Searching for a nano-blockbuster

Andreas M. Nyström offers a perspective on nanomedicine advances and challenges in research and business

Nanomedicine is a broad scientific area spanning the research areas of biology, medicine, chemistry, and engineering, which aim to utilise nanoscale platforms for the detection and treatment of cancer and other diseases with high selectivity and improved outcome. Features such as improvements in contrast for imaging applications, multivalent specific binding of diseased tissue, redirecting the biodistribution of therapeutics, improved bioavailability of therapeutics, and reduced toxicity of therapeutics have all been successfully realised by the utilisation of nanoscale constructs in both animal models and in some cases human phase studies.

In addition, nanomedical applications are attracting growing interest in both academia and in the pharmaceutical industry. This is exemplified by a growing number of drugs on the market, and by the high number of preclinical trials currently being undertaken (approximately 50)¹. An industrial and academic success for nanomedicines is Abraxane, the protein based nanoparticle formulation of paclitaxel that was introduced in the US in 2005 and in the EU in 2008 and sold for more than $400 million in 2012². Abraxane has the potential, provided approval in new indications such as pancreatic cancer, to become a nano blockbuster drug, signifying the market value of new technologies stemming from basic research in industry and, in particular, nanotechnology. Considerable investments from society’s funding agencies have over the last decade spurred the expansion of researchers involved in nanomedicine research, with big funding schemes introduced in the USA and Europe, as well as Asia³, based on the expected revolution that the utilisation of nanotechnology can bring to modern medicine. But how has the field risen to the challenge and the monumental hope that many patients and relatives hold for the developments of new treatments for diseases that challenge our society?

Foremost, nanomedicines are just like other active therapeutics but packaged in a “nanoformat”. This means that mandated testing in pre-clinical and clinical settings prior to approval of the regulatory agencies is and should be the same⁴. The time frame for the bench to bed-side translation for nanomedicines is relevant to reflect on: a typical small molecule drug takes on average 12 years to make it to the market as an approved drug. One in 1,000 small molecule drugs successfully navigate this journey to reach human phase testing, and each approved drug comes with an aggregated R&D expenditure amounting to approximately $350 million⁵.

Despite this, there are several approved nanomedicines on the market today, including liposomal formulations⁶; protein-based particle formulation systems⁷ that mainly reduce side-effects and toxicity, nanocrystals⁸;and protein-polymer conjugates⁹ which improve bioavailability and extend plasma life-time. However, most of the research behind these was performed well before the rapidly expanding funding schemes (the fundaments for liposomal delivery systems are from the 1960s)¹⁰.

This suggests that research funded by the large, mainly governmental schemes is yet to yield its full results and we can expect to see more nanomedicine drug candidates entering clinical trials in the near future.

The industry itself (as seen from the time frame and success rate listed above) has had a troubling decade with considerable reorganisation and shifting the focus back on to biological drugs such as monoclonal antibodies, which may have limited corporate R&D expenditure directed towards nanomedicines.

Importantly, although most of the nanomedicine drugs that are approved for clinical use mainly improve treatment via reduced side effects¹¹, they do not typically show any major improvements in efficacy that would help to justify their substantially added cost to treatment¹². As several prominent scientists have recently stated, the industry and research communities are waiting to harness the full potential of nanotechnology in medicine i.e. achieving the “magic bullet”¹³, via ligand targeting approaches or more recently by creating theranostic nanomedical devices¹⁴.

The “magic bullet” has been the thematic goal for most nanomedical research in academia over the past two decades, and promises the possibility of tumour-specific delivery of chemotherapeutics, allowing for reduced bystander tissue damage, greater efficacy as well as potential treatment of some inoperable indications. The rapid development of biological therapeutics, such as monoclonal antibodies, combined with significant advances in biotechnology (screening and production) of targeting peptides presents a plethora of potential targeting strategies towards disease-specific, up regulated, extracellular ligands using nanoscale drug delivery systems¹⁵.

A quick glance in the literature results in more than 1,000 papers on the topic (80% in the last four years)¹⁶ and suggests that this is a highly vivid area, but that much more research is necessary. Combining a drug with a nanocarrier and a targeting ligand as a sandwich construct is complicated both from a biomedical and engineering point of view.

