Society Spotlight: European Commission-supported development of targeted nanomedicines: did MediTrans make a difference?

Consortium & research overview

MediTrans represents a multidisciplinary Integrated Project dealing with targeted nanomedicines and sponsored by the European Commission (EC) (Figure 1)[1]. Platform technologies are being developed with broad applicability to disease treatment, as exemplified by the choice for chronic inflammatory disorders (rheumatoid arthritis, Crohn’s disease [CD] and multiple sclerosis), and cancer as target pathologies. The disease characteristics imply that systemic administration was often the administration route of choice. Nanomedicines (based on carrier materials such as polymeric and lipidic nanoparticles, nanotubes and fullerenes) were endowed with targeting and (triggerable) drug release properties. In parallel, MRI probes were designed to report on the in vivo localization of the targeted nanomedicines. Moreover, the imaging probes were endowed with additional abilities; for example, to visualize specific biomarkers, to report on key-steps of the drug release process or on the therapeutic outcome (imaging-guided drug delivery). At the start (1 January 2007) the consortium consisted of 30 partners from nine EU member states (including one new member state) and three associated states, and includes 13 industrial companies, 11 universities and six research institutes. The project came to an end 31 March 2011. The total budget amounted to approximately €15 million with 70% EC contribution and 30% industrial support.

To manage a project of this size and complexity, a well-thought structure is mandatory. The work was divided in seven subprojects and 14 Work Packages (WP), each including partners with relevant expertise (Figure 2). In view of the scope of MediTrans, it is obvious that the research deals with delivery systems based on targeted drug carriers. Below, we will briefly highlight the approaches followed for the carrier, drug and targeting aspects.

Research efforts within MediTrans have been structured around nanocarrier materials classified as Emerging Materials, Candidate Materials and Established Materials. The focus was on their utility for the design of particulate nanocarriers. In the case of Emerging Materials, no or only very little proof of principle for drug delivery purposes was available at the start of the project, and it was timely to include carbon nanotubes and fullerenes. For nanocarriers based on Candidate Materials, preclinical proof of principle was already demonstrated in animal studies, but considerable further optimization and experimentation is still required before they can move into the industrial exploitation phase (subproject V, WP11 in Figure 2). Various types of candidate materials were evaluated within the framework of MediTrans, including, for example pDNA- and siRNA-containing polyplexes, molecularly imprinted nanoparticles, polymeric micelles, iron oxide nanoparticles, amino acid-based nanoparticles and stimuli-sensitive liposomes. Established Materials refer to materials that were already extensively studied as nanocarriers, clinical studies already finalized and, in some cases, approved for clinical use. Prototypic examples of Established Materials evaluated within MediTrans are PLGA-based nanoparticles and PEGylated liposomes. Regarding the former, we aimed at developing an oral PLGA-based formulation to improve the treatment of CD. Nanoparticulate systems with promising characteristics for in vivo application were then extensively evaluated in animal models of disease (subproject III, WP7–9), in order to select suitable ones for entry (in years 3 and 4 of the project) in subproject IV (Toxicity Risk Assessment) and subproject V (Industrial Exploitation). The aim of the latter two subprojects was to prepare suitable systems for clinical evaluation by addressing their suitability for development into a marketable product, in adherence to good manufacturing practice (GMP) rules, by performing preclinical toxicology screening, and assessing critical issues related to the design of upscalable preparation processes of clinical batches, which show the proper characteristics and long-term stability.

Regarding the drug molecules to be delivered, the work concentrated particularly on already marketed drugs (with small molecular weight), which suffer from a low therapeutic index. In addition to typical cytotoxic agents, anti-inflammatory agents (with corticosteroids as prototype) were considered as the inflammatory response is an important contributor to the progression of a large variety of diseases, including the diseases spotlighted by MediTrans. Partly due to major reorganizations occurring within big pharma (i.e., mergers that involved extensive re-positioning of company’s strategies) occurring during the lifetime of the project, we met some limitation in respect to the initial plan to also include proprietary drug molecules in development by the industries concerned. On the other hand, a considerable amount of work has been devoted by several academic and SME partners to the targeted delivery of nucleic acids (siRNA, miRNA and pDNA).

