John Sterling Editor in Chief Genetic Engineering & Biotechnology News

A Growing Number of Researchers Cite Its Potential Therapeutic Benefits

Nanotechnology drug delivery is witnessing rapid growth, and increased nanotech R&D is developing novel nanomedicines with applications in a number of areas, such as cancer, neurology, anti-infectives, obesity, and cardiovascular disorders.

The global nanotechnology drug-delivery market has been segmented into the categories of nanocrystals, nanoparticles, liposomes, micelles, nanotubes, and others. The nanoparticles segment dominated the global nanotechnology drug-delivery market in 2014, and the nanotubes segment is expected to expand at the highest CAGR during the forecast period from 2015 to 2023.

The global nanotechnology drug-delivery market was valued at approximately $41 billion in 2014 and is projected to reach $118 billion by 2023, expanding at a compound annual growth rate (CAGR) of 12.5% from 2015 to 2023, according to Transparency Market Research.

One important and active nanotech drug-delivery application is transporting drugs to their final location for therapeutic intervention. Much of this innovative work in nanomedicine is taking place at universities and academic centers.

Phenanthriplatin-Carrying Nanoparticles

Scientists at Case Western Reserve University and MIT have demonstrated that the drug candidate phenanthriplatin can work better than an approved drug in vivo, and that a plant virus-based carrier successfully delivers a drug in vivo.

Triple-negative breast cancer tumors of mice treated with the phenanthriplatin-carrying nanoparticles were four times smaller than those treated either with cisplatin or free phenanthriplatin injected intravenously into circulation. Researchers believe this work is a promising step toward clinical trials.

“We may have found the perfect carrier for this particular drug candidate,” said Nicole Steinmetz, Ph.D., an assistant professor of biomedical engineering at Case Western Reserve University School of Medicine, who has spent 10 years studying the use of plant viruses for medical purposes. She teamed with Stephen J. Lippard, Ph.D., Arthur Amos Noyes Professor of chemistry at MIT, and an expert in biological interactions involving platinum-based chemotherapies.

Platinum-based drugs are used to treat more than half of cancer patients receiving chemotherapy. Two of the most commonly used drugs are cisplatin and carboplatin, which form bifunctional cross-links with DNA in cancer cells, blocking the DNA from transcribing genes and resulting in apoptosis, according to Dr. Lippard explained.

Despite widespread use, cisplatin is most effective against testicular cancer with a cure rate of abnout 90%. Dr. Lippard's lab altered cisplatin by replacing a chloride ion with phenanthridine and found that the new molecule also binds to DNA. Instead of forming cross-links, however, phenanthriplatin binds to a single site but still blocks transcription.

His lab also found that phenanthriplatin is up to 40 times more potent than traditional platins when tested directly against cancer cells of lung, breast, bone, and other tissues. This molecule also appears to avoid defense mechanisms that convey resistance. But when his team injected the drug in mouse models of cancer, it performed no better than standard platins. Dr. Lippard realized phenanthriplatin wasn't reaching its target and that he had a drug-delivery problem.

He found a potential solution when he visited Case Western Reserve's campus more than a year ago. There he heard Dr. Steinmetz explain her work investigating tobacco mosaic virus (TMV) for drug delivery . “I envisioned that TMV would be the perfect vehicle,” Dr. Lippard said. “So we formed a collaboration.”

The long, thin TMV nanoparticles are naturals for delivering the drug candidate into tumors, said Dr. Steinmetz. The virus particles, which won't infect humans, are hollow with a central tube about 4 nanometers (nm) in diameter that runs the length of the shell; the tube’s lining carries a negative charge.

The phenanthriplatin molecule is about 1 nm across and, when treated with silver nitrate, has a strong positive charge. Thus, it readily enters and binds to the central lining of the TMV nanoparticle. Because of its elongated shape, the TMV nanoparticle causes tumbling along the margins of blood vessels, remaining unnoticed by immune cells, passing through the leaky vasculature of tumors, and accumulating inside. Little healthy tissue is exposed to the toxic drug.