A recent and frequently debated paper on the topic of targeting ligands on nanoparticles which gives a critical and important lead on the issue was published earlier in 2013 by Professor Dawson’s group at University College Dublin¹⁷. The group utilised transferrin as a ligand for targeting of silica based nanoparticles and highlights the importance of the instantaneous coating on the particle after its suspension in a biological medium (the biocorona). This biological corona blocks receptor-specific binding of the nanoparticle to the intended cell and, as a consequence, diminishes its targeting capabilities.

Many researchers in the field see this as one of the critical problems that limits the translation of in vitro results to in vivo results and onwards towards pre-clinical models. The biocorona on the particle also has a strong influence on the biodistribution and pharmacokinetics of naked nanoparticles, increased hydrophilicity (typically via linking poly(ethylene glycol)) reduces protein deposition and increases plasma half-life in general. Moreover, the role of the biocorona and the activation of the immune system remains a topic that needs to be systematically understood for an efficient translation of targeted and non-targeted nanomedicines to the pre-clinical and clinical setting. Patients need new novel treatment options for many indications, especially in cancer therapy, and research should focus on understanding the critical limitations that hinders the clinical progress.

I will leave this perspective with some of the remaining research questions that we, as an interdisciplinary research community, must solve in order to push the true potential of ligand targeted nanomedicine into clinical reality:

• How should the ideal nanomaterials be constructed to achieve a controlled biocorona that allows for predictable and tunable PK/PD profile without immunological activation?
• How should nanoparticle structures be constructed to allow for the successful presentation of a targeted ligand beyond the biocorona interface in a predictable manner?
• Which nanomaterial systems have “clinical” credibility from a toxicological and degradability perspective?
• How can nanomedicines be produced to include complex targeting entities, active compounds, with the necessary stringency and control over size, shape, number of ligands and drug concentration?

Contact: andreas.nystrom@ki.se

References

1. www.clinicaltrials.gov
2. http://www.epvantage.com/Universal/View.aspx?type=Story&id=450077&isEPVantage=yes
3. http://nano.cancer.gov/action/programs/ccne.asp and http://www.etp-nanomedicine.eu/public
4. Andreas M. Nyström, Bengt Fadeel, Safety assessment of nanomaterials: Implications for nanomedicine, Journal of Controlled Release, 2012, 2 (161), 403–408
5. http://www.drugs.com/fda-approval-process.html
6. http://www.cancerresearchuk.org/cancer-help/about-cancer/treatment/cancer-drugs/liposomal-doxorubicin
7. http://www.abraxane.com/
8. Junghanns JU.A.H., Müller R.H., Nanocrystal technology, drug delivery and clinical applications,International Journal Nanomedicine, 2008, 3 (3), 295–310
9. http://www.pegintron.com/peg/pegintron/consumer/index.jsp
10. Duncan R, Gaspar R. Nanomedicine(s) under the microscope. Molecular Pharmaceuticals. 2011, 8(6) 2101-2141
11. Etheridge ML, Campbell SA, Erdman AG, Haynes CL, Wolf SM, McCullough J., The big picture on nanomedicine: the state of investigational and approved nanomedicine products. Nanomedicine. 2013, 9(1), 1-14.
12. Venditto VJ, Szoka FC Jr. Cancer nanomedicines: so many papers and so few drugs! Advanced Drug Delivery Reviews. 2013, 65(1), 80-88.
13. The concept of selective delivery of for example chemotherapeutics is indeed not new, Paul Ehrlich, Nobel laureate in 1908, hypothesised about the silver bullet for selective treatment of cancer in the early 1900’s.
14. Nyström AM, Wooley KL. The importance of chemistry in creating well-defined nanoscopic embedded therapeutics: devices capable of the dual functions of imaging and therapy. Accounts of Chemical Research. 2011, 44(10), 969-978.
15. Stegha A.H. Toward personalized cancer nanomedicine – past, present, and future. Integrative Biology. 2013, 5, 48-65.
16. Web of Science, search string ”Targeted nanomedicine” 5th of September 2013.
17. Salvati A, Pitek AS, Monopoli MP, Prapainop K, Bombelli FB, Hristov DR, Kelly PM, Åberg C, Mahon E, Dawson KA. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nature Nanotechnology. 2013, 8(2), 137-143.