Archive for the ‘Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics’ Category

Activation of Efficient and Multiple Site-specific Nonstandard Amino Acid Incorporation

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Cytoskeleton, De novo synthesis, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Toxicity, Evolutionary cognition, Experimental validation, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, Immunodiagnostics, Infectious Disease & New Antibiotic Targets, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Molecular Genetics & Pharmaceutical, Pharmaceutical Analytics, Pharmacologic toxicities, Population Health Management, Genetics & Pharmaceutical, Proteomics, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Research, Translational Science, tagged activation of biosynthesis, amino acid incorporation, Cell-free Protein Synthesis, chemical and biological engineering, incorporation of nonstandard AAs, Multiple Site-specific Nonstandard Amino Acid Incorporation, Release Factor 1, Synthetic biology on June 20, 2014| Leave a Comment »

Larry Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/6-19-3014/larryhbern/Activation of Efficient and Multiple Site-specific Nonstandard Amino Acid Incorporation

 

Cell-free Protein Synthesis from a Release Factor 1 Deficient Escherichia coli Activates Efficient and Multiple Site-specific Nonstandard Amino Acid Incorporation

Seok Hoon Hong †‡, Ioanna Ntai ‡§, Adrian D. Haimovich #, Neil L. Kelleher ‡§, Farren J. Isaacs #, and Michael C. Jewett *†‡

^†Department of Chemical and Biological Engineering,^‡Chemistry of Life Processes Institute, ^§Department of Chemistry, and Department of Molecular Biosciences,Northwestern University, Evanston, Illinois 60208,United States of America

Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520, United States of America

^# Systems Biology Institute, Yale University, West Haven, Connecticut 06516, United States of America

Member, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, United States of America

Institute of Bionanotechnology in Medicine, Northwestern University, Chicago, Illinois 60611, United States of America

ACS Synth. Biol., 2014, 3 (6), pp 398–409

DOI: 10.1021/sb400140t

Publication Date (Web): December 13, 2013

Copyright © 2013 American Chemical Society

*Tel: +1 847 467 5007. Fax (+1) 847 491 3728. E-mail: m-jewett@northwestern.edu

Site-specific incorporation of nonstandard amino acids (NSAAs) into proteins

 

 

 

 

 

 

 

 

 

Site-specific incorporation of nonstandard amino acids (NSAAs) into proteins enables the creation of biopolymers, proteins, and enzymes with new chemical properties, new structures, and new functions. To achieve this, amber (TAG codon) suppression has been widely applied. However, the suppression efficiency is limited due to the competition with translation termination by release factor 1 (RF1), which leads to truncated products. Recently, we constructed a genomically recoded Escherichia coli strain lacking RF1 where 13 occurrences of the amber stop codon have been reassigned to the synonymous TAA codon (rEc.E13.ΔprfA). Here, we assessed and characterized cell-free protein synthesis (CFPS) in crude S30 cell lysates derived from this strain. We observed the synthesis of 190 ± 20 μg/mL of modified soluble superfolder green fluorescent protein (sfGFP) containing a single p-propargyloxy-l-phenylalanine (pPaF) or p-acetyl-l-phenylalanine. As compared to the parentrEc.E13 strain with RF1, this results in a modified sfGFP synthesis improvement of more than 250%. Beyond introducing a single NSAA, we further demonstrated benefits of CFPS from the RF1-deficient strains for incorporating pPaF at two- and five-sites per sfGFP protein. Finally, we compared our crude S30 extract system to the PURE translation system lacking RF1. We observed that our S30 extract based approach is more cost-effective and high yielding than the PURE translation system lacking RF1, 1000 times on a milligram protein produced/$ basis. Looking forward, using RF1-deficient strains for extract-based CFPS will aid in the synthesis of proteins and biopolymers with site-specifically incorporated NSAAs.

Keywords: 

cell-free protein synthesis; PURE translation; nonstandard amino acid;release factor 1; genomically recoded organisms

 

 

 

 

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Demythologizing sharks, cancer, and shark fins

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, Molecular Genetics & Pharmaceutical, Nutritional Supplements: Atherogenesis, lipid metabolism, tagged Antibody, Cancer - General, immune system, Johns Hopkins University, Luer, Massachusetts Institute of Technology, Mote Marine Laboratory, Smithsonian Institution on June 22, 2013| 1 Comment »

Larry H Bernstein, MD, Writer, Curator
http://pharmaceutical intelligence.com/2013/06/22/ Demythologizing sharks, cancer, and shark fins/lhbern

 

Sharks have survived some 400 million years on Earth. Could their longevity be due in part to an extraordinary resistance to cancer and other diseases? If so, humans might someday benefit from the shark’s secrets—but leading researchers caution that today’s popular shark cartilage “cancer cures” aren’t part of the solution.

 

The belief that sharks do not get cancer is not supported in fact, but it is the basis for decimating a significant part of the shark population for shark fins, and for medicinal use.  The unfortunate result is that there is no benefit.

 

A basis for this thinking is that going back to the late 1800s, sharks have been fished commercially and there have been few reports of anything out of the ordinary when removing internal organs or preparing meat for the marketplace.  In addition, pre-medical students may have dissected dogfish sharks in comparative anatomy, but you don’t see reports of cancerous tumors.

 

Carl Luer of the MOTE Marine Laboratory’s Center for Shark Research in Sarasota, Florida, has been studying sharks’ cancer resistance for some 25 years.  Systematic surveys of sharks are difficult to conduct, as capturing the animals in large numbers is time-consuming, and cancer tests would likely require the deaths of large numbers of sharks. Of the thousands of fish tumors in the collections of the Smithsonian Institution, only about 15 are from elasmobranchs, and only two of these are thought to have been malignant.

 

Scientists have been studying cancerous tumors in sharks for 150 years.

 

The first chondrichthyes’ (cartilaginous fishes, including sharks) tumor was found on a skate and recorded by Dislonghamcps in 1853. The first shark tumor was recorded in 1908. Scientists have since discovered benign and cancerous tumors in 18 of the 1,168 species of sharks. Scarcity of studies on shark physiology has perhaps allowed this myth to be accepted as fact for so many years.

 

In April 2000, John Harshbarger and Gary Ostrander countered this shark myth with a presentation on 40 benign and cancerous tumors known to be found in sharks, and soon after a blue shark was found with cancerous tumors in both its liver and testes. Several years later a cancerous gingival tumor was removed from the mouth of a captive sand tiger shark, Carcharias Taurus. Advances in shark research continue to produce studies on types of cancer found in various species of shark.  Sharks, like fish, encounter and take in large quantities of environmental pollutants, which may actually make them more susceptible to tumorous growth. Despite recorded cases of shark cancer and evidence that shark cartilage has no curative powers against cancer sharks continue to be harvested for their cartilage.

 

Sharks and their relatives, the skates and rays, have enjoyed tremendous success during their nearly 400 million years of existence on earth, according to Dr. Luer. He points out that one reason for this certainly is their uncanny ability to resist disease. Sharks do get sick, but their incidence of disease is much lower than among the other fishes. While statistics are not available on most diseases in fishes, reptiles, amphibians, and invertebrates, tumor incidence in these animals is carefully monitored by the Smithsonian Institution in Washington, D.C.

 

The Smithsonian’s enormous database, called the Registry of Tumors in Lower Animals, catalogs tissues suspected of being tumorous, including cancers, from all possible sources throughout the world. Of the thousands of tissues in the Registry, most of them are from fish but only a few are from elasmobranchs. Only 8 to 10 legitimate tumors are among all the shark and ray tissues examined, and only two of these are thought to have been malignant.

 

An observation by Gary Ostrander, a Professor at Johns Hopkins University, is that there may be fundamental differences in shark immune systems so that they aren’t as prone to cancer.  The major thrust of the Motes research focuses on the immunity of sharks and their relatives the skates and rays. While skates aren’t as interesting to the public as their shark relatives, their similar biochemical immunology and their ability to breed in captivity make them perhaps more vital to Luer’s lab work.   The result is to study the differences and similarities to the higher animals, and what might possibly be the role of the immune system in their low incidence of disease.

