The Two Directions of Nanomedicine in the Treatment of Cancer


direction of cancer download

The cancer nanomedicine field is heading in two directions — debating whether the clinical translation of nanomaterials should be accelerated or whether some of the long-standing drug delivery paradigms have to be challenged first.

At the International Conference on Nanomedicine and Nanobiotechnology that was held in Munich, 16–18 October, the most striking talk was not given by a scientist, nor a clinician, but by Lora Kelly — a six-year pancreatic cancer survivor.

By telling her story of how it actually feels to receive chemotherapy, immunotherapy and radiation, she reminded everyone about the urgent need to improve cancer treatment regimes. The main goal remains to kill the cancer; however, it has become more evident how equally important it is to improve the quality of life of patients during treatment, that is, to reduce the often devastating side effects.

This is where nanomedicine comes in. Nanomaterials have the potential to direct drugs to specific tissues and to improve drug activity, as well as its transport in blood. Indeed, nanoparticles could ensure that therapeutic treatments act locally and not systemically, and thus improve anti-cancer efficacy while reducing damage to healthy tissues.

However, recent setbacks, including the bankruptcy of a prominent nanomedicine company1 and the less than 1% delivery efficiency claim2 (quoted at every cancer nanomedicine conference on at least one slide) have stirred discussions about the usefulness of nanomedicines for cancer treatment.

Some argue that the field is stuck in preclinical animal models owing to a lack of insight into the basics of nanomaterial–tissue interactions in the human body, from traversing biological barriers to clearance.

 

While less than 1% delivery efficiency might not be much, pharmacological parameters, such as peak drug concentration, clearance rate and elimination half-life, are often not as bad3, and these should be considered with equal importance.

Moreover, there are also clinical success stories of nanomedicines. Onpattro, a lipid nanoparticle-based short interfering RNA (siRNA) drug for the treatment of polyneuropathies, was approved by the US Food and Drug Administration in 2018, marking the first approved nanoparticle for nucleic acid delivery.

In a Comment in this issue, Akinc et al. report the endeavour of developing this nanomedicine, from the idea to preclinical and clinical testing4, to the final approval. There are further many opportunities for nanomaterials complementary to drug delivery, including bioimaging, modulation of the immune system and the tumour microenvironment, and, of course, local administration.

 

From an Editorial perspective, the ongoing discussion is reflected in the many manuscripts we receive, which often include both basic investigations and claims of clinical application. Naturally, this can lead to mixed peer-review reports echoing the disconnection between clinical vision and fundamental science.

Reviewers with a background in materials science or biomedical engineering often point out the gaps in the basic understanding of how a nanomaterial interacts with the biological environment, and clinicians would like to see more preclinical animal work. Indeed, a thorough fundamental study does not always need the claim of a specific application, as it might be exactly such overstatements that have precluded the field to deliver on the promise of revolutionizing drug delivery.

Along the same line, studies of nanoparticle transport through specific cells or nanomaterial–cell interactions at a molecular scale, do not necessarily require complex in vivo models; by contrast, applied studies claiming a therapeutic benefit need a robust in vivo validation in a relevant animal model — preferably with an intact immune system.

 

Going back to the goal of improving a patient’s life, possible side effects and impact on tissues other than tumours should also be reported. However, this data is often found, at best, somewhere in the supplementary information.

Regardless of the mouse model, the discussion rarely goes beyond the weight loss and the histology of organs. If the idea is to improve therapies, side effects need to be thoroughly investigated — even at an early preclinical stage. Similarly, we will make sure that studies claiming superiority of a therapeutic treatment compared to state-of-the-art treatment regimes are reviewed by clinical experts to ensure that clinical translation is — at least — possible and feasible.

Also, keeping regulatory requirements in mind, the more complex the new nanoparticle or nanoscale delivery agent, the more difficult it will be to get approval; and this is a valid criticism.

 

At Nature Nanotechnology, we consider both clinically relevant manuscripts and fundamental studies investigating the various barriers nanoparticles face on their journey through the body. We endeavour to assess the manuscripts we receive as fairly and consistently as possible, with the ongoing discussion in mind. We look forward to learning about possible alternative mechanisms and the heterogeneity of the enhanced permeability and retention (EPR) effect, nanoparticle interactions in the liver, spleen and kidneys during clearance, migration of nanomaterials through the tumour microenvironment, and nanoparticle uptake, lysosomal escape (or not) and transport in different cell types.

Such studies will shine a light on nanomaterial–tissue interactions, and also greatly contribute to the development of improved nanomedicines. Equally important, detailed investigations of nanoparticles in preclinical animal models as well as relevant organoid cultures will allow the optimization of treatment strategies and the reduction of side effects. Regardless of the aim, we urge authors to calibrate their claims in accordance with their data and scope of the investigation to preserve trust in cancer nanomedicine as a whole.

Nanoplatform developed with three (3) molecular imaging modalities for tumor diagnosis – Making it possible to expand detection to more types of cancer


nanoplatform for tumor diagnosisThe composition and application of the JANUS nanoplatform for multimodal medical imaging. Credit: Marco Filice

Researchers at the Complutense University of Madrid (UCM) have developed a hybrid nanoplatform that locates tumours using three different types of contrast simultaneously to facilitate multimodal molecular medical imaging: magnetic resonance imaging (MRI), computed tomography (CT) and fluorescence optical imaging (OI).

The results of this study, led by the UCM Life Sciences Nanobiotechnology research team directed by Marco Filice and published in ACS Applied Materials & Interfaces, represent a major advance in medical diagnosis since just one session using a single contrast medium yields more precise, specific results with higher resolution, sensitivity and capacity to penetrate tissues.

“No single molecular imaging modality provides a perfect diagnosis. Our nanoplatform is designed to enable multimodal molecular imaging, thus overcoming the intrinsic limitations of each single image modality while maximising their advantages,” noted Marco Filice, a researcher in the Department of Chemistry and Pharmaceutical Sciences at the Complutense University of Madrid and the director of the study.

The platform, which has been tested on mice, targets solid cancers such as sarcomas. “However, due to its flexibility, the proposed nanoplatform can be modified, and with a suitable design of recognition element siting, it will be possible to expand detection to more types of cancer,” Filice said.

Named after the Roman god Janus, usually depicted as having two faces, these nanoparticles also “have two opposing faces, one of iron oxide embedded in a silica matrix that serves as a contrast medium for MRI and another of gold for CT,” explained Alfredo Sánchez, a researcher in the UCM Department of Analytical Chemistry and the first author of the study.

In addition, a molecular probe sited in a specific manner in the golden area permits fluorescence optical imaging while a peptide selective for hyperexpressed receptors in tumours (RGD sequence) and sited on the silica surface enveloping the  identifies the tumour and makes it possible to direct and transport the nanoplatform to its target.

Once the research team had synthesised the nanoparticles and determined their characteristics and toxicity, they then tested them in mouse models reared to present a fibrosarcoma in the right leg. The nanoparticle was injected in the tail. “Excellent imaging results were obtained for each modality tested,” reported Filice.

Although there is still much to do before these experiments can be applied to humans, this research shows that personalised treatment is closer than ever to becoming a reality, thanks to nanotechnology and biotechnology.

 Explore further: Nanoparticles on track to distinguish tumour tissue

More information: Alfredo Sánchez et al, Hybrid Decorated Core@Shell Janus Nanoparticles as a Flexible Platform for Targeted Multimodal Molecular Bioimaging of Cancer, ACS Applied Materials & Interfaces (2018). DOI: 10.1021/acsami.8b10452