Regarding the targeting aspect, key in any targeted nanomedicine, both passive and active targeting strategies were pursued. After systemic administration, the nanocarrier system has to deliver the drug to the site of action. To achieve this, the so called ‘passive targeting’ phenomenon can be employed. Inflamed tissues are characterized by enhanced vascular permeability, which allows small, long-circulating drug carrier systems to extravasate at these regions and to be retained in the extravascular space (often referred to as the enhanced permeability and retention [EPR] effect). Passive targeting and the EPR effect make the use of long-circulating nanoparticles attractive for improving the therapeutic index of the MediTrans’ drugs. ‘Active targeting’ was also investigated. By coupling targeting ligands to the surface of the nanocarriers, specific cell populations (e.g., endothelial cells) were targeted at the pathological site. To actively target intracellular locations, particularly endosomal escape enhancement (e.g., using a combination of photosensitizers and light, referred to as photochemical internalization [PCI]) and nuclear entry promotors (e.g., nuclear localization signals [NLS]) were investigated.

Besides the development of novel and innovative carrier materials for improving the balance between the efficacy and toxicity of therapeutic agents, an important part of the MediTrans project was also devoted to the design of theranostic nanomedicines, specifically systems that combine disease diagnosis and therapy and that can be used to visualize various important aspects of the drug delivery process (i.e., image-guided drug delivery). With regard to this, several different gadolinium- and iron oxide-containing nanomaterials have been developed for this purpose. Significant progress has been made in developing systems that enable the monitoring of the various steps associated with biodistribution, target localization and drug release. In this context a new class of MRI agents (so-called CEST agents) has been developed and used in combination with the classical relaxation agents.

Outcome & impact

As will be clear from the above description, MediTrans was an ambitious project focused on the development of platform technologies that can be used for the treatment of serious diseases by exploitation of similar targeting principles. Now, retrospectively, the question arises: did MediTrans make a difference?

The major mission of the MediTrans project was to advance selected targeted nanomedicine formulations towards industrial exploitation and clinical application. As the duration of the project was too short (only 51 months), clinical evaluation studies were not initiated. However, completely in line with this major ‘bench-to-clinic’ objective, four targeted nanomedicine systems were identified on the basis of their preclinical behaviour and entered the subprojects IV and V. Two therapeutic and two diagnostic (theranostic) formulations were selected (Table 1). These ‘fruits’ of our project clearly demonstrate that MediTrans has paved the way for the introduction of promising marketable nanomedicine formulations, and therefore fulfilled its major mission.

But this is certainly not all. There is a tremendous academic output – in the form of hundreds of publications, lectures, posters and courses/workshops – and this output will likely increase in the near future, since at the time of appearance of this publication we are still close to the formal termination date for the MediTrans work, and still many research findings need to seek their way to respected journals in the pharmaceutical, imaging and other related fields.

A major beneficial outcome of our project deals with the creation of a strong link between the community of pharmaceutical scientists and the community of imaging probes’ developers to boost the emerging field of imaging-guided drug delivery in Europe. As a result, a new initiative has been undertaken that has led, in December 2010, to the approval, in the frame of EU-COST activities, of the Research Concerted Action TD1004 (‘Theranostics imaging and therapy: an action to develop novel nanosized systems for imaging-guided drug delivery’). The Action aims at further widening the interdisciplinary collaboration efforts that have been at the basis of the MediTrans project. By gathering the major European research groups working at the development of combined diagnostic/therapeutic agents, the objective of the Action is to demonstrate the huge potential of image-guided therapies for the treatment of diseases with high social impact.

Last but not least, it is worth mentioning that a particularly valuable asset of MediTrans deals with the fact that the consortium has delivered many scientists (PhDs, postdocs, and permanent personnel in companies and academia) well trained in nanomedicine research and available for further development of targeted nanomedicines in Europe. This, in combination with the creation of a sustainable academia-industry network, can contribute to making Europe more competitive with USA and Asia.

Altogether, despite the relatively short duration (4 years with 3 months extension) and the problem of unfavorable industry dynamics (structural changes in big pharma that urged us to modify the original commitments in the project), we conclude that MediTrans has yielded a sustainable, successful outcome and that the EC Framework Program support has proven to be a valuable instrument to promote the development of well-characterized targeted nanomedicines with broad applicability to disease treatment.