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The Mega-Appeal of Nanomedicine

The European Union is banking on big returns from nanotechnology in the fight against AD.

European Union Throws Megabucks at Nanomedicine

Good things come in small packages; at least that’s what the European Union (EU) is banking on. The EU’s current major funding initiative for research, the Seventh Framework Programme (FP7), is making a push for projects that apply nanotechnology to disease diagnosis and therapy. About $15 million went to one big collaborative project on Alzheimer’s disease (AD), and millions more to other joint projects, individual investigators, and training grants, according to a July 28 editorial in Nanomedicine by Cristina Gabellieri and Heico Frima of the EU’s directorate general for research and innovation. Nanotechnology in Alzheimer’s is a young field, with data starting to appear in the literature only in the past couple of years and more coming out this past summer.

Most research in the 27 EU member countries is funded at the national level by private and public sources, but the framework programs, which have been ongoing since 1984, provide additional cash for European researchers. The FP7, which started in 2007 and will continue until 2013 with a budget of €53.2 billion (US$75.9 billion), identified nanotechnology as one of 10 research themes to fund through its cooperation program. That program supports collaborative projects and accounts for 60 percent of the FP7 budget. FP7 has already invested €265 million (US$378 million) in projects that apply nanotechnology to disease-related research, a field known as nanomedicine. The support so far represents a 31 percent increase compared to what was funded through the nanotechnology theme within the entire FP6, which ran from 2002 to 2006, write Gabellieri and Frima. An additional €55 million went to nanomedicine projects funded through the “health” theme within the FP7. (View a listing of funded projects in targeted nanopharmaceuticals and early diagnostics.)

Although this funding is substantial, especially when it comes to a field that is largely untested, the EU has put in place measures to ensure that the cash is well spent. To apply for a cooperation grant, researchers need to lay out at the proposal stage a detailed work plan with a list of deliverables and milestones to be met during the course of the project as explained in the Guide to Applicants. Once a grant is awarded, the consortium has to report to the funding body every 18 months—or every 12 months for projects receiving more than €10 million. “The consortium has to send a report on the scientific activities, dissemination of the results, management, explanation on the use of the resources,” wrote Gabellieri in an e-mail to ARF. Each project has a coordinator who makes sure that the project is implemented according to schedule. “If a project falls behind schedule, a revised work plan has to be presented to readdress the pending issues, which still have to be in line with the original call and evaluation. If these changes are major, an amendment of the contract is required. In case of major failure, the whole project or the participation of some partners may be terminated,” wrote Gabellieri.

Among the funded projects, Gabellieri and Frima’s article highlights a project dubbed NAD, or Nanoparticles for Therapy and Diagnosis of Alzheimer's Disease. It aims to design nanometer-sized particles that incorporate different combinations of functional groups—from those that target amyloid and gain access into the brain, to imaging contrast agents and chemicals that make the particles more stable—in an effort to find compounds that can slow down the progression of AD. With a budget of €14.37 million (US$20.8 million) over five years, of which €10.92 million comes from the FP7 and the rest from host institutions (such contributions are a requirement of these EU grants), NAD is “one of the larger projects we are funding in nanomedicine,” Gabellieri told ARF.

What is the benefit of applying nanomedicine to AD, the esteemed reader may well ask? In a sense, nanoscale materials have been a part of AD research for a while—that is, in some of the amyloid imaging agents used. But nanomedicine as a discipline unto itself has really taken off in the past decade, mostly in the cancer field. There, a handful of agents has been approved for clinical use, for example, Doxil, in which the drug doxorubicin is bound to liposomes, and hundreds are in clinical trials. In cancer therapy, nanoparticles—which can be organic molecules like lipids or proteins or inorganic ones like gold spheres—are decorated with drugs and other components that can seek out and bind to tumor cells. “Nanoparticles change the biodistribution of a drug to help increase its concentration in tumors,” said Terry Allen, a pharmacologist who works on drug-delivery methods at the University of Alberta, Canada. Nanoparticles provide other advantages, such as protecting bound molecules from degradation. “They can also release drug more slowly over longer periods of time, so that you have to give the drug less often to a patient,” added Allen.