 

This low incidence of tumors among the sharks and their relatives has prompted biochemists and immunologists at Mote Marine Laboratory (MML) to explore the mechanisms that may explain the unusual disease resistance of these animals. To do this, they established the nurse shark and clearnose skate as laboratory animals. They designed experiments to see whether tumors could be induced in the sharks and skates by exposing them to potent carcinogenic (cancer-causing) chemicals, and then monitored pathways of metabolism or detoxification of the carcinogens in the test animals. While there were similarities and differences in the responses when compared with mammals, no changes in the target tissues or their genetic material ever resulted in cancerous tumor formation in the sharks or skates.

 

The chemical exposure studies led to investigations of the shark immune system. As with mammals, including humans, the immune system of sharks probably plays a vital role in the overall health of these animals. But there are some important differences between the immune arsenals of mammals and sharks. The immune system of mammals typically consists of two parts which utilize a variety of immune cells as well as several classes of proteins called immunoglobulins (antibodies).

 

Compared to the mammalian system, which is quite specialized, the shark immune system appears primitive but remarkably effective. Sharks apparently possess immune cells with the same functions as those of mammals, but the shark cells appear to be produced and stimulated differently. Furthermore, in contrast to the variety of immunoglobulins produced in the mammalian immune system, sharks have only one class of immunoglobulin (termed IgM). This Immunoglobulin normally circulates in shark blood at very high levels and appears to be ready to attack invading substances at all times.

 

Another difference lies in the fact that sharks, skates, and rays lack a bony skeleton, and so do not have bone marrow. In mammals, immune cells are produced and mature in the bone marrow and other sites, and, after a brief lag time, these cells are mobilized to the bloodstream to fight invading substances. In sharks, the immune cells are produced in the spleen, thymus and unique tissues associated with the gonads (epigonal organ) and esophagus (Leydig organ). Some maturation of these immune cells occurs at the sites of cell production, as with mammals. But a significant number of immune cells in these animals actually mature as they circulate in the bloodstream. Like the ever-present IgM molecule, immune cells already in the shark’s blood may be available to respond without a lag period, resulting in a more efficient immune response.

 

Research was being carried out during the 1980’s at the Massachusetts Institute of Technology (MIT) and at Mote Marine Laboratory designed to understand how cartilage is naturally able to resist penetration by blood capillaries. If the basis for this inhibition could be identified, it was reasoned, it might lead to the development of a new drug therapy. Such a drug could control the spread of blood vessels feeding a cancerous tumor, or the inflammation associated with arthritis.

 

The results of the research showed only that a very small amount of an active material, with limited ability to control blood vessel growth, can be obtained from large amounts of raw cartilage. The cartilage must be subjected to several weeks of harsh chemical procedures to extract and concentrate the active ingredients. Once this is done, the resulting material is able to inhibit blood vessel growth in laboratory tests on animal models, when the concentrated extract is directly applied near the growing blood vessels.  One cannot assume that comparable material in sufficient amount and strength is released passively from cartilage when still in the animal to inhibit blood vessel growth anywhere in the body.

 

Tumors release chemicals stimulating the capillary growth so a nutrient-rich blood supply is created to feed the tumorous cells. This process is called angiogenesis. If scientists can control angiogenesis, they could limit tumor growth. Cartilage lacks capillaries running through it. Why should this be a surprise?  Cartilage cells are called chondrocytes, and they fuction to produce a acellular interstitial matrix consisting of hyaluronan (complex carbohydrate formed from hyaluronic acid and chondroitin sulfate) which is protective of interlaced collagen.   Early research into the anti-angiogenesis properties of cartilage revealed that tiny amounts of proteins could be extracted from cartilage, and, when applied in concentration to animal tumors, the formation of capillaries and the spread of tumors was inhibited.

 

Henry Brem and Judah Folkman from the Johns Hopkins School of Medicine first noted that cartilage prevented the growth of new blood vessels into tissues in the 1970s. The creation of a blood supply, called angiogenesis, is a characteristic of malignant tumors, as the rapidly dividing cells need lots of nutrients to continue growing.  It is valuable to consider that these neovascular generating cells are not of epithelial derivation, but are endothelial and mesenchymal. To support their very high metabolism, tumors secrete a hormone called ‘angiogenin’ which causes nearby blood vessels to grow new branches that surround the tumor, bringing in nutrients and carrying away waste products

 

Brem and Folkman began studying cartilage to search for anti-angiogenic compounds. They reasoned that since all cartilage lacks blood vessels, it must contain some signaling molecules or enzymes that prevent capillaries from forming. They found that inserting cartilage from baby rabbits alongside tumors in experimental animals completely prevented the tumors from growing. Further research showed calf cartilage, too, had anti-angiogenic properties.

 

 

 

A young researcher by the name of Robert Langer repeated the initial rabbit cartilage experiments, except this time using shark cartilage. Indeed, shark cartilage, like calf and rabbit cartilage, inhibited blood vessels from growing toward tumors. Research by Dr. Robert Langer of M.I.T. and other workers revealed a promising anti-tumor agent obtainable in quantity from shark cartilage. The compound antagonistic to the effects of angiogenin, called ‘angiogenin inhibitor’, inhibits the formation of new blood vessels, neovascularization, that is essential for supporting cancer growth.

 

The consequence of the”shark myth” is not surprising. An inhabitant of the open ocean, the Silky Shark is ‘hit’ hard by the shark fin and shark cartilage industries – away from the prying eyes of a mostly land bound public. As a consequence of this ‘invisibility’, mortality of Silkies is difficult to estimate or regulate.  North American populations of sharks have decreased by up to 80% in the past decade, as cartilage companies harvest up to 200,000 sharks every month in US waters to create their products. One American-owned shark cartilage plant in Costa Rica is estimated to destroy 2.8 million sharks per year. Sharks are slow growing species compared to other fish, and simply cannot reproduce fast enough to survive such sustained, intense fishing pressure. Unless fishing is dramatically decreased worldwide, a number of species of sharks will go extinct before we even notice.

 

Sources:
1.  National Geographic News: NATIONALGEOGRAPHIC.COM/NEWS

 

2. Do Sharks Hold Secret to Human Cancer Fight?
by Brian Handwerk for National Geographic News.  August 20, 2003

 

3. Busting Marine Myths: Sharks DO Get Cancer!
by Christie Wilcox   November 9th 2009

 

 

 

Related articles

 

• Sharks Extinction Imminent If Current Illegal Trade Persists (guardianlv.com)
• Cancer Cells More Than Just Proliferate, Overuse Blood Sugar To Evade Immune System [VIDEO] (medicaldaily.com)
• Combating Metastatic Cancer Through Immune System Modulation (medicalnewstoday.com)
• Study Finds Ways of Training Immune System to Fight Cancer (counselheal.com)

 

Sand tiger shark (Carcharias taurus) at the Newport Aquarium. (Photo credit: Wikipedia)

 

Angiogenesis (Photo credit: Wikipedia)

 

 

 

 

 

 

 

 

 

 

 

The immune response (Photo credit: Wikipedia)

 

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Naked Mole Rats Cancer-Free

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Biology and its relations to Metabolic Disease, Genome Biology, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, International Global Work in Pharmaceutical, tagged Cancer - General, DNA, genetics, Harvard School of Public Health, Naked mole rat, Spalax, University of Texas Health Science Center, University of Texas System on June 20, 2013| Leave a Comment »

Larry H. Bernstein, MD, Reviewer and Curator
Leaders in Pharmaceutical Intelligence
https://pharmaceuticalintelligence.com/2013/06/20/Naked Mole Rats Cancer-Free/lhbern

This discussion is a novel piece of investigations now and earlier  published in the Proceedings of the National Academy of Sciences, and another in Nature pertaining to aging, longevity, and cancer.  The blind mole rat has an unexpected lifespan compared to other rodents.  There are also findings of a related naked mole rat that comes into the picture.  They are related, but not exactly the same. In both cases, the moles are cold-blooded, live underground with a queen and workers and they don’t develop cancer. The naked mold rates don’t develop cancer because of the presence of an imbalance in the intercellular matrix caused by abundant naturally produced, sticky complex carbohydrate also found in human joints that repels the cells at their interstices.

