magnetic nanoparticles via surface modifications and functionalizations. In order to combine optical or nuclear with MR for multimodal imaging, optical dyes and radio-isotope labeled tracer molecules are conjugated onto the moiety of magnetic nanoparticles

Since most functionalities assembled by magnetic nanoparticles are accomplished by the surface modifications, the chemical and physical properties of nanoparticle surface as well as surface coating materials have considerable effects on the function and ability of MRI contrast enhancement of the nanoparticle core.

The longitudinal and transverse relaxivities, Ri (i=1, 2), defined as the relaxation rate per unit concentration (e.g., millimole per liter) of magnetic ions, reflects the efficiency of contrast enhancement by the magnetic nanoparticles as MRI contrast agents. In general, the relaxivities are determined, but not limited, by three key aspects of the magnetic nanoparticles:

1. Chemical composition,
2. Size of the particle or construct and the degree of their aggregation
3. Surface properties that can be manipulated by the modification and functionalization.

(It is also recognized that the shape of the nanoparticles can affect the relaxivities and contrast enhancement. However these shaped particles typically have increased sizes, which may limit their in vivo applications. Nevertheless, these novel magnetic nanomaterials are increasingly attractive and currently under investigation for their applications in MRI and image-directed drug delivery).

Composition Effect: The composition of magnetic nanoparticles can significantly affect the contrast enhancing capability of nanoparticles because it dominates the magnetic moment at the atomic level. For instance, the magnetic moments of the iron oxide nanoparticles, mostly used nanoparticulate T2 weighted MRI contrast agents, can be changed by incorporating other metal ions into the iron oxide.  The composition of magnetic nanoparticles can significantly affect the contrast enhancing capability of nanoparticles because it dominates the magnetic moment at the atomic level. For instance, the magnetic moments of the iron oxide nanoparticles, mostly used nanoparticulate T2 weighted MRI contrast agents, can be changed by incorporating other metal ions into the iron oxide.

Size Effect: The dependence of relaxation rates on the particle size has been widely studied both theoretically and experimentally. Generally the accelerated diphase, often described by the R2* in magnetically inhomogeneous environment induced by magnetic nanoparticles, is predicted into two different regimes. For the relatively small nanoparticles, proton diffusion between particles is much faster than the resonance frequency shift. This resulted in the relative independence of T2 on echo time. The values for R2 and R2*are predicted to be identical. This process is called “motional averaging regime” (MAR). It has been well demonstrated that the saturation magnetization Ms increases with the particle size. A linear relationship is predicted between Ms1/3 and d-1. Therefore, the capability of MRI signal enhancement by nanoparticles correlates directly with the particle size. 

Surface Effect: MRI contrast comes from the signal difference between water molecules residing in different environments that are under the effect of magnetic nanoparticles. Because the interactions between water and the magnetic nanoparticles occur primarily on the surface of the nanoparticles, surface properties of magnetic nanoparticles play important roles in their magnetic properties and the efficiency of MRI contrast enhancement. As most biocompatible magnetic nanoparticles developed for in vivo applications need to be stabilized and functionalized with coating materials, the coating moieties can affect the relaxation of water molecules in various forms, such as diffusion, hydration and hydrogen binding.

The early investigation carried at by Duan et al suggested that hydrophilic surface coating contributes greatly to the resulted MRI contrast effect. Their study examined the proton relaxivities of iron oxide nanocrystals coated by copolymers with different levels of hydrophilicity including: poly(maleic acid) and octadecene (PMO), poly(ethylene glycol) grated polyethylenimine (PEG-g-PEI), and hyperbranched polyethylenimine (PEI). It was found that proton relaxivities of those IONPs depend on the surface hydrophilicity and coating thickness in addition to the coordination chemistry of inner capping ligands and the particle size.

The thickness of surface coating materials also contributed to the relaxivity and contrast effect of the magnetic nanoparticles. Generally, the measured T2 relaxation time increases as molecular weight of PEG increases.

In Summary

Much progress has taken place in the theranostic applications of engineered magnetic nanoparticles, especially in MR imaging technologies and nanomaterials development. As the feasibilities of magnetic nanoparticles for molecular imaging and drug delivery have been demonstrated by a great number of studies in the past decade, MRI guiding and monitoring techniques are desired to improve the disease specific diagnosis and efficacy of therapeutics. Continuous effort and development are expected to be focused on further improvement of the sensitivity and quantifications of magnetic nanoparticles in vivo for theranostics in future.

The new design and preparation of magnetic nanoparticles need to carefully consider the parameters determining the relaxivities of the nanoconstructs. Sensitive and reliable MRI methods have to be established for the quantitative detection of magnetic nanoparticles. The new generations of magnetic nanoparticles will be made not only based on the new chemistry and biological applications, but also with combined knowledge of contrast mechanisms and MRI technologies and capabilities. As new magnetic nanoparticles are available for theranostic applications, it is anticipated that new contrast mechanism and MR imaging strategies can be developed based on the novel properties of engineered magnetic nanoparticles.

