The smallest of revolutions

Designed to operate at the cellular or subcellular level and often exhibiting unique physical properties due to their increasingly small size – engineered nanometric tools offer huge potential developments in medicine

The nanotechnology story can be traced back to 1959 when Richard Feynman invited scientists to enter a new field of physics1: “Biology is not simply writing information; it is doing something about it. Consider the possibility that we too can make a thing very small. Atoms on a small scale behave like nothing on a large scale, for they satisfy the laws of quantum mechanics.”

From this period, one of most exciting features of “manoeuvring things by atoms” was the very new physical, chemical, biological, electrical and mechanical properties arising from engineered objects at the nanoscale. This scale perfectly matches the size of biological structures, giving the potential to act at the cellular and subcellular levels.

Both nanoscience and nanotechnology deal with matter at the nanometre scale, i.e. one nanometre is one million of a millimetre. The size of engineered nanoscale objects for healthcare may range between 1 and 1000nm and typically, a protein lies between 3 and 10nm whereas a red blood cell can be sized between 6000 and 8000nm.

One key feature of material at a nanoscale is that reducing the size of objects can impact or change their physical properties; being ‘nano’ gives unique properties or functions that cannot be achieved at other size scale. Examples of quantum size effect may be found in semiconductor nanocrystals (quantum dots) or gold nanoparticles with quantum dots possessing electronic properties intermediate between those of bulk semiconductors and of discrete molecules, and gold nanoparticles exhibiting specific optical properties which are dependent upon the nanoparticles’ shape and size.

The European Technology Platform on Nanomedicine (ETPN) proposes a definition of ‘nanomedicine’ as the application of nanotechnology to achieve breakthrough in healthcare. It exploits the improved and often novel physical, chemical and biological properties of materials at the nanometre scale. Nanomedicine has the potential to enable early detection and prevention, and to essentially improve diagnosis, treatment and follow-up of diseases2.

It is interesting to note that nature uses physical properties such as shape, compartmentalisation and mechanical properties to control numerous biological functions. Modern science has recently learned how to synthesise a bewildering array of artificial materials with structure that is engineered at the atomic scale. Indeed, nanomedicine has created an unprecedented opportunity to “twist” the original biological structures, using ‘inert’ engineered objects as ‘nanometric tools’ that have the ability to enter, translocate within, and impact on the cellular physiology. Consequently, nanomedicine is an interdisciplinary science involving competencies of biologists, chemists, physicists, engineers and clinicians.

The nanomedicine field has already covered a broad range of applications, offering new tools for the in vitro and in vivo diagnosis, therapy, or regenerative medicine3,4.

[caption id="attachment_36632" align="alignright" width="200"] Schematic showing how nanosized objects have evolved to become the active therapeutic or diagnostic principle and can bring a physical mode of action at the cellular or subcellular level.[/caption]

New in vitro diagnostic tools aim to increase test performance, improve reliability and accuracy of the results, enable the miniaturisation of tools, and allow cost reduction. In vitro diagnostic tools typically include sensors (bio-sensors or chemo-sensors) and nanoanalytical tools. A biosensor is a sensor that contains a biological element, such as an enzyme, capable of recognising and “signalling” the presence, activity or concentration of a specific biological molecule in solution – applications include pregnancy tests or blood glucose tests currently used by diabetics. Nanoanalytical tools on the other hand comprise surface microscopy, imaging mass spectrometry and advanced ultrasonic technologies, which can be used to analyse the composition of tissues in the body, for example.

Similarly, novel in vivo diagnostic tools aim to improve early detection of diseases, bring more powerful imaging technologies, increase targeting and specificity, decrease detection threshold and enable miniaturisation of tools. These tools typically include imaging markers with examples being fluorescent nanoparticles, or radioactive tracers and devices such as endoscopic probes and catheters coupled with nanosensors.

There are increasingly innovative therapeutic tools which aim to increase the efficacy of a drug while decreasing its potential toxicity, reduce the cost of a treatment by decreasing the quantity of the active ingredient needed, get more targeted therapies, and develop new therapeutic approaches and mechanisms of action. These innovative therapies include drug delivery systems, devices such as those used in cardiac surgery and active nanoelements. Classical drug delivery systems are based on liposomes, nanocrystals or virus-like particles whereas active nanoelements include nanoparticles that may be activated by an external source, such as ultrasounds, laser, magnetic field or ionising radiations source. They may also be active per se such as embospheres which are used in embolisation procedures.

In addition to new therapeutics, nanomedicine can be applied to regenerative medicine – a field which holds promise for repairing or replacing damaged tissues and organs in the body. Regeneration of tissues can be achieved by the combination of living cells, which will provide biological functionality, and nanomaterials, which act as scaffolds to support cell proliferation.

The profusion of nanomedicine applications is growing remarkably with patent activities rising steeply since 2000 – more than 2000 patents were filled in 2003 compared to about 500 in 20005. In a recent detailed search of the literature, clinical trial data, and the web, 247 applications and products were identified as being approved for use, under clinical study, or on the verge of clinical study6 and it is thought that by 2015, the nanomedicine market could represent a $170 billion opportunity3.