Another application of nanomedicines is the development of imaging agents for tumors. One approach uses semiconductor quantum dots—2 to 10 nanometer-wide crystals that emit light of different color depending on their size—that can be coupled to molecules that bind tumor cells. When used in conjunction with magnetic resonance imaging (MRI), quantum dots can produce higher-contrast images than conventional dyes, although concerns about possible toxicity of these nanoparticles still need to be addressed before they can make their way into the clinic. Quantum dots are also starting to appear in AD research as tools for imaging amyloid-β (Aβ) aggregates (see ARF related news story on Tokuraku et al., 2009) and studying Aβ toxicity (see ARF related news story on Renner et al., 2010).

Given initial promising developments in cancer, more and more researchers are starting to look at Alzheimer’s as a possible indication for nanoscale approaches. “We know a lot about nanoparticles in cancer. It is a natural progression to move this technology to Alzheimer’s, where there is a lack of diagnosis and treatment,” said Tara Spires-Jones at Massachusetts General Hospital, who is applying nanomedicine to the early diagnosis of AD. “We need all the new ideas for therapies that we can get,” said William Klunk of the University of Pittsburgh, Pennsyvania.

Part 2 of this series discusses some of the challenges of nanomedicine in AD and the progress NAD researchers and others have made in tackling them.—Laura Bonetta

This is Part 1 of a two-part series. See also Part 2.

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References

News Citations

  1. Quantum Leap? Nanoprobes Track Aβ Aggregation in Real Time
  2. Aβ Oligomers: A Fatal Attraction for Glutamate Receptors?
  3. EU Consortium Applies Nanotechnology to Study AD

Paper Citations

  1. . Real-time imaging and quantification of amyloid-beta peptide aggregates by novel quantum-dot nanoprobes. PLoS One. 2009;4(12):e8492. PubMed.
  2. . Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron. 2010 Jun 10;66(5):739-54. PubMed.

External Citations

  1. listing of funded projects
  2. Guide to Applicants

Further Reading

EU Consortium Applies Nanotechnology to Study AD

Most research into nanomedicine, the application of nanoscale materials and processes to medical problems, has focused on cancer. Now researchers are starting to see opportunities for these approaches in Alzheimer’s disease (AD). With its Seventh Framework Programme (FP7) for research, the European Union (EU) has boosted funding of nanomedicine, especially projects involving large cross-European collaborations, to help move the technology forward (see Part 1). One project that has benefited is Nanoparticles for Therapy and Diagnosis of Alzheimer's Disease, aka NAD. With a budget of €14.37 million (US$20.8 million), this project aims to find nanometer-sized particles that can slow the progression of AD.

One of the challenges for applying nanomedicine approaches to AD is that the drugs or imaging agents have to be transported across the blood-brain barrier to the brain—no easy feat. To solve this problem, Massimo Masserini of the Universitá Degli Studi di Milano-Bicocca in Italy, who heads the NAD project, said, “It was important to put together a big task force.” Masserini assembled a group of 19 research groups from 13 European countries spanning different areas of expertise. “NAD is a very large consortium. They have experts in the chemistry of ligands and nanoparticles, biochemists, pharmacologists, people in charge of commercializing medical products, and clinicians,” said Terry Allen, a pharmacologist who works on drug-delivery methods at the University of Alberta, Canada, and is a member of the international advisory board for NAD. “I don’t know of another large group taking this nanotechnology-based approach to AD.”

Since the project’s launch in October 2008, NAD researchers have designed a number of natural and synthetic nanoparticles that are eventually degraded in the body, reducing concerns about toxicity. Julien Nicolas, a polymer chemist in Patrick Courvreur’s group at the Université Paris-Sud in Châtenay-Malabry, France, synthesized biodegradable polymeric nanoparticles covered by chains of polyethylene glycol (PEG), which helps hide the nanoparticles from the immune system. Other groups in NAD have developed solid lipid nanoparticles and liposomes. As a second step, these nanoparticles have been linked to an array of ligands that interact with amyloid-β (Aβ), such as acidic phospholipids, anti-Aβ antibodies, and a derivative of the molecule curcumin, which is purported to break up Aβ aggregates (see ARF related news story on Yang et al., 2005). Since last December, the NAD group has published several papers showing that various combinations of ligands and nanoparticles bind Aβ in blood and brain tissue samples (Brambilla et al., 2010; Canovi et al., 2011; Mourtas et al., 2011; Gobbi et al., 2010). They then reported that these agents, when applied to neurons in culture, can reduce Aβ toxicity, said Masserini (Bereczki et al., 2011).

