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More than a decade ago, nanotechnology became an integral part of the overall scientific research world. Governments started funding programs specifically aimed at nanotechnology, research universities opened their facilities and coursework to the new discipline, and journals focusing on nano research became commonplace.And now, many researchers believe, its nanomedicines turn to do the same. Nanomedicinewhich has emerged as nanotechnologys most important sub-disciplineis the application of nanotechnology to the prevention and treatment of disease in the human body. It is already having an impact clinically among some of the deadliest diseases in the world.

Nanomedicine is far from the stuff of science fiction. The possibilities for nanomedicine to help us diagnose, treat and image diseases are endless. Imagine a smart nanomedicine that is able to bind to tumor cells and enhance imaging and diagnosis, at the same time as being able to deliver a gene therapy or chemotherapy agent. With the technologies available to us and our multidisciplinary teams, this will be possible in my lifetime, said Phoebe Phillips, head of the pancreatic cancer translational research group at the University of New South Wales in Sydney.

Phillips and her team have created a nanoparticle that dramatically increases its effectiveness as an anti-cancer drug for patients with pancreatic cancers, which is one of the fastest killing cancers from time of initial detection, often leaving patients with no suitable treatment options and only weeks to live.

While nanomedicine canand likely willplay a role in diagnostics, regenerative medicine, prosthetics and more, the effect the sub-discipline is currently having on the treatment of autoimmune diseases and cancers is significant.

Nanomedicine for HIVThirty years ago, a diagnosis of HIV/AIDS was essentially a guarantee of a painful, protracted death. It wasnt until 1996 that researchers discovered antiretroviral drugs, and the potent combination therapy that leads to successful management of HIV/AIDS in most cases. However, not much has changed since that discovery. Those suffering from the autoimmune disease still require daily oral dosing of three to four pills, and chronic oral dosing has significant complications that can arise from the high pill burden experienced by patients, leading to non-adherence to therapies for a variety of reasons.

Ive been working in HIV for over 20 years, Andrew Owen, professor of molecular and clinical pharmacology at the University of Liverpool (UK) told Laboratory Equipment. I was trying to understand the variability in drug exposure that occurs between different individuals and the genetic basis for that. We were finding a lot of interesting things, but they werent clinically implementable. They gave us a good understanding of why drug exposure was variable, but it didnt actually help the patients in any way.

In an attempt to solve the problem rather than just characterize it, Owen turned to nanomedicine in 2009, eventually becoming part of the first team to conduct human trials of orally dosed nanomedicines for HIV. Since then, Owen and his interdisciplinary team at the Liverpool Nanomedicine Partnership have secured more than 20 million of research funding for a multitude of nanomedicine-based approaches to HIV, such low-dose oral delivery, long-acting injectable medications and targeted delivery of antiretrovirals.

Some of Owens most important research to date tackles two of the pharmaceutical industrys biggest challenges: oral delivery of potent drugs and supply and demand.

One of the major problems that has plagued drug discovery and drug development over the last 30 years has been compatibility with oral drug delivery, Owen explained. The pharmaceutical industry has wrestled with that because they can develop very potent molecules across diseases, but actually delivering those molecules orally is very challenging. As you try to design into the molecule oral bioavailabilty, you usually get further away from the potency you want.

The Liverpool team solved this problem with the creation of Solid Drug Nanoparticles. The technology consists of combining a normal drug, in its solid form, with particles on that drug that are measurable within the nanometer scale. There are other things packed into the formulation as well, such as FDA-approved stabilizers that are proven to help disperse the drug. Owen says it is all about increasing the surface area covered by the drug.

If you imagine you take a granulated form of the drug, youre going to get big chunks of drugs in the intestinal tract when dissolution happens. But if you have nanometer-sized particles within the GI tract, then you are going to get a complete coating of the inside of the intestine after you take the drug, Owen explained. What that does is it massively increases the surface area covered by the drug, which saturates all sorts of drug influx processes within the GI tract.

Since 80 percent of a humans immune system is concentrated in the gut, the Solid Drug Nanoparticles are the perfect mechanism. The immune cells in the gut instinctually move toward the particles, creating a pathway for the drugs to cross the intestines, move through the lymphatic system, and finally into the systematic circulation.

In February, Owen presented the results of two trials at the Conference on Retroviruses and Opportunistic Infections (CROI) that confirmed his Solid Drug Nanoparticles can be effective at a 50 percent dose reduction. Specifically, Owen and his team applied the nanomedicine-based approach to the formulation of two drugs: efvirenz (EFV) and lopinavir (LPV). EFV is the current WHO-recommended regimen, with 70 percent of adult HIV patients in low- and middle-income countries taking the medication. At 50 percent of the dose, the patients in the trial were able to maintain plasma concentrations of the conventional dose.