References:

1http://www.omicsonline.org/2157-7439/2157-7439-2-115.php

2http://www.clinical-mri.com/pdf/CMRI/8036XXP14Ap454-472.PDF

3http://www.thno.org/v02p0086.htm

4http://www.omicsonline.org/2157-7439/2157-7439-2-115.pdf

5http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017480/

6http://www.nature.com/nmeth/journal/v7/n12/full/nmeth1210-957.html

7http://endomagnetics.com/wp-content/uploads/2011/01/TargOncol_Review_2009.pdf

8http://www.nature.com/nnano/journal/v2/n5/abs/nnano.2007.105.html

9http://www.azonano.com/article.aspx?ArticleID=2680

Factors affecting the PK of the nanocarrier: Pharmaceutical Intelligence

Author: Tilda Barliya PhD

Title: Factors affecting the PK of the nanocarrier.

Category: Nanotechnology in drug delivery

A plethora of new products are emerging as potential therapeutic agents. This calls for detailed studies of their unique pharmacologic characteristics and mechanisms of action in humans. This review written by Caron WP et al (Zamboni’s group) provides a major overview of the factors that affect the pharmacokinetics (PK) and pharmacodynamics (PD) of nanoparticle carries in preclinical models and patients (1). I will use this article as the main source as it was so nicely written yet many other references are added within.

The disposition of carrier-mediated agents (CMAs) is dependent on the carrier and not on the parent drug, until the drug is released from the carrier into the system and includes encapsulated (the drug within or bound to the carrier), released (the active drug that gets released from the carrier), and sum total (encapsulated drug plus released drug).

After the drug has been released from its carrier, it is pharmacologically active and subjected to the same routes of metabolism and clearance (CL) as the non-carrier form of the drug (1,2).

In theory, the PK disposition of the drug after it is released from the carrier should be the same as after administration of the small-molecule or standard formulations. Therefore, the pharmacology and PK of CMAs are complex and call for comprehensive analytical studies to assess the disposition of encapsulated and released forms of the drug in plasma and tumor.

Interindividual variability in drug exposure, represented by area under the plasma concentration– time curve (AUC) of the encapsulated drug and several factor can potentially affect it:

• Physical characteristics of the CMA (size, charge, surface modification). Figure 1
• Host-associated characteristics such as gender and age as well as the host mononuclear phagocyte system (MPS), which is a collective term for the immune cells.

 

 

Figure 1 here (=figure 3 in the original paper. ref 1) : Nanoparticle clearance and biocompatibility are dependent on various factors including physical characteristics of the carrier as well as physiologic parameters such as the mononuclear phagocyte system (MPS) (reticuloendothelial system (RES)) recognition and enhanced permeability and retention (EPR) effect. There are qualitative relationships between the independent variables, namely, particle size, particle zeta-potential (surface charge), and solubility, and the dependent variable, namely, biocompatibility. Biocompatibility, or extent of exposure (area under the plasma concentration–time curve), includes the route of uptake and clearance (shown in green as the EPR effect and renal and biliary clearance), cytotoxicity (shown in red, can represent either efficacy or toxicities/ adverse events in anticancer treatment), and MPS/RES recognition (shown in blue).

The effect on the immune cells is divided into two categories:  (i) responses to nanoparticles that are specifically modified to stimulate the immune system (e.g., vaccine carriers) and (ii) undesirable interactions and/or side-effects.

Immune cells that participate in nanoparticle uptake are circulating monocytes, platelets, leukocytes, and dendritic cells in the bloodstream (3,4).  In addition, nanoparticles can be taken up in tissues by phagocytes, e.g., by Kupffer cells in the liver, by dendritic cells in the lymph nodes, by B cells in the spleen, and by macrophages

Uptake mechanisms may occur through different pathways and can often be facilitated by the adsorption of opsonins to the nanoparticle surface

Physical characteristics:

• Particle size: In one study of liposomes, particles that had a hydrodynamic diameter between 100 and 200 nm had a fourfold higher rate of uptake in tumors than particles <50 nm or >300 nm.
• Surface modification: Conjugated PEG polymer onto the surface- is known to minimize opsonization and thus subsequent decreased rate of MPS uptake overall plasma exposures of drugs contained within PEGylated liposomes were six fold higher than those contained within non-PEGylated liposomes
• Surface charge: Uncharged liposomes have lower CLs than either positively or negatively charged liposomes (probably due to reduced opsonization by MPS. rate of CL from blood was significantly higher for negatively charged particles than for uncharged particles

It can be summarized as for their rate of clearance from highest (left) to lowest (right) as:

positive>negative> neutral

Note: PEGylation can alter the alter this rate significantly for example,

Levchenko et al. showed that the negative charge on liposomes can be shielded with this physical alteration, leading to a significantly reduced rate of liver uptake and consequent prolongation of their presence in circulating blood (5).