The scientists are now planning to deploy their arsenal of compounds in two ways: One is to couple them with other ligands that will get them across the blood-brain barrier into the brain, where they can target amyloid deposits directly; the other is to try to clear Aβ from the blood and hope it will reduce Aβ in the brain through a sink effect (see ARF related news story on Yamada et al., 2009). “There is a theory that Aβ in the blood and brain are in equilibrium,” said Nicolas. “Some people believe that removal of Aβ from blood will displace this equilibrium and cause Aβ to clear the brain.” Researchers have had some success with this approach in mouse models (see ARF related news story on DeMattos et al., 2001) and an anti- Aβ antibody postulated to work in this way has been advanced to Phase 3 trials (seesolanezumab and ARF related news story). To test this approach, “we have made some nanoparticles in such a way that they will not have a long circulating time,” said Sophia Antimisiaris of the University of Patras in Greece. “But they stay in the circulation long enough that they can bind Aβ and extract it from the blood.” Taking this strategy would bypass the problem of having to cross the blood-brain barrier, but Antimisiaris acknowledged that it is a longshot, as the peripheral sink hypothesis remains controversial. Even so, the group has started to test their initial non-barrier-crossing compounds in animal models of AD. “We are really at the beginning of the story,” said Gianluigi Forloni of the Mario Negri Institute in Milan, Italy, whose group is carrying out the animal work.

At the same time, the NAD group is designing nanoparticles that will access the brain by incorporating ligands such as the molecule transferrin, which binds to a receptor on the endothelial cells of the blood-brain barrier (Markoutsa et al., 2011) and is already being tested for ferrying antibodies into the brain to block Aβ production (see ARF related news story). NAD researchers are also adding to the nanoparticles PET and MRI contrast agents for Aβ so that they could monitor the progression of disease at the same time they deliver therapy (Skouras et al. 2011). Masserini refers to this approach as theranostics, variously spelled theragnostics (e.g., Zetterberg et al., 2011).

The NAD project is about halfway through its funding cycle. In the next two and a half years, Masserini said the consortium should complete experiments testing several compounds in transgenic mice. “It is a high-risk but potentially high-reward project if it works out,” said Cristina Gabellieri of the EU’s directorate general for research and innovation.

Not Just Therapy
Although new therapies against AD are sorely needed, just as important are methods to diagnose the disease at an earlier stage than is currently possible, as the failure of several candidate drugs at Phase 3 trials suggest that treatment may have started when it was already too late (see ARF related news story). “The real potential for nanotechnology may lie in detecting disease at an early stage. If we can do that, we can then apply therapies either delivered by nanoparticles or in a traditional fashion,” said Tara Spires-Jones at Massachusetts General Hospital. “Right now we have a wonderful agent, PIB, that crosses the blood-brain barrier and binds to Aβ plaques, but we have no way of imaging oligomeric or soluble Aβ. We also have no markers for tau that cross the blood-brain barrier,” she added (see ARF related news story). Such agents might allow the detection of disease at earlier stages than imaging plaques. Although NAD is not investigating such compounds, this is something that Spires’ group and others are doing, but that work has not yet been published.

Besides delivering imaging agents to the brain, nanoscale approaches can help detect AD biomarkers in the CSF or blood (see ARF related news story on Haes et al. 2005). The EU FP7 has given a separate €9 million grant to a large consortium called NADINE (Nanosystems for the Early Diagnosis of Neurodegenerative Diseases) that aims to develop a nanofluidics-based system for measuring AD biomarkers in blood. “Nanotechnology opens the door for lower-cost tests and developing devices that can detect small amounts of the biomarker,” said Susana Aznar Kleijn at the Technical University of Denmark in Kongens Lyngby, north of Copenhagen, the project’s coordinating center. The consortium is currently conducting experiments to establish the best biomarkers and sensor approaches.