Globally, the supply of drugs needed to treat every patient with HIV is outstripping manufacturing capabilitymeaning we, as a human species, cannot physically make enough HIV medication to treat everyone with the disease. A 50 percent reduction in dose means twice as many patients served with the existing drug supply.Owen and his team are working with multiple global partners to move the technology forward. For the drugs already formulated, the Medicines Patent Pool and Clinical Health Access are helping to scale up and take them to market. Meanwhile, USAIDs Project OPTIMIZE is applying the nanoparticle technology to the newest HIV drugs for use in low- and middle-income countries.

For their latest collaboration with Johns Hopkins University, the Liverpool team was just awarded $3 million to examine the use of implantable technologies that can deliver drugs for weeks, or even months.

The current oral drug regimens for HIV comprises three drugs in combinationone is the major driver for efficacy, and the other two are nucleoside reverse transcriptase inhibitors that prevent resistance to the main drug. However, current injectable formulations are only available with the main drugnone include the nucleoside reverse transcriptase inhibitors.

So, our project aims to develop the first long-acting injectable nucleoside reverse transcriptase inhibitors so that we can use them to have a fully long-acting regimen that matches the current clinical paradigm for therapy, Owen said.

The Liverpool/Hopkins team has also thought about applying their long-acting injectable technology to other chronic diseases, such as malaria and tuberculosis, as well as some cardiovascular applications.

Nanomedicine for diabetesWhen the nanoparticles he was working with as an imaging tool didnt produce the desired results, Pere Santamaria grew frustratedbut he didnt give up. Instead, the doctor and professor at the University of Calgary (Canada) changed his assumptions and pursued his experimentuntil the data came pouring in that confirmed it wasnt a failed experiment at all. Rather, it was a discovery.

The discovery of Navacims was a bit serendipitous, Santamaria told Laboratory Equipment. Thankfully I am a little OCD and I didnt let the failed experiment go.Navacims are an entirely new class of nanomedicine drugs that harness the ability to stop disease without impairing normal immunity. Santamaria has been studying Navacims for the past 17 years, ever since unintentionally developing them. He even started a spin-off company, Parvus Therapeutics, Inc., to help bring the drugs to market.

In autoimmune diseases, white blood cells, which are normally responsible for warding off foreign invaders and disease, turn on the body, attacking the good cells and causing their destruction. Each specific autoimmune disease results from an attack against thousands of individual protein fragments in the targeted organ, such as the insulin-producing pancreatic cells in the case of type 1 diabetes.

But Santamarias studies show that nanoparticles decorated with protein targets acting as bait for disease-causing white blood cells can actually be used to reprogram the cells to rightfully suppress the disease they once intended to cause.

Once the immune system recognizes the presence of a Navacim, a white blood cell is reprogrammed by epigenetic changes into a lymphocyte that no longer wants to cause tissue damage, but rather work to suppress disease. According to Santamaria, the reprogramming step is immediately followed by an expansion of that population of lymphocytesone now-good white blood cell dividing into a million.

Basically they turn the tables on the immune system, and then there is a very sophisticated series of downstream cellular events that arise from that reprogramming event that involves the recruitment of other lymphocytes and other cell types that completely suppress the inflammation in the organ that is being infected, Santamaria explained. This happens extremely efficiently and comprehensively. This is an approach that can efficiently, selectively and specifically blend a complex response without impairing basic immunity.

In addition, the design of Navacims is modular, meaning the nanomedicine can be applied to severalif not allautoimmune diseases, including multiple sclerosis and rheumatoid arthritis. Navacims can be altered to target different diseases by simply changing a small portion of the bait molecules on the nanoparticles. Santamarias studies have shown this to work in about seven autoimmune diseases thus far.

In April, Santamarias company Parvus entered into a license and collaboration agreement with Novartis for Navacims. Under the terms of the agreement, Novartis receives exclusive worldwide rights to use Parvus Navacim technology to develop and commercialize products for the treatment of type 1 diabetes, and will be responsible for clinical-stage development and commercialization. Parvus will still be responsible for conducting ongoing preclinical work in the diabetes area, with some research funding from Novartis.

Weve had such a long time to prove ourselves, that this is not a flash in the pan, that this is something serious and robust, Santamaria said. We know so much about the mechanisms of our actions, and so much granularity. I think there are no other drugs that have reached the clinic with this level of understanding. That was painful in the beginning for us, but in the end its going to be good.

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The Promise of Nanomedicine - Laboratory Equipment

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