Where do nanosized objects bring value? A characteristic feature of nanotechnology is its potential for adding new functionality to existing products. The drug delivery systems aim ideally to improve the bioavailability of the drug. Doxil, a pegylated-stabilised liposomal doxorubicin, and Abraxane, an albumin protein-bound paclitaxel, are examples of drug delivery systems on the market for cancer treatment: another is Bind-014, a targeted multifunctional polymeric nanoparticle complex containing docetaxel currently in the clinic for advanced or metastatic solid tumours. These drug delivery systems certainly bring more efficient tools but they do not change the fundamental of treatment.

A new area of research is now emerging where nanosized objects are used to develop novel therapies in which they play the pivotal therapeutic role. Those engineered nano-objects have bridged the gap between the molecular tools (drugs or biologics), and macroscopic tools (radiation sources, imaging systems, etc.). Nanosized tools alone can bring a physical mode of action at the cellular or subcellular level, which constitutes an unprecedented way of medical intervention (Figure 1).

Prominent examples for such a nanomedicine are nanotechnologies developed for the local treatment of cancers. For instance, heat is an interesting mechanism of action of new anticancer nanoproducts. Nanospectra Biosciences, a spin off from Rice University, has developed core-shell nanoparticles (AuroShell) consisting of a gold metal shell and a dielectric silica core. Nanospectra Biosciences’ AuroLase therapy utilises the unique "optical tunability" of this new class of nanoparticles that can convert light (from a near-infrared laser) into heat to thermally destroy a solid tumour. The company is currently running two clinical trials in patients with primary and/or metastatic lung tumours and in patients with refractory and/or recurrent tumours of the head and neck. Also, MagForce Nanotech, a German company, has developed superparamagnetic iron oxide nanoparticles which generate heat when activated by an alternating magnetic field. Magforce Nanotech received the European regulatory approval for their NanoTherm therapy (CE European conformity marking) in 2011.

From a medical perspective, ionising radiation is the most powerful anticancer tool based on physics. Radiation is a universal cytotoxic which breaks DNA, as the principle molecular target for killing tumour cells; however, radiation always crosses through and affects tissues surrounding the tumour and often the dose required to effectively shrink the tumour cannot be delivered (frequently demonstrated by cancer relapse) because it would damage the healthy tissues. To address this challenge, Nanobiotix S.A. has developed nanoparticles which offer the possibility to deposit a high amount of energy within the cancer cells when exposed to ionising radiations. These nanoparticles constitute high electron density objects, of well-defined size and shape, which are internalised by the cancer cells and increase the dose of lethal energy inside, without passing the normal tissues.

The French company has built the NanoXray pipeline based on nanoparticles, which bring a physical mode of action, that of radiotherapy, at the subcellular level. The foundation of the NanoXray therapeutics is based on the highly electron dense material hafnium oxide, at the nanometre scale. The hafnium oxide nanoparticles are activated by X-rays and the excitation determines the production of a significant amount of energy within the cancer cells, triggering destruction of the tumour. This anticancer approach represents a breakthrough, as a physical mode of action directly generated within the tumour structure. Nanobiotix’s lead product NBTXR3 is currently being evaluated in two Phase I clinical trials for patients with locally advanced cancers: adult soft tissue sarcomas and squamous cell carcinomas of the oral cavity and oropharynx.

In conclusion, nanomedicine – the application of the nanotechnology to the healthcare field – is essential to address the unmet medical needs of both today and in the future. The most promising approaches are likely to rely on innovative breakthroughs, which use nanosized objects as the active therapeutic or diagnostic principle. Also in this context, the use of nanomaterials applied to synthetic biology may open up the possibility of regenerating tissues and functions, something which has to date not yet been achieved. These new nanometre tools are revolutionising ways of approaching the treatment and diagnosis of diseases in most medical fields and nanoproducts for human healthcare are opening new and significant opportunities to the pharmaceutical industry.

References

1. Richard Feynman. There’s Plenty of Room at the Bottom; An invitation to enter a new field of physics. Engineering and science, 1960.

2. Nanomedicine, Nanotechnology for Health. European Technology Platform, Strategic Research Agenda for Nanomedicine. November, 2006.

3. Keys results of 2008. LEEM, Nanomedicine Study. 8 October 2008.

4. Boisseau P., Loubaton B. Nanomedicine, nanotechnology in medicine. C.R. Physique, 2011, 12:620-636.

5. Wagner V., Dullaart A., Bock A-K., Zweck A. The emerging Nanomedicine landscape. Nature Biotechnology, 2006, 24(10):1211-1217.

6. Etheridge M.L., Campbell S.A., Erdman A.G., Haynes C.L., Wolf S.M., McCullough J. The big picture on Nanomedicine: the state of investigational and approved Nanomedicine products. Nanomedicine: Nanotechnology, Biology, and Medicine, 2013, 9:1-14.

Authors Dr Agnès Pottier, Head of Discovery and Intellectual Property and Dr Elsa Borghi, Development and Medical Affairs Department Director at Nanobiotix.

Contact +33 (0)1 40 26 07 55 sarah.gaubert@nanobiotix.com