A smaller FP7 project also developing a blood test for AD is Nanognostic. With a budget of €5.3 million (of which €4 million comes from the FP7), this collaborative project will attempt to develop a diagnostic for AD based on five proteins chosen from a panel of 18 shown to be predictive of AD (see ARF related news story on Ray et al., 2007). Their strategy uses fluorescence resonance energy transfer (FRET) from luminescent lanthanide complexes to semiconductor quantum dots, both of which are linked with antibodies and aptamers that recognize the five proteins. “The system that we are developing can measure small amounts of proteins in blood sensitively and very quickly. You can measure multiple proteins simultaneously in one sample,” said Niko Hildebrandt at the Université Paris-Sud in Orsay, France. In a proof-of-principle paper, the scientists showed that the technique can work with proteins unrelated to AD (Geissler et al., 2010); they are now applying the method to samples from AD patients.

“The EU has been very quick in calling for proposals for new promising technology that they want to grow, and in having researchers with existing expertise work together,” said Pieter Jelle Visser at Maastricht University in The Netherlands and a member of the European Alzheimer's Disease Consortium and the EU’s Joint Programming Initiative on Neurodegeneration. “I think it’s a good thing.”—Laura Bonetta

This concludes a two-part series on nanomedicine. See also Part 1.

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References

News Citations

  1. European Union Throws Megabucks at Nanomedicine
  2. Curry Ingredient Spices Things Up by Blocking Aβ Aggregation
  3. Sink or Swim?—New Take on Aβ Antibody’s Modus Operandi
  4. Two Ways to Attack Amyloid: Metal Chelator and Antibody
  5. Chicago: Lilly’s Antibody Appears to Do No Harm, But Will It Help?
  6. Smuggling Antibodies to BACE Across the Blood-Brain Barrier
  7. Paris: More Trial News, Mixed at Best
  8. Hot Stuff—PIB News From the Pacific Rim
  9. Nanosensor Sizes up Amyloid-β Oligomers in CSF
  10. A Blood Test for AD?

Therapeutics Citations

  1. Curcumin
  2. Solanezumab

Paper Citations

  1. . Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005 Feb 18;280(7):5892-901. PubMed.
  2. . New method based on capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) to monitor interaction between nanoparticles and the amyloid-β peptide. Anal Chem. 2010 Dec 15;82(24):10083-9. PubMed.
  3. . The binding affinity of anti-Aβ1-42 MAb-decorated nanoliposomes to Aβ1-42 peptides in vitro and to amyloid deposits in post-mortem tissue. Biomaterials. 2011 Aug;32(23):5489-97. PubMed.
  4. . Curcumin-decorated nanoliposomes with very high affinity for amyloid-β1-42 peptide. Biomaterials. 2011 Feb;32(6):1635-45. PubMed.
  5. . Lipid-based nanoparticles with high binding affinity for amyloid-beta1-42 peptide. Biomaterials. 2010 Sep;31(25):6519-29. PubMed.
  6. . Liposomes functionalized with acidic lipids rescue Aβ-induced toxicity in murine neuroblastoma cells. Nanomedicine. 2011 Oct;7(5):560-71. PubMed.
  7. . Abeta immunotherapy: intracerebral sequestration of Abeta by an anti-Abeta monoclonal antibody 266 with high affinity to soluble Abeta. J Neurosci. 2009 Sep 9;29(36):11393-8. PubMed.
  8. . Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8850-5. Epub 2001 Jul 3 PubMed.
  9. . Uptake and permeability studies of BBB-targeting immunoliposomes using the hCMEC/D3 cell line. Eur J Pharm Biopharm. 2011 Feb;77(2):265-74. PubMed.
  10. . Magnetoliposomes with high USPIO entrapping efficiency, stability and magnetic properties. Nanomedicine. 2011 Oct;7(5):572-9. PubMed.
  11. . Use of theragnostic markers to select drugs for phase II/III trials for Alzheimer disease. Alzheimers Res Ther. 2010;2(6):32. PubMed.
  12. . Detection of a biomarker for Alzheimer's disease from synthetic and clinical samples using a nanoscale optical biosensor. J Am Chem Soc. 2005 Feb 23;127(7):2264-71. PubMed.
  13. . Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med. 2007 Nov;13(11):1359-62. PubMed.
  14. . Quantum dot biosensors for ultrasensitive multiplexed diagnostics. Angew Chem Int Ed Engl. 2010 Feb 15;49(8):1396-401. PubMed.

Further Reading