This is fascinating because it is also an important aspect of joint mobility.  In the situation of chondomalacia before erosion of the articular cartilage, the movement and shearing stresses initially induced production of more chondrocytes and with that, a thickened cartilage that becomes taxed until it loses matrix fluid, followed by loss of matrix and loss of collagen by shearing stress.  This type of motion and shear stress plays no part in the life of the naked mole rat, which has a rough skin.  The property of the cellular matrix seems to be characterized by both the production of the intercellular goo…called hyalurenan (like hyaluronic acid) and sparse hyaluronidase to remove and remodel the cell architecture.  How this is related to extreme aging and no loss of cellular growth control, having sparce ubiqitination that is involve in cell death and repair is unclear.

The hyaluronidases (EC 3.2.1.35) are a family of enzymes that degrade hyaluronic acid.  In humans, there are six associated genes, including HYAL1, HYAL2, HYAL3, and PH-20/SPAM1. By catalyzing the hydrolysis of hyaluronan, a constituent of the extracellular matrix (ECM), hyaluronidase lowers the viscosity of hyaluronan.  http://upload.wikimedia.org/wikipedia/commons/2/2f/Hyaluronidase-1OJN.png

The blind mole rat is closely related, but it differs in that it has a mechanism by which the cells have limited proliferation and don’t proliferate to the point of getting out of control.  This is because after several generations of cellular proliferation they produce a protein,  IFN-β.  This protein induces massive apoptosis, limiting the size of the sell population. There are findings in these investigations that might be relevant to understanding cancer resistance, and perhaps it could provide clues to treatment approaches.  If that is too much to ask for, it gives us great insight into how cells organize.

Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism

Gorbunovaa V, Hinea C, Tiana X, Ablaevaa J, Gudkovb AV, Nevoc E, and Seluanova A.
Contributed by Eviatar Nevo, October 3, 2012 (sent for review August 28, 2012)

Abstract

Blind mole rats Spalax (BMR) are small subterranean rodents common in the Middle East. BMR is distinguished by its adaptations to life underground, remarkable longevity (with a maximum documented lifespan of 21 y), and resistance to cancer. Spontaneous tumors have never been observed in spalacids. To understand the mechanisms responsible for this resistance, we examined the growth of BMR fibroblasts in vitro of the species Spalax judaei and Spalax golani. BMR cells proliferated actively for 7–20 population doublings, after which the cells began secreting IFN-β, and the cultures underwent massive necrotic cell death within 3 d. The necrotic cell death phenomenon was independent of culture conditions or telomere shortening. Interestingly, this cell behavior was distinct from that observed in another long-lived and cancer-resistant African mole rat, Heterocephalus glaber, the naked mole rat in which cells display hypersensitivity to contact inhibition. Sequestration of p53 and Rb proteins using SV40 large T antigen completely rescued necrotic cell death. Our results suggest that cancer resistance of BMR is conferred by massive necrotic response to overproliferation mediated by p53 and Rb pathways, and triggered by the release of IFN-β. Thus, we have identified a unique mechanism that contributes to cancer resistance of this subterranean mammal extremely adapted to life underground.

Source:

1To whom correspondence may be addressed. E-mail:  vera.gorbunova@rochester.edu, nevo@research.haifa.ac.il, or andrei.seluanov@rochester.edu.

2Present address: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115.

http://www.pnas.org/content/early/2012/10/31/1217211109

Image: Greg Goebel/Flickr

Long-Lived Rat May Hold Clues to Combating Aging

BY BRANDON KEIM02.17.09

The extraordinarily durable proteins in the world’s longest-lived rodent may contain a vital piece of the puzzle of aging.

• Like short-lived mice, the cells of naked mole rats are suffused with free-floating, cell-damaging oxygen free radicals. 
• Unlike the mice — and every other species that appears compromised by oxidative deterioration, including humans — they’ve found a way to live with it.

“When we compare the lab mouse with the naked mole rat, we find a striking difference in their systems,” said study co-author Asish Chaudhuri, a University of Texas Health Science Center biochemist. “Their proteins are still working. Even when damaged, the functions are maintained.”

The findings, published Monday in the Proceedings of the National Academy of Sciences, represent a new wrinkle in the oxidative-stress theory of aging. According to the theory, mitochondria — cellular machines that produce our bodies’ energy — pump out highly reactive oxygen molecules during respiration. Called free radicals, these molecules bind easily with other molecules, including DNA. Over time, DNA breaks down, compromising cellular function. Eventually whole tissues and organs no longer function.  Multiple studies have found evidence of mitochondrial malfunction in a range of diseases that become more common with age, from heart disease to neurodegeneration to cancer. Drugs designed to rejuvenate mitochondria have shown promise in treating diabetes, and are celebrated as possible therapies for other conditions.

DNA repair rate is an important determinant of cell pathology (Photo credit: Wikipedia)

Chaudhuri’s team’s findings don’t contradict the role of mitochondria, but expand the theory to include cellular proteins other than DNA. They also explain a condundrum: some long-lived species display plenty of oxidative damage. “We’ve studied a dozen species, half short-lived and the others long-lived. One long-lived species would have lots of oxidative damage, and another would have little. The one thing that seemed to be consistent was protein stability,” said University of Texas Health Sciences Center gerontologist Steven Austad, who was not involved in the current study. “Until recently I’ve focused on DNA damage and repair, but this strikes me as even more fundamental. For DNA repair to work, you need all the repair proteins to work properly.”  Mole rats caught the researchers’ attention because they can live for 30 years, or ten times longer than lab mice, even though the two are similarly sized.

They found that mole rats do have efficient mitochondria that release fewer free radicals than expected. But their mitochondria aren’t perfect. Free radicals still gather and cause damage. Two-year-old mole rats show just as much oxidative stress two-year-old mice — and then live for another quarter-century.  The key appears to be their proteins, which continue to function despite damage. Study co-author Rochelle Buffenstein, a University of Texas Health Sciences Center physiologist, likened the phenomena to rusting cars: in other species, the axles rust, but in naked mole rats, it’s just the doors.  With heat and urea — both of which typically cause complex protein spools to unfold — the researchers tried to break down the proteins, but to no avail.  “You can basically hit them with a sledgehammer, and the proteins don’t unfold,” said Buffenstein. “Something makes them inherently more stable. There might be small molecules that tack on to proteins and help them retain structure in the face of cellular stress.”

Mole rats also appear to delay protein repair until the last possible moment, thus saving energy and resources. When proteins finally do break down, mole rats do an especially efficient job of cleaning them up. Only a tiny bit of ubiquitin — the chemical tag used to label damaged proteins for disposal — is required.  Finally, specialized protein-disposal structures, called proteosomes (tied to ubiqitination), don’t appear to break down with age in mole rats.

English: Damaraland mole-rat (Fukomys damarensis) (Photo credit: Wikipedia)

The researchers will next try to determine what maintains the mole rat’s proteins and proteosome. If, as Buffenstein suspects, it turns out to be an as-yet-unidentified protein protectant, scientists could apply the findings to people. “If we can identify those proteins, we can use them to study aging and age-related diseases. These animals don’t have any symptoms of neurodegeneration, even in old age,” said Chaudhuri. “Then we can design peptides that act like the protein, and take it as a drug.”

Citation:

Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat.

By Viviana I. Perez, Rochelle Buffenstein, Venkata Masamsetti, Shanique Leonard, Adam B. Salmon, James Meleb, Blazej Andziak, Ting Yang, Yael Edrey, Bertrand Friguet, Walter Ward, Arlan Richardson and Asish Chaudhuri. Proceedings of the National Academy of Sciences, Vol. 106 No. 7, Feb. 16, 2009.

Why Blind Mole Rats Don’t Get Cancer

By Ian Steadman, Wired UK

Blind mole rats don’t get cancer. in 2011 it was found they have a gene that stops cancerous cells from forming. The same team thought that two other cancer-proof mole rat species might have similar genes, but instead it turns out that they do develop cancerous cells. It’s just that those cells are programmed to destroy themselves if they become dangerous.

