Many candidate and established drugs have less than ideal properties with consequently unfavourable therapeutic implications. Particulate drug targeting systems can be designed to improve the therapeutic behaviour of such drugs, which are commonly administered orally and parenterally. Nanoparticulate-based drug targeting has come a long way since Paul Ehrlich introduced the concept early in the last century. Progress has been slow, but several products have reached the market. Nanotechnology-inspired approaches to particle design and formulation, an improved understanding of (patho)physiological processes and biological barriers to drug targeting, as well as the lack of new chemical entities in the ‘pipeline’, are causing large pharmaceutical companies problems in bringing new drug compounds to the market. This indicates that there is a bright future for targeted nanoparticles as pharmaceuticals. It is now well known that a reliable targeting system is essential for successful drug delivery in many serious disease situations. Targeting systems can target a drug to the intended site of action in the body, thus enhancing its therapeutic efficacy (site-specific delivery), and / or direct a drug away from those body sites that are particularly sensitive to the toxic action of it (site-avoidance delivery). A multidisciplinary research approach, employing the combined forces of many scientific disciplines, is a key factor for success. It is becoming increasingly recognised that a major limitation, impeding the entry of targeted delivery systems into the clinic, is that new concepts and innovative research ideas within academia are not being developed and exploited in collaboration with the pharmaceutical industry. Thus, an integrated ‘bench-to-clinic’ approach realised within a structural collaboration between industry and academia, is required to safeguard and promote the progression of targeted nanomedicines towards clinical application.
The development of effective, safe, and innovative drug targeting systems, is a complicated multi-step process. There is an increasing need to select and / or identify appropriate matrix materials, surface coatings, and targeting ligands with advanced properties. Therapeutic agents (small molecules, but also macromolecules like proteins and nucleic acids) to be loaded into nanocarriers vary widely in their physicochemical properties and it remains a challenge to balance the nanoscale dimensions of the particulate with the types and amounts of drugs that are clinically required. Proper structural and physicochemical characterisation is required to guarantee reproducible effects in vivo. Advances in particle engineering (e.g. surface modification with ‘stealth’ polymers, like poly(ethyleneglycol) (PEG) and targeting ligands) have already yielded nanoparticles which can reach major pathological sites in vivo, after intravenous and local routes of injection. Examples of target sites that are accessible in vivo include sites of malignancy and inflammation. Here, the most common method of targeting is passive extravasation through ‘leaky’ vasculature (the Enhanced Permeability and Retention (EPR) effect) using stealth polymer coated nanoparticles, which circulate in the bloodstream for a sufficiently long period of time (‘passive targeting’). Ligand-mediated targeting (‘active targeting’) to endothelial cells lining blood vessels present within the site of pathology has also been used successfully. Vascular targeting ligands are directed against receptors, which are specifically (over)expressed on the pathological vasculature because of the angiogenesis process. To date, most research in this field has been directed towards solid tumours. MEDITRANS has a lot to contribute by applying similar principles when targeting chronic inflammatory diseases, as the underlying pathophysiological processes are central to the development and perpetuation of inflammation. In addition to the development of nanomedicines for systemic targeting, the development of nanomedicines that release the drug locally in diseased parts of the gastrointestinal tract (e.g. inflamed gut tissue in inflammatory bowel disease), after oral administration, will also yield distinct improvements compared with existing, non-specific, drug delivery methods.
Rapid, noninvasive monitoring of the in vivo targeting process urgently needs to be developed. High-resolution imaging techniques (like Magnetic Resonance Imaging (MRI)) offer unique possibilities for this. Recent evidence indicates that co-incorporation of certain imaging agents into drug-loaded nanoparticles allows MRI-guided monitoring of the drug release process, the imaging of the pathological process, the probing of pathophysiological parameters (e.g. pH) within the target tissue, and even therapeutic follow-up of targeted nanomedicines. The challenge addressed in this IP is to perfect these techniques for in vivo use.
Once the nanocarrier has localised in the pathological target tissue, then the drug must be released at a sufficient rate and extent to become therapeutically active. It is this issue, which represents a major concern, as targeted carriers are generally designed such that they show a high degree of stability to avoid release of the drug during transport to the pathological tissue. Therefore, to advance beyond the current status, this IP will develop systems with preprogrammed instability which will stimulate drug release, either because they are composed of polymeric material with predictable and tailored degradability, or even smarter systems from which drug release can be induced ‘on demand’ because of externally applied stimuli (e.g. heat, light, ultrasound). Such triggered release following MRI-guided drug delivery has great appeal. To avoid the release problem, it is attractive also to develop nanoparticles that do not need any drug incorporation and release, like ferromagnetic nanoparticles responding to a magnetic field. In the case of new macromolecular biopharmaceuticals (e.g.peptides, proteins, DNA, siRNA), the release problem is encountered within the cellular interior (often in the cytosol or nucleus) after internalisation of the targeted nanocarriers. The problem of poor intracellular targeting strongly limits activity, and therefore this needs urgent attention in this IP. This will be done by developing methods to enhance endosomal escape (e.g. photochemical internalisation (PCI)) and by the use of intracellular trafficking ligands (e.g. NLS, TAT peptides).
The MEDITRANS project
finished on 31.03.2011
The overall aim is to advance health care via the development of innovative targeted drug / imaging agent delivery with controlled release, and imaging guidance procedures for the detection of the underlying targeting / (triggered) drug release processes.