Inside tumors, the nanoparticles gather inside the lysosomal compartments of cancer cells, where they are, in essence, digested. Because the pH is much lower than in the circulating blood, explained  Dr. Steinmetz, the nanoparticle shell deteriorates and releases phenanthriplatin.

The shell is broken down into proteins and cleared through metabolic or natural cellular processes within a day while the drug candidate starts blocking transcription. The result is greater amounts of cell death via apoptosis than occurs with cross-linking platins.

The researchers say delivery of the phenanthriplatin into the tumor has led to its improved performance over cisplatin or free phenanthriplatin.

Drs. Lippard and Steinmetz say they continue to collaborate, investigating use of this system to deliver other drugs or drug candidates, for use in other types of cancers, and adding agents on the exterior of the nanoparticle shell to increase accumulation inside tumors and more.

Delivering Antiobesity Drugs

In Cambridge, Massachusetts, a team from Brigham and Women's Hospital and MIT have reported the development of nanoparticles that can deliver antiobesity drugs directly to fat tissue. Overweight mice treated with these nanoparticles lost 10% of their body weight over 25 days  without showing any negative side effects.

The drugs work by transforming white adipose tissue, which is made of fat-storing cells, into brown adipose tissue, which burns fat. The drugs also stimulate the growth of new blood vessels in fat tissue, which positively reinforces the nanoparticle targeting and aids in the white-to-brown transformation.

These drugs, which are not FDA approved to treat obesity, are not new, but the research team developed a novel method to deliver them so that they accumulate in fatty tissues, helping to avoid unwanted side effects in other parts of the body.

“The advantage here is now you have a way of targeting it [the drug] to a particular area and not giving the body systemic effects. You can get the positive effects that you'd want in terms of antiobesity but not the negative ones that sometimes occur,” says Robert Langer, Sc.D., the David H. Koch Institute Professor at MIT and a member of MIT's Koch Institute for Integrative Cancer Research.

Dr. Langer and his colleagues have shown that promoting angiogenesis can help transform adipose tissue and lead to weight loss in mice. However, drugs that promote angiogenesis can be harmful to the rest of the body.

To try to overcome these harmful effects, Dr. Langer and Omid Farokhzad, M.D., director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women's Hospital, turned to the nanoparticle drug-delivery strategy they have developed in recent years to treat cancer and other diseases. By targeting these particles to the disease site, they say they can deliver a powerful dose while minimizing the drug's accumulation in other areas.

The researchers designed the particles to carry the drugs in their hydrophobic cores, bound to a polymer known as poly(lactic-co-glycolic acid) (PLGA), which is used in many other drug-delivery particles and medical devices. They packaged two different drugs within the particles—rosiglitazone, which has been approved to treat diabetes but is not widely used due to adverse side effects, and an analog of prostaglandin. Both drugs activate the peroxisome proliferator-activated receptor (PPAR), which stimulates angiogenesis and adipose transformation.

The outer shell of the nanoparticles consists of a poly(ethylene glycol) (PEG) polymer embedded with targeting molecules that guide the particles to the correct destination. These targeting molecules bind to proteins found in the lining of the blood vessels that surround adipose tissue.

The researchers tested the particles in mice that had become obese after being fed a high-fat diet. The mice lost about 10% of their body weight, and their levels of cholesterol and triglycerides  also dropped. The mice also became more sensitive to insulin. (Obesity often leads to insulin insensitivity, which is a risk factor for type 2 diabetes). The mice did not show any side effects from the treatment, which was delivered every other day for 25 days.

With the current system, the particles are injected intravenously, which could make this approach suitable for morbidly obese patients who are at significant risk of obesity-related diseases, says Dr. Farokhzad. “For it to be more broadly applicable for treatment of obesity, we have to come up with easier ways to administer these targeted nanoparticles, such as orally,” he says.