The blind mole rat (Spalax typhlus) has tiny eyes completely covered by a layer of skin. (Photo credit: Wikipedia)

Mole rats, which live in underground burrows throughout Southern and Eastern Africa, and the Middle East, are fascinating creatures. The naked mole rat, in particular, is the only cold-blooded mammal known to man, doesn’t experience pain, and is also arguably the only mammal (along with the Damaraland mole rat) to demonstrate eusociality — that is, they live in large hierarchical communities with a queen and workers, like ants or bees.

The two species examined by the University of Rochester’s Vera Gorbunova and her team were the Judean Mountains blind mole rat (Spalax judaei) and the Golan Heights blind mole rat (Spalax golani), which live within small regions of Israel. The team took cells from the rodents and put them in a culture that would force them to multiply beyond what would happen within the animals’ bodies. For the first seven to 20 multiplications, things looked fine, but beyond 20 multiplications the cells started rapidly dying off.  Examining the cells as they died revealed that they had started to produce a protein, IFN-β, that caused them to undergo “massive necrotic cell death within three days”. In effect, once the cells had detected that they had multiplied beyond a certain point, they killed themselves. The cells of naked mole rats have a self-preservation mechanism tied to a hypersensitivity to overcrowding, which stops them from multiplying too much.  On the one hand (blind mole rat) you have self-destruction at a point at which there is crowding due to IFN-β.  On the other hand, you find an aversion to overcrowding (naked mole rat).

In the Proceedings of the National Academy of Sciences, Gorbunova hypothesizes that the blind mole rats’ unique habitat — almost entirely underground — might mean that they “could perhaps afford to evolve a long lifespan, which includes developing efficient anti-cancer defences”. Blind mole rats have extremely long lifespans by rodent standards, often living beyond 20 years at a time.

The reasons why this is, though, are still all hypothetical, as the precise mechanism that triggers the production of the IFN-β is still unknown. The hope is that this research could eventually lead to new therapies for cancer in humans.

Super Sugar Keeps Naked Mole Rats Cancer-Free

BY ELIZABETH PENNISI, SCIENCENOW 06.20.13

Although they are quite ugly and confined to a life underground, naked mole rats have at least one attribute that other animals, even humans, might aspire to: They don’t get cancer. Now, researchers have discovered that the secret to this rodent’s good health is a complex sugar that helps keeps cells from clumping together and forming tumors.  It exists in the spaces between cells called the extracellular matrix, “the work underlines the very important regulatory role of [the] extracellular matrix in cancer,” says Bryan Toole, a cancer biologist at the Medical University of South Carolina in Charleston who was not involved with the study. Molecular and cell biologist Vera Gorbunova of the University of Rochester in New York wanted to take a different tack and focus on animals that seem protected from tumors. So she tracked down the lifespans of 20 different rodents, looking for the ones that live a long time. Beavers and gray squirrels last a couple of decades, but naked mole rats outlive those larger animals by 10 years.  Furthermore, naked mole rats have a unique social structure, with one queen that produces all the young for an underground colony full of helpers. Thanks to these studies, scientists know for sure that this species doesn’t get cancer. Given that naked mole rats live long and are resistant to cancer, “we fell in love with them right away,” Gorbunova says.

At first, she and her colleagues did not know where to look for the source of animals’ cancer resistance. But when they grew naked mole rat cells in a lab dish, they noticed that cells wouldn’t get too close together. Furthermore, the dish contents got very gooey, and when they eliminated the goo, the cells would clump together. The researchers tracked the stickiness to a complex sugar called hyaluronan, which cells make and release into the extracellular matrix.  Hyaluronan exists in all animals, helping lubricate joints and serving as an essential component in skin and cartilage. However, naked mole rat hyaluronan is unusual in that each molecule is about 5 times the size of hyaluronan molecules from mice, rats, and humans. In addition, the researchers discovered that the enzyme that breaks down this sugar (hyaluronidase) is not very active in naked mole rats, allowing the compound to accumulate to higher concentrations than it does in other animals. The researchers think that this sugar evolved to make naked mole rat skin more elastic and able to cope with the tight squeeze of the narrow underground tunnels.

But does it prevent cancer? Gorbunova and her colleagues tried to stimulate naked mole rat cells to form tumors by exposing them to viral proteins that in mice lead to tumor growth. These proteins inactivate genes that suppress cancer, yet still naked mole rat cells did not show uncontrolled growth. However, when the researchers interfered with the production of hyaluronan or revved up the activity of the enzyme that breaks the sugar down, thereby reducing its concentrations, tumors did form in live animals, they report online today in Nature.

The work is “very thought-provoking [and] adds an interesting wrinkle to the role of the extracellular matrix in cancer,” says Roy Zent, a cell biologist at Vanderbilt University Medical Center in Nashville. Toole agrees. “It pushes our thoughts forward [about hyaluronan] in a very dramatic way,” he notes. “It establishes hyaluronan as an important player in cancer.”  “If we could alter our [hyaluronan] or stabilize it somehow, we may be able to suppress cancers,” suggests Carlo Maley, an evolutionary cancer biologist at the University of California, San Francisco, who was not involved with the work. The next step, he adds, is to “put the naked mole rat [hyaluronan] gene into mice and test if they are cancer resistant.”

Related articles

• Scientists have figured out why naked mole rats don’t get cancer (io9.com)
• Cancer Cure Found In Naked Mole Rats? Chemical, Hyaluronan, May Contain Anti-Cancer Properties (medicaldaily.com)
• The Latest Update on Naked Mole Rat Cancer Immunity (fightaging.org)
• “Goo” from naked mole rat appears to offer cancer protection (cbsnews.com)
• Naked Mole Rats Provide Cancer-Killing Insights: It’s All in the Goo [Video] (latinospost.com)
• Biologists identify chemical that makes naked mole rats cancer-proof (wired.co.uk)

English: Naked mole rats. Cropped version of File:Naked Mole Rats.jpg. (Photo credit: Wikipedia)

Naked Mole rat baby (Photo credit: Wikipedia)

English: Spalax leucodon, syn. Nannospalax leucodon Magyar: Földikutya (Photo credit: Wikipedia)

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Vascular Repair: Stents and Biologically Active Implants

Posted in Advanced Drug Manufacturing Technology, Cardiac & Vascular Repair Tools Subsegment, Coagulation Therapy and Internal Bleeding, Computational Biology/Systems and Bioinformatics, Drug Delivery Platform Technology, FDA Regulatory Affairs, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, Health Economics and Outcomes Research, Health Law & Patient Safety, Medical Devices R&D Investment, PCI, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stents & Tools, Technology Transfer: Biotech and Pharmaceutical, Valves & Tools, tagged American College of Cardiology, Artery, Cardiovascular disease, Doctor of Philosophy, Drug delivery, Drug-eluting stent, health, Key, Stent on May 4, 2013| 14 Comments »

Vascular Repair: Stents and Biologically Active Implants

Author and Curator: Larry H Bernstein, MD, FACP

and

Curator: Aviva Lev-Ari, PhD, RN

This is the second article of a three part series recognizing the immense contribution of Elazer Edelman, MD, PhD, and his laboratory group at MIT to vascular biology, cardiovascular disease studies, and the bioengineering, development, and use of stenting technology for drug delivery, vascular repair, and limitation of vessel damage caused by stent placement.

The first article, published on this Open Access Online Scientific Journal

Drug Eluting Stents: On MIT‘s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

was concerned with vascular biology, and largely on both the impact of drug delivery design and placement on the endothelium of the vessel wall, and on the kinetics of drug delivery based on the location of stent placement versus intravascular injection as well as the metabolic events taking place in the arterial endothelium, intima, and muscularis.

This second article, is concerned with stents and drug delivery as it has evolved since the last decade of the 20th century based on biomaterials development and vascular biology principles to minimize inherent injury risk over this period.

The third. will be concerned with the lessons from biomaterials and stent mechanics going forward.

Heart care is in the midst of a transformation. Patients who once required heart surgery are treated with a stent, catheters for repair of valves, rhythm abnormalities, and a growing number of heart or vascular distrbances.