Host characteristics

• Age: In some cases, age-related effects on the PK of some PEGylated liposomal agents have been reported, where in younger male patients (<60) there was a higher rate of clearance of two different agents (Doxil and CDK602) compared to older patients (>60). In other words, in older age, the CL rate was lower and therefore higher AUC/dose. No relation to age was observed for female patients, in the same study.

Alterations in the PK and PD of CMAs may involve accerelated decline in immune system functioning, specifically the association between aging and the functioning of monocytes (6). In theory, there is a loss of MPS activity or function in elderly patients, and this decreases the CL of CMAs by the MPS, leading to increased drug exposures and toxicity in elderly patients. In terms of efficacy, greater age was inversely proportional to progression-free survival; however, no correlation was found between age and overall survival.

•  Gender: In similar study to the one presented above, female patients had overall lower CL of DOXIL, IHL-305 and CDK602 compared to male patients of the same age.

The basis for the gender-related differences in the PK and PD of CMAs is unclear. It has been hypothesized that some of the differences may be attributed to the effects of sex hormones such as testosterone and estrogen on immune cell function.

Delivery of CMAs Into Tumor

Major advances in the understanding of tumor biology have led to the discovery of targeted agents that can deliver drugs to the desired site while minimizing exposure in normal tissues, thereby minimizing the associated adverse effects. Whereas conventional drugs encounter numerous obstacles en route to their target, CMAs can take advantage of a tumor’s leaky vasculature to extravasate into tissue, via the enhanced permeability and retention effect (EPR).

Note: The extend of the EPR effect is highly debated since although passive targeting through the EPR effect has been a key concept in delivering CMAs to tumors, it does not ensure uniform delivery to all regions of tumor. Furthermore, not all tumors exhibit an EPR effect, and the permeability of vessels may not be the same across any single tumor.

Active targeting may overcome these limitations. The CMAs can be enabled to bind to specific cells in a tumor by using surface attached ligands that are capable of recognizing and binding to cells of interest.

Antibody-mediated targeting has been the method of choice, other targeting strategies using nucleic acids, carbohydrates, peptides, aptamers, vitamins, and other agents are also being evaluated.

Other major points that can affect the PK disposition

• The linearity and nonlinearity of the CLs of a drug (might be associated with the dose like with S-CKD602)(7).
• Drug-drug interaction (single agent vs combination)
• Body composition (Body surface area, body weight)

There are a multitude of properties of CMAs that differ from those of the active small-molecule drugs they contain. These differences lead to significant variability in the PK and PD of carrier- mediated drugs. It has been shown that physical properties, the MPS, the presence of tumors in the liver, EPRs, drug–drug interactions, age, and gender all contribute in varying degrees to the PK disposition and PD end points of CMAs in patients.

Areas of research that can aid in an understanding of how these agents should be used and how we may predict their actions in patients include pharmacogenomics, cellular function (probing the MPS), more sensitive and accurate analytical PK methods, and identification of the optimal preclinical (animal and in vitro) models.

References:

1. W P Caron, G Song, P Kumar, S Rawal and W C Zamboni.Interpatient PK and PD variability of carrier-mediated anticancer agent.  Clinical Pharmacology and Therapeutics 2012 91, 802-812 http://www.nature.com/clpt/journal/vaop/ncurrent/full/clpt201212a.html

2. Zamboni, W.C. Liposomal, nanoparticle, and conjugated formulations of anticancer agents. Clin. Cancer Res. 11, 8230–8234 (2005).

http://clincancerres.aacrjournals.org/content/11/23/8230.long

http://clincancerres.aacrjournals.org/content/11/23/8230.full.pdf+html

3. Dobrovolskaia, M.A., Aggarwal, P., Hall, J.B. & McNeil, S.E. Preclinical studies to understand nanoparticle interaction with the immune system and its potential effects on nanoparticle biodistribution. Mol. Pharm. 5, 487–495 (2008). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613572/

4. Dobrovolskaia, M.A. & McNeil, S.E. Immunological properties of engineered nanomaterials. Nat. Nanotechnol. 2, 469–478 (2007). http://www.ncbi.nlm.nih.gov/pubmed/18654343

5. Levchenko, T.S., Rammohan, R., Lukyanov, A.N., Whiteman, K.R. & Torchilin, V.P. Liposome clearance in mice: the effect of a separate and combined presence of surface charge and polymer coating. Int. J. Pharm. 240, 95–102 (2002). http://www.ncbi.nlm.nih.gov/pubmed/12062505

6. Lloberas, J. & Celada, A. Effect of aging on macrophage function. Exp. Gerontol. 37, 1325–1331 (2002). http://www.ncbi.nlm.nih.gov/pubmed/12559402

7. Zamboni, W.C. et al. Pharmacokinetic study of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies. Clin. Pharmacol. Ther. 86, 519–526 (2009). http://www.nature.com/clpt/journal/v86/n5/abs/clpt2009141a.html

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