The challenge to delivering nanoparticles orally is that it is difficult for them to penetrate the lining of the intestines. In a previous study, however, Drs. Langer and Farokhzad developed a nanoparticle coated with antibodies that bind to receptors found on surfaces of cells lining the intestine, allowing the nanoparticles to be absorbed through the digestive tract. More recently, Dr. Farokhzad and colleagues have developed another orally delivered nanoparticle that uses transferrin, a protein involved in the transport of iron in the body, to facilitate active transport of nanoparticles across the intestine.

The researchers also hope to find more specific adipose tissue targets for the nanoparticles, which could further reduce the possibility of side effects, and they may also investigate using other drugs with lower toxicity.

Microbivacs and Genital Herpes

An effective vaccine against the virus that causes genital herpes has evaded researchers for decades. (Note thought that the University Medical Center in Utrecht, The Netherlands, published a paper on June 30 in PLOS Pathogens that suggests that attacking herpesvirus DNA with CRISPR/Cas9 genome-editing technology can suppress virus replication and, in some cases, lead to elimination of the virus.)

Researchers at the University of Illinois at Chicago (UIC) working with scientists from Germany have shown that zinc-oxide nanoparticles shaped like jacks—zinc-oxide tetrapod nanoparticles or ZOTEN—can prevent the virus from entering cells and help natural immunity to develop.

“We call the virus-trapping nanoparticle a microbivac, because it possesses both microbicidal and vaccine-like properties,” says corresponding author Deepak Shukla, Ph.D., professor of ophthalmology and microbiology and immunology in the UIC College of Medicine. “It is a totally novel approach to developing a vaccine against herpes, and it could potentially also work for HIV and other viruses.”

The particles could serve as a powerful active ingredient in a topically applied vaginal cream that provides immediate protection against herpes virus infection while simultaneously helping stimulate immunity to the virus for long-term protection, he explained. Herpes simplex virus 2 (HSV-2), which causes serious eye infections in newborns and immunocompromised patients, as well as genital herpes, is one of the most common human viruses.

“Your chances of getting HIV are three to four times higher if you already have genital herpes, which is a very strong motivation for developing new ways of preventing herpes infection,” according to Dr. Shukla.

HSV-2 therapies include daily topical medications to suppress the virus and shorten the duration of outbreaks when the virus is active and genital lesions are present. However, drug resistance is common, and little protection is provided against further infections. Efforts to develop a vaccine have been unsuccessful because the virus does not spend much time in the bloodstream, where most traditional vaccines do their work.

ZOTEN have negatively charged surfaces that attract the HSV-2 virus, which has positively charged proteins on its outer envelope. ZOTEN are uniform in size and shape, thus making them attractive for use in other biomedical applications. They were synthesized using technology developed by material scientists at Germany's Kiel University and protected under a joint patent with UIC.

When bound to the nanoparticles, HSV-2 cannot infect cells. But the bound virus remains susceptible to processing by dendritic cells that patrol the vaginal lining. The dendritic cells present the virus to other immune cells that produce antibodies, which cripple the virus and trigger the production of killer cells that identify infected cells and destroy them before the virus can take over and spread.

The researchers showed that female mice swabbed with HSV-2 and an ointment containing ZOTEN had significantly fewer genital lesions than mice treated with a cream lacking ZOTEN. Mice treated with ZOTEN also had less inflammation in the central nervous system, where the virus can hide out.

The researchers were able to watch immune cells pry the virus off the nanoparticles for immune processing, using high-resolution fluorescence microscopy. “It's very clear that ZOTEN facilitate the development of immunity by holding the virus and letting the dendritic cells get to it,” said Dr. Shukla, adding that if found safe and effective in humans, a ZOTEN-containing cream ideally would be applied vaginally just prior to intercourse.


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