The catheters are threaded in through the femoral artery, and sometimes through the radial artery. The American College of Cardiology annual meeting highlights research on these devices.  The procedure allows patients to leave the hospital after a day or two post-implant, but the initial cost of the novel devices is high.  Not everyone qualifies for the treatment, and it will take a few years to compare the long term results with the benefits from surgery. But these procedures have allowed many patients treatment alternatives to surgery, and they offer an option for people who cannot be successfully managed by conservative medical therapy.

The effects of stent placement on vascular injury and the initiation of an inflammatory response

Leukocytes are recruited early and abundantly to experimentally injured vessels,

• in direct proportion to cell proliferation and intimal growth.

Activated circulating leukocytes and Mac-1 (CD11 by CD18, aMb2) (monocytic) expression are

• markers of restenosis risk in patients undergoing angioplasty.

Angioplastied vessels lack endothelium but have extensive fibrin(ogen) and platelet deposition.  Consequently, Mac-1-dependent adhesion to fibrin(ogen)  would be expected to

• signal leukocyte recruitment and function, thereby
• promote intimal growth

In this study

• M1/70, an anti-CD11b blocking mAb, was  administered to rabbits before, and every 48 hr for 3, 6, or 14 days after iliac artery balloon denudation.
• M1/70 was bound to isolated rabbit monocytes.

The result was

• Mac-1-mediated dose-dependent
• inhibition of fibrinogen binding in vitro, thereby,
• reducing by half leukocyte recruitment at 3, 6, and 14 days after injury.

Neointimal growth 14 days after injury was markedly attenuated by treatment with M1/70 –

intimal area after balloon injury, 0.12+0.09 mm2, compared with

•  0.32+0.08 mm2 in vehicle treated controls, P<0.01, and
•  0.38+0.08mm2 in IgG-treated controls, P<0.005;

intimal area after stent injury, 0.56+0.16 mm2, compared with

•  0.84+ 0.13 mm2 in vehicle-treated controls, P <0.05, and
•  0.90+0.15 mm2 in IgG-treated controls, P <0.02).

Mac-1 blockade reduces experimental neointimal thickening. These findings suggest that

• leukocyte recruitment to and
• infiltration of injured arteries

may be a valid target for preventing intimal hyperplasia. (1) Emerging data indicate that the inflammatory response after mechanical arterial injury

• correlates with the severity of neointimal hyperplasia in animal models
• and post angioplasty restenosis in humans.

The present study was designed to examine whether a nonspecific

• stimulation of the innate immune system,
• induced in close temporal proximity to the vascular injury,
• would modulate the results of the procedure.

A LPS dose was chosen to be sufficient to induce systemic inflammation but not septic shock. Key markers of inflammation increased after LPS administration were:

• serum interleukin-1 levels, and
• monocytic stimulation (CD14 levels on monocytes)

Arterial macrophage infiltration at 7 days after injury was

• 1.7+1.2% of total cells in controls and
• 4.2+1.8% in LPS-treated rabbits (n=4, P<0.05).

The injured arteries 4 weeks after injury had significantly increased

• luminal stenosis:   38+4.2% versus 23+2.6%, mean+SEM; n=8, P<0.05; and
• neointima-to-media ratio:  1.26+0.21 versus 0.66+0.09, P<0.05 in LPS-treated animals compared with controls.

This effect was abolished by anti-CD14 Ab administration. Serum Il-1 levels and monocyte CD14 expression were significantly increased

• in correlation with the severity of intimal hyperplasia.
• LPS treatment increased neointimal area after stenting
  • from 0.57+0.07 to 0.77+0.1 mm2, and
• stenosis from 9+1% to 13+1.7% (n=5, P<0.05).

Nonspecific systemic stimulation of the innate immune system

• concurrently with arterial vascular injury
• facilitates neointimal formation, and conditions associated with
• increased inflammation may increase restenosis.(2)

Millions of patients worldwide have received drug-eluting stents

• to reduce their risk for in-stent restenosis.

The efficacy and toxicity of these local therapeutics depend upon

• arterial drug deposition,
• distribution, and
• retention.

To examine how administered dose and drug release kinetics control arterial drug uptake, a model was created using principles of

• computational fluid dynamics and
• transient drug diffusion–convection.

The modeling predictions for drug elution were validated using

• empiric data from stented porcine coronary arteries.

Inefficient, minimal arterial drug deposition was predicted when a bolus of drug was released and depleted within seconds.

Month-long stent-based drug release

• efficiently delivered nearly continuous drug levels, but
• the slow rate of drug presentation limited arterial drug uptake.

Uptake was only maximized when

• the rates of drug release and absorption matched,
• which occurred for hour-long drug release.

Of the two possible means for increasing the amount of drug on the stent,

• modulation of drug concentration potently impacts
• the magnitude of arterial drug deposition,
• while changes in coating drug mass affect duration of release.

We demonstrate the importance of drug release kinetics and administered drug dose

• in governing arterial drug uptake and suggest
• novel drug delivery strategies for controlling spatio-temporal arterial drug distribution.(3)

Arterial drug concentrations determine local toxicity. Therefore, the emergent safety concerns surrounding drug-eluting stents mandate an investigation of the factors contributing to fluctuations in arterial drug uptake.

• Drug-eluting stents were implanted into porcine coronary arteries, arterial drug uptake was followed and modeled using 2-dimensional computational drug transport.

Arterial drug uptake in vivo occurred faster than predicted by free drug diffusion, thus

• an alternate, mechanism for rapid transport has been proposed involving carrier-mediated transport.

Though there was minimal variation in vivo in release kinetics from stent to stent,

• arterial drug deposition varied by up to 114% two weeks after stent implantation.
• extent of adherent mural thrombus fluctuated by 113% within 3 days.

The computational drug transport model predicted that focal and diffuse thrombi

• elevate arterial drug deposition in proportion to the thrombus size
• by reducing drug washout subsequently increasing local drug availability.

Variable peristrut thrombus can explain fluctuations in arterial drug uptake even in the face of a narrow range of drug release from the stent. The mural thrombus effects on arterial drug deposition may be circumvented by forcing slow rate limiting arterial transport, that cannot be further hindered by mural thrombus. (4)

1.  A mAb to the b2-leukocyte integrin Mac-1 (CD11byCD18) Reduces Intimal Thickening after Angioplasty or Stent Implantation in Rabbits. C Rogers, ER Edelman, and DI Simon. PNAS Aug 1998; 95: 10134–10139.

http://dx.doi.org/10.1073/pnas.95.17.10134

2.  Formation After Balloon and Stent Injury in Rabbits Systemic Inflammation Induced by Lipopolysaccharide increases Neointimal Formation After Balloon and Stent Injury in Rabbits. HD Danenberg, FGP Welt, M Walker, III, P Seifert, et al. Circulation 2002;105;2917-2922; http://dx.doi.org/10.1161/01.CIR.0000018168.15904.BB

3.  Intravascular drug release kinetics dictate arterial drug deposition, retention, and distribution.

B Balakrishnan, JF Dooley, G Kopia, ER Edelman. J Controlled Release  2007;123:100–108.
http://dx. doi.org/10.1016/j.jconrel.2007.06.025.

4.  Thrombus causes fluctuations in arterial drug delivery from intravascular stents. B Balakrishnan, J Dooley, G Kopia, ER Edelman. J Control Release 2008. http://dx.doi.org/10.1016/j.jconrel.2008.07.027

Perivascular Graft Repair

Heparin remains the gold-standard inhibitor of the processes involved in the vascular response to injury. Though this compound has profound and wide-reaching effects on vascular cells, its clinical utility is unclear. It is clear that the mode of heparin delivery is critical to its potential and it may well be that

• routine forms of administration are insufficient
• to observe benefit given the heparin’s short half-life and complex pharmacokinetics.

When ingested orally, heparin is degraded to inactive oligomer fragments while systemic administration

• is complicated by the need for continuous infusion
• and the potential for uncontrolled hemorrhage.

