Decoding the Hype and Fear of Nanomedicines

Q: Nanotechnology is often hyped as either a miracle cure-all or a potential danger. How much of this is grounded in truth and what is the practical reality of the technology?

The rational design of advanced drug delivery systems and innovative nano-sized therapeutics (nanomedicines) began almost half a century ago. There are already more than 40 products approved by regulatory agencies for routine use, and many more technologies are also in clinical development. These first-generation products are making an important contribution and are seen to be safe and efficacious with an adequate risk–benefit. Follow-on products are also starting to emerge, as well as novel second-generation nanotechnologies that can be used as therapeutics, imaging agents and combined theranostics.

(VICTOR HABBICK VISIONS/GETTY IMAGES)

Innovative nanoscience in concert with the increased knowledge arising from genomics and proteomics research is creating exciting opportunities for nanomedicine development using advances in materials science and, in some cases, innovative therapeutics such as siRNA and aptamers. There is also real potential to develop novel multicomponent systems (e.g., those involving gold or iron nanoparticles, and polymers and therapeutics as single agents or combination therapies). More in depth discussion about the opportunities and challenges in these areas can be read in a Duncan and Gaspar paper (1).

Q: What new therapies can nanotechnology enable?

To answer this question, I advise readers to take a look at an interesting historical overview by B. Munos (2). He explains that during the last 60 years, the FDA has approved approximately 1200 new chemical entities, as well as around 120 biologicals/proteins. Roughly 40 nanomedicine products have also reached the market, which is interesting given the relatively minor investment of pharma companies in this area compared with that for low-molecular weight chemical entities and biotech products.

In the coming years, I believe we will see an increasing number of nanomedicine products. Consider for instance that low-molecular weight synthetic chemotherapy was only born at the beginning of the last century.

In my view, some of the particularly interesting opportunities/advances in nanomedicines include:

• A combination therapy with liposomes containing two drugs is already in Phase I/II development by Celator Pharmaceuticals (US).

• Polymer therapeutics—several polymeric drugs, polymer-proteins/polymer aptamer and block copolymer micelles are now on the market and there is a strong pipeline for further clinical development

• New manufacturing techniques and template manufacturing (PRINT approach) that are applicable to many areas of advanced drug delivery. Interesting insight can be read in a Petros and DeSimone paper (3).

• New opportunities for intracellular/cytosolic delivery of macromolecular therapeutics.

• Continuing efforts to improve the delivery of poorly soluble or unstable drugs, improve disease specific targeting and create new technologies for vaccine delivery.

Q: How fast (or slow) has the pharma industry been to embrace nanotechnology?

The 40 or so first-generation nanomedicines on the market began to arrive in 1990 and now there are many follow-up products and novel nanotechnology approaches in pipelines. In particular, specific technologies, such as nanocrystals, have been rapidly embraced over the last decade because they can help solve specific formulation challenges, such as poor water solubility.

When all these technologies emerged as first in class, they were, as with any new, high-risk technology, embraced very slowly by pharma companies. However, once a technology has arrived in the market, there is always a sudden burst of interest, particularly as some products gain blockbuster status. With nanotechnology now well established, coupled with the high-drug attrition rate for low-molecular weight chemical entities, interest in this area has certainly increased.

Q: It has been claimed that many Big Pharma companies are losing interest in nano-enabled drugs. Do you agree with this statement?

Have they ever been very interested?

This statement is not true given my understanding of the term "nanomedicine". It is always dangerous to make generalisations such as overhyping a field at the outset and then over condemning it later on.

Certainly, parenteral drug-targeting strategies have never been an easy fix and scientific experts in this area have always known that. There are too many claims of 'platform technologies' that able to deliver any drug candidate, but this is naive because every system needs to be optimised on a case-by-case basis.

Many basic science publications claim that new technologies—not only nanotechnology—are not practical for translation/industrial development. This can be because of:

• difficulty in achieving reproducible quality

• safety issues regarding the dose and route of administration

• lack of enhanced efficacy

• issues regarding scale-up potential or cost/practicality for clinical use.

However, if you look at the drug attrition rate for candidates that have entered clinical trials, I don't believe that nano-enabled systems have fared any worse than traditional low-molecular chemical entities. I think more data in this area would be beneficial.

Q: How are regulators addressing nanotechnology?

The development and routine use of nanomedicines is not new. Regulators review each new technology on its own merit and make an integrated assessment of quality, safety and efficacy to understand whether the risk–benefit profile is acceptable. This will continue to happen for all medicines, nano or otherwise.

With the advent of novel nanomaterials and the growing interest in complex, multicomponent nanomedicines, regulatory agencies continue to review all specific/emerging needs in this field. Both the FDA and the EMA have established specific teams to address nanomedicines at both national and international levels.

Q: What key factors are necessary to develop practical, safe and effective nanomedicines?

As with any medicine, an understanding of the critical product attributes that govern safety and efficacy is vitally important, as well as the ability to ensure characterisation of these parameters using validated analytical techniques. With nanomedicines, it is also important to consider the route of administration, dose, frequency of administration, fate of the nanomaterial (all components from the product), any detrimental bioactivity, antigenicity, immunogenicity and haematocompatibility.

As nano-sized medicines often display very different pharmacokinetics and body distribution compared with low-molecular chemical entities at the whole body and cellular level, the pharmacokinetics–pharmacodynamics relationship needs to be carefully considered during the establishment of critical product attributes relating to safety and efficacy. For each product, it is also essential to consider the proposed clinical setting for use.

Ruth Duncan is Professor Emerita at Cardiff University (UK), and visiting professor at CIPF (Spain) and the University of Greenwich (UK).

References

1. R. Duncan and R. Gaspar, "Nanomedicine(s) under the microscope", Mol. Pharmaceutics online, DOI: 10.1021/mp200394t, 5 Oct., 2011.

2. B. Munos, Nat. Rev. Drug Discov., 8(12), 959–968 (2009).

3. R.A. Petros and J.M. DeSimone, Rev. Drug Discov., 9(8), 615–627 (2010).