Thus alternative heparin delivery systems have been proposed to maximize regional effects while limiting systemic toxicity. Yet, as heparin is such a potent antithrombotic compound and since existing local delivery systems lack the ability to

• precisely regulate release kinetics,
• even site-specific therapy is prone to bleeding.

Authors now describe the design and development of a novel biodegradable system for the perivascular delivery of heparin to the blood vessel wall with well-defined release kinetics.

This system consists of heparin-encapsulated

• poly(DL lactide-co-glycolide) (pLGA) microspheres sequestered in an alginate gel.

Controlled release of heparin from this heterogeneous system is obtained for a period of 25 days.

The experimental variables affecting heparin release from these matrices were investigated by

• gel permeation chromatography (GPC) and scanning electron microscopy (SEM)
• to monitor the degradation process and correlated well with the release kinetics.

Heparin-releasing gels inhibited growth in tissue culture of

• bovine vascular smooth muscle cells in a dose-dependent manner.
• and also controlled vascular injury in denuding and
• interposition vascular graft animal models of disease even when uncontrolled bleeding was evident with standard matrix-type release.

This system provided an effective means of examining

• the effects of various compounds in
• the control of smooth muscle cell proliferation in accelerated arteriopathies and also
• shed light on the biologic nature of these processes.(1)

Soft tissue adhesives are employed to repair and seal many different organs that range in both

• tissue surface chemistry and
• mechanical effects during organ function.

This complexity motivates the development of tunable adhesive materials with

• high resistance to uniaxial or multiaxial loads
• dictated by a specific organ environment.

Co-polymeric hydrogels comprising

• aminated star polyethylene glycol and
• dextran aldehyde (PEG:dextran)

are materials exhibiting physico-chemical properties that can be modified

Here we report that resistance to failure

• under specific loading conditions, as well as
• tissue response at the adhesive material–tissue interface, can be modulated through regulation of
• the number and density of adhesive aldehyde groups.

Author found that atomic force microscopy (AFM) can

• characterize the material aldehyde density available for tissue interaction,
• facilitating rapid, informed material choice.

Further, the correlation between AFM quantification of nanoscale unbinding forces

• with macroscale measurements of adhesion strength
• by uniaxial tension or multiaxial burst pressure allows the design of materials with specific cohesion and adhesion strengths.

However, failure strength alone does not predict optimal in vivo reactivity. The development of adhesive materials is significantly enabled when

• experiments are integrated along length scales to consider
• organ chemistry and mechanical loading states concurrently
• with adhesive material properties and tissue response. (2)

Cell culture and animal data support the role of endothelial cells and endothelial-based compounds in regulating vascular repair after injury.

Authors describe a long-term study in pigs in which the biological and immunological

• responses to endothelial cell implants were investigated 3 months after angioplasty,
• approximately 2 months after the implants have degraded.

Confluent porcine or bovine endothelial cells grown in polymer matrices were implanted adjacent to 28 injured porcine carotid arteries.

Porcine and bovine endothelial cell implants significantly

• reduced experimental restenosis compared to control by 56 and 31%, respectively.

Host humoral responses were investigated by detection of an increase in serum antibodies that bind to the bovine or porcine cell strains used for implantation.

A significant increase in titer of circulating antibodies to the bovine cells was observed

• after 4 days in all animals implanted with xenogeneic cells.

Detected antibodies returned to presurgery levels after Day 40.

No significant increase in titer of antibodies to the porcine cells was observed during the experiment in animals implanted with porcine endothelial cells.

No implanted cells, Gelfoam, or focal inflammatory reaction could be detected

• histologically at any of the implant sites at 90 days.

Suggesting that tissue engineered endothelial cell implants

• may provide long term control of vascular repair after injury,
• rather than simply delaying lesion formation and that
• allogeneic implants are able to provide a greater benefit than xenogeneic implants. (3)

Vascular access complications are a major problem in hemodialysis patients. Native arteriovenous fistulae, historically the preferred mode of access, have a patency rate of only 60% at 1 year.

The most common mode of failure is due to progressive stenosis at the anastomotic site.

Authors have previously demonstrated that perivascular endothelial cell implants

• inhibit intimal thickening following acute balloon injury in pigs, and now seek to determine if these
• implants provide a similar benefit in the chronic and more complex injury model of arteriovenous anastomoses.

Side-to-side femoral artery-femoral vein anastomoses were created in 24 domestic swine.

• toxicological,
• biological and
• immunological responses

were investigated 3 days and 1 and 2 months postoperatively to allogeneic endothelial cell implants . The anastomoses were wrapped with polymer matrices containing

• confluent porcine aortic endothelial cells (PAE; n = 14) or
• control matrices without cells (n = 10).

PAE implants significantly reduced intimal hyperplasia at the anastomotic sites

• compared to controls by 68% (p ! 0.05) at 2 months.

The beneficial effects of the PAE implants were not due to

• differences in the rates of reendothelialization between the groups.

No significant immunological response to the allogeneic endothelial cells that impacted on efficacy was detected in any of the pigs.

No apparent toxicity was observed in any of the animals treated with endothelial implants.

These data suggest that perivascular endothelial cell implants

• are safe and reduce early intimal hyperplasia in a porcine model of arteriovenous anastomoses. (4)

1.  Perivascular graft heparin delivery using biodegradable polymer wraps. ER Edelman, A Nathan,

M Katada, J Gates, MJ Karnovsky. Biomaterials 2000; 21:2279 -2286.
onlinelibrary.wiley.com/doi/10.1002/anie.200461360/full

2.  Tuning adhesion failure strength for tissue-specific applications. N Artzi, A Zeiger, F Boehning,

A bon Ramos, K Van Vliet, ER Edelman.  Acta Biomateriala 2010.
http://dx.doi.org/10.1016/j.actbio.2010.07.008.

3. Endothelial Implants Provide Long-Term Control of Vascular Repair in a Porcine Model of Arterial Injury. HM Nugent, ER Edelman. J Surg Res 2001; 99:228–234.  http://dx.doi.org/10.1006/jsre.2001.6198

4.  Perivascular Endothelial Implants Inhibit Intimal Hyperplasia in a Model of Arteriovenous Fistulae: A Safety and Efficacy Study in the Pig. HM Nugent, A Groothuis, P Seifert, et al. J Vasc Res 2002;39:524–533.

http://dx.doi.org/10.1159/000067207

Luminal Flow and Arterial Drug Delivery

Endovascular stents reside in a dynamic flow environment and yet the impact of flow

• on arterial drug deposition after stent-based delivery is only now emerging.

Authors employed computational fluid dynamic modeling tools to investigate

• the influence of luminal flow patterns on arterial drug deposition and distribution.

Flow imposes recirculation zones distal and proximal to the stent strut that extend

• the coverage of tissue absorption of eluted drug and
• induce asymmetry in tissue drug distribution.

Our analysis now explains how the disparity in

• sizes of the two recirculation zones and
• the asymmetry in drug distribution are determined by a complex interplay of local flow and strut geometry.

When temporal periodicity was introduced as a model of

• pulsatile flow,
• the net luminal flow served as an index of flow-mediated spatiotemporal tissue drug uptake.

Dynamically changing luminal flow patterns are intrinsic to the coronary arterial tree. Coronary drug-eluting stents should be appropriately considered where

• luminal flow,
• strut design and
• pulsatility

have direct effects on tissue drug uptake after local delivery.(1)

The efficacy of drug-eluting stents (DES) requires delivery of potent compounds directly to the underlying arterial tissue.

The commercially available DES drugs rapamycin and paclitaxel bind specifically to

• their respective therapeutic targets, FKBP12 and polymerized microtubules,
• while also associating in a more general manner with other tissue elements.

As it is binding that provides biological effect, the question arises as to whether other

• locally released or systemically circulating drugs can
• displace DES drugs from their tissue binding domains.

Specific and general binding sites for both drugs are distributed across the media and adventitia with higher specific binding associated with the binding site densities in the media.

The ability of rapamycin and paclitaxel to compete for specific protein binding and general tissue deposition

• was assessed for both compounds simultaneously and
• in the presence of other commonly administered cardiac drugs.

Drugs classically used to treat standard cardiovascular diseases, such as hypertension and hypercoaguability,

• displace rapamycin and paclitaxel from general binding sites, possibly
• decreasing tissue reserve capacity for locally delivered drugs.

Paclitaxel and rapamycin do not affect the other’s binding

• to their biologically relevant specific protein targets, but
• can  displace each other from tissue at three log order molar excess,
• decreasing arterial loads by greater than 50%.

Local competitive binding therefore should not limit the placement of rapamycin and paclitaxel eluting stents in close proximity.(2)

Stent thrombosis is a lethal complication of endovascular intervention. There is concern about the inherent risk associated with specific stent designs and drug-eluting coatings

Authored examined whether drug-eluting coatings are inherently thrombogenic and whether the response to these materials was determined to any degree

• by stent design and
• stent deployment with custom-built stents.

Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold; P 0.011).

Thick-strutted (162 m) stents were 1.5-fold more thrombogenic than otherwise

• identical thin-strutted (81 m) devices in ex vivo flow loops (P< 0.001),

commensurate with 1.6-fold greater thrombus coverage

• 3 days after implantation in porcine coronary arteries (P 0.004).

When bare metal stents were deployed in

• malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold, P < 0.001; and 2.32-fold, P <0.001).

The thrombogenicity of polymer-coated stents with thin struts was

• lowest in all configurations and remained insensitive to incomplete deployment.

Computational modeling– based

• predictions of stent-induced flow derangements
• correlated with spatial distribution of formed clots.

Drug/polymer coatings do not inherently increase acute stent clotting;

• they reduce thrombosis.

However, strut dimensions and positioning relative to the vessel wall

• are critical factors in modulating stent thrombogenicity.

Optimal stent geometries and surfaces, as demonstrated with thin stent struts,

• help reduce the potential for thrombosis
• despite complex stent configurations and variability in deployment. (Circulation. 2011;123:1400-1409.) (3)

1. Luminal flow patterns dictate arterial drug deposition in stent-based delivery.

VB Kolachalama, AR Tzafriri, DY Arifin, ER Edelman. J Control Release 2009; 133:24–30.

http:/dx.doi.org/10.1016/j.jconrel.2008.09.075

2. Local and systemic drug competition in drug-eluting stent tissue deposition properties.

AD Levin, M Jonas, Chao-Wei Hwang, ER Edelman.  J Control Release 2005; 109:236-243.

http://dx.doi.org/10.1016/j.jconrel.2005.09.041

3. Stent Thrombogenicity Early in High-Risk Interventional Settings Is Driven by

Stent Design and Deployment and Protected by Polymer-Drug Coatings

Kumaran Kolandaivelu, Rajesh Swaminathan, William J. Gibson,.. ER Edelman

Circulation ; http://dx.doi.org/10.1161/CIRCULATIONAHA.110.003210

Management of Obstructive Coronary Artery Disease

Multiple studies have shown that diabetes mellitus (DM) can affect the

• efficacy of revascularization therapies and subsequent clinical outcomes.

Selecting the appropriate myocardial revascularization strategy is critically important

• in the setting of multivessel coronary disease.

Optimal medical therapy is an appropriate first-line strategy in patients with DM and mild symptoms. When medical therapy does not adequately control symptoms,

• revascularization with either PCI or CABG may be used.

In patients with treated DM, moderate to severe symptoms and complex multivessel coronary disease,

• coronary artery bypass graft surgery provides better survival,
• fewer recurrent infarctions and
• greater freedom from re-intervention.

Decisions regarding revascularization in patients with DM must take into account multiple factors and as such require a multidisciplinary team approach (‘heart team’). (1)

An incomplete understanding of the transport forces and local tissue structures

• that modulate drug distribution has hampered
• local pharmacotherapies in many organ systems.

These issues are especially relevant to arteries, where stent-based delivery allows fine control of locally directed drug release.

Local delivery produces tremendous drug concentration gradients

• these are in part derived from transport forces,
• differences in deposition from tissue to tissue

This suggests that tissue ultrastructure also plays an important role.

Authors measured the equilibrium drug uptake and the penetration and diffusivity of

• dextrans (a model hydrophilic drug similar to heparin) and albumin
• in orthogonal planes in arteries explanted from different vascular beds.

Authors found significant variations in drug distribution with

• geometric orientation and
• arterial connective tissue content.

Drug diffusivities parallel to the connective tissue sheaths were

• one to two orders of magnitude greater than across these sheaths.

This diffusivity difference remained relatively constant for drugs up to 70 kDa

• before decreasing for larger drugs.

Drugs also distributed better into elastic arteries, especially at lower molecular weights,

• with almost 66% greater transfer into the thoracic aorta
• than into the carotid artery.

Arterial drug transport is thus highly anisotropic and

• dependent on arterial tissue content.

The role of the local composition and geometric organization of arterial tissue

• in influencing vascular pharmacokinetics

is likely to become a critical consideration for local vascular drug delivery (2)

Radiolabeled drug-eluting stents have been proposed

• to potentially reduce restenosis in coronary arteries.

A P-32 labeled oligonucleotide (ODN) loaded on a polymer coated stent

• is slowly released in the arterial wall to deliver a therapeutic dose to the target tissue.

A relatively low proportion of drugs is transferred to the arterial wall (< 2%– 5% typically). This raises questions about the degree to which radiolabeled drugs eluted from the stent

• can contribute to the total radiation dose delivered to tissues.

A three-dimensional diffusion-convection transport model is used

• to model the transport of a hydrophilic drug released
• from the surface of a stent to the arterial media.

Large drug concentration gradients are observed

• near the stent struts giving rise to a
• non-uniform radiation activity distribution for the drug
• in the tissues as a function of time.

A voxel-based kernel convolution method is used to calculate the radiation dose rate

• resulting from this activity build-up in the arterial wall
• based on the medical internal radiation dose formalism.

Measured residence time for the P-32 ODN in the arterial wall and

• at the stent surface obtained from animal studies
• are used to normalize the results in terms of absolute dose to tissue.

The results indicate radiation due to drug eluted from the stent

• contributes only a small fraction of the total radiation delivered to the arterial wall,
• the main contribution comes from the activity embedded in the stent coating.

For hydrophilic compounds with rapid transit times in arterial tissue and minimal binding interactions,

• the activity build-up in the arterial wall contributes only a small fraction
• to the total dose delivered by the P-32 ODN stent.

For these compounds, it is concluded that radiolabeled drug-eluting stent

• would not improve the performance of radioactive stents in treating restenosis.

Also, variability in the efficacy of drug delivery devices

• makes accurate dosimetry difficult and
• the drug washout in the systemic circulatory system

may yield an unnecessary activity build-up and dose to healthy organs. (3)

The first compounds considered for stent-based delivery,

• such as heparin have failed to stop restenosis clinically.

More recent compounds, such as paclitaxel, are of a different sort.

They are hydrophobic, and their effects after local release seem far more profound.

This dichotomy raises the question of whether drugs that have an effect when released from a stent do so because of

• differences in biology or differences in physicochemical properties and targeting.

Authored applied continuum pharmacokinetics to examine the effects of

• transport forces and device geometry on

the distribution of stent-delivered hydrophilic and hydrophobic drugs.

Stent-based delivery leads to large concentration gradients.

Drug concentrations range from nil to several times the

• mean tissue concentration over a few micrometers.

Concentration variations were a function of the Peclet number (Pe),

• the ratio of convective to diffusive forces.

Although hydrophobic drugs exhibit greater variability than hydrophilic drugs,

• they achieve higher mean concentrations and
• they remain closer to the intima.

Inhomogeneous strut placement influences hydrophilic drugs

• more negatively than hydrophobic drugs, and notably
• affect local concentrations without changing mean concentrations.

Local concentrations and gradients are inextricably linked to biological effect. Therefore,

• these results provide a potential explanation for the variable success of stent-based delivery.

Authors conclude that mere proximity of delivery devices to tissues

• does not ensure adequate targeting,
• because physiological transport forces cause
• local concentrations to deviate significantly from mean concentrations. (4)

1.  Role of CABG in the management of obstructive coronary arterial disease in patients with diabetes mellitus. D Aronson, ER Edelman.  Curr Opin Pharmacol 2012, 12:134–141. Issue on Cardiovascular and renal. [Eds: JY Jeremy, K Zacharowski, N Shukla, S Wan].  http://dx.doi.org/10.1016/j.coph.2012.01.011

2.  Arterial Ultrastructure Influences Transport of Locally Delivered Drugs. Chao-Wei Hwang, ER Edelman. Circ Res. 2002; 90:826-832. http://www.circresaha.org/dx.doi.org/10.1161/01.RES.0000016672.26000.9E

3.  Dose model for stent-based delivery of a radioactive compound for the treatment of restenosis in coronary arteries. C Janickia, Chao-Wei Hwang, ER Edelman.  Med Phys 2003; 30(10), 2622-7.    http://dx.doi.org/10.1118/1.1607506

4.  Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery. Chao-Wei Hwang, D Wu, ER Edelman. Circulation. 2001;104(5) :600-605; e14 – e9010.     http://dx.doi.org/10.1161/hc3101.09221

Stent-Versus-Stent Equivalency Trials. Are Some Stents More Equal Than Others? Elazer R. Edelman, Campbell Rogers Circulation. 1999; 100(9): 896-898; e47 – e47.  http://dx.doi.org/10.1161/01.CIR.100.9.896

New endovascular stent designs are displacing tried and-true devices for use in an ever-broader array of lesions. There is disagreement as to which device is most advantageous and whether design determines outcome. Preclinical research says that this should be the case. Clinical trials have failed to validate design dependence. Can the divergent results be reconciled? More than 50 different stent configurations are available. The processes of industrial development and federal regulatory evaluation support the importance of design.

Stents are made from

• a spectrum of materials
• a range of manufacturing techniques, and have
  • variable surfaces,
  • dimensions,
  • surface coverage, and
  • strut configurations.

The number of parameters involved may doom the number of subsets to approach the number of designs. Moreover, each device seems to have a unique optimal mode of placement.  Differences have been reported in

• flexibility,
• tracking ability,
• expansion,
• radiovisibility,
• side-branch access, and
• resistance to compression and recoil for different devices.

Regulatory approval includes standards for safety:

• toxicity,
• biocompatibility,
• structural and material analysis, and
• fatigue testing

It has been suggested that

• hoop strength,
• surface cracking,
• uniformity of expansion, and
• other features become standardized as well.

Four different direct comparisons of first-generation Palmaz-Schatz slotted-tube stents and

second-generation stents have been made. In several studies there were no significant differences

in restenosis at follow-up, including

• minimal luminal diameter (MLD),
• percent diameter stenosis,
• late loss, or
•  binary restenosis rate.

In the fourth study, restenosis was far greater for the Gianturco-Roubin II (GR-II) stent (Cook) than

• the Palmaz-Schatz stent (Cordis-Johnson & Johnson).

The data for all stents bunch across trials: with the exception of the GR-II stent,

variability between the test stent groups was no greater than

• the variability between the Palmaz-Schatz stent groups in the different trials.

Three distinct possibilities exist to explain the absence of clinical evidence that different designs behave differently:

(1) no differences in clinical outcomes exist between devices;

(2) differences exist but are so slight as to be clinically meaningless; and

(3) differences exist that may be clinically meaningful, but trials performed to date were not designed to detect them.

Schematic representation of device performance plotting outcome against indication indicates that

• complication rates rise as lesion complexity increases.

When 2 devices are clinically different, their curves are displaced, and when they are indistinguishable, their curves overlap.

Clinical trials that restrict the test population to lesions low on the complexity scale

• ensure safety for all patients but are not the ideal venues in which to detect differences between devices.

Thus, although stents 1 and 2 may have different clinical outcomes, in a restricted-criteria equivalency trial with low complexity, they appear identical. It is only when the test device performs worse than the standard, that differences can be appreciated.

In contrast, an open registry will not only show when a test stent is worse than the standard stent but also when it is better.

Equivalency Trials

Stent-versus-stent trials are equivalency trials, designed to show that a test device performs “as well as” a standard, currently acceptable device.  This is a valid regulatory threshold but

• not the means to evaluate the full potential of a device.

Equivalency trials must by definition commence with a patient population for whom the standard device is safe. Trials with currently approved devices as the standard necessitate that

• patient entry and lesion selection be determined by
• limitations of the standard, not the device.

to observe a difference in such a trial

•  the test device performs worse

For the test device to perform better, both the test and the standard must be challenged.

This was not the case for the trials in which

• the average reference vessel size was 3.0+0.05 mm and
• American College of Cardiology type B2 and C lesions accounted for only ~65% of lesions.

These lesions are those for which the Palmaz-Schatz stent is approved and technically suited, but

• they represent only a minority of those lesions now receiving stents

Complexity, Equivalence, and Better

In truth, it may be most appropriate to think about parameters of device success and safety as a continuum, describing a correlation between events such as

• thrombosis or restenosis and
• a continuous measure of indication,
• vessel dimension, or lesion complexity (Figure).

A given device may be represented by a characteristic response over a range of indications.

When there is a lateral offset to the curves,

• differences in potential performance are anticipated.

Curves might even cross, rather than run parallel, indicating that devices might be matched

to lesions and indications. Open trials would consider the entire range of the curves.

• equivalency trials are limited to a small region of the curve.

The first-generation stents were a major innovation in interventional cardiology, and their place in medical history and biotechnology is unassailable.

Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents

Demonstration that new stents are better than old will require that evaluations be

• performed in lesions for which current devices have marginal or limited application.

Complex or acutely unstable lesions, small arteries, and diseased bypass grafts are

• the next great challenges of interventional cardiology.

Perhaps in these settings, future stent trials will provide firm evidence that

• the manner in which blood vessels are manipulated dictates biological sequelae.

Proof that stent design can alter clinical outcomes may then unleash the potential

• to change the way in which we consider design, approval, and use of new devices.

REFERENCES

Menichelli, M. (2006). Sirolimus Stent vs. Bare Stent in Acute Myocardial Infarction Trial. Presented at The European Paris Course on Revascularization (EuroPCR), May 16-19, 2006, Paris, France Paris, France.http://www.medscape.com/viewprogram/5505?rss

Pfisterer, P.E. (2006). Basel Stent Cost-effectiveness Trial-Late Thrombotic events (BASKET LATE) Trial. Presented at American College of Cardiology 55th Annual Scientific Session, March 11 – 14, 2006, Atlanta, Georgia.http://www.medscape.com/viewprogram/5185 

Rogers, C. Edelman E.R. (2006). Pushing drug-eluting stents into uncharted territory, Simpler then you think – more complex than you imagine. Circulation,113, 2262-2265.

Shirota, T., Yasui, H., Shimokawa, H. & Matsuda, T. (2003). Fabrication of endothelial progenitor cell (EPC)-seeded intravascular stent devices and in vitro endothelialization on hybrid vascular tissue. Biomaterials 24(13), 2295–2302.

Simonton, C. (2006). The STENT Registry: A real-world look at Sirolimus- and Pacitaxel-Eluting Stents. Cath Lab Digest, 14 (1), 1-10.

Turco, M. (2006). TAXUS ATLAS Trial – 9-Month results: Evaluation of TAXUS Liberte vs. TAXUS Express. Presented at The European Paris Course on Revascularization (EuroPCR), May 16-19, 2006, Paris, France Paris, France.http://www.medscape.com/viewprogram/5505?rss

Verma, S. and Marsden, P.A. (2005). Nitric Oxide-Eluting Polyurethanes – Vascular Grafts of the Future? New England Journal Medicine, 353 (7), 730-731.

Wood, S. (2006). Guidant suspends release of Xience V everolimus-eluting stent due to manufacturing standards http://www.theheart.org/article/679851.do 

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Image via CrunchBase

Diagram showing the location of vascular smooth muscle cells (Photo credit: Wikipedia)

English: simplified diagram of the human Arterial system in anterior view. Français : Diagramme simplifié du système artériel humain en vue antérieure (en anglais). (Photo credit: Wikipedia)

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