Nanocarriers for drug delivery are one of the most important trends in healthcare research. The TargetCaRe (Targeting Cartilage Regeneration in joint and intervertebral disc diseases) project, undertaken with the support of the Marie Skłodowska-Curie programme, provides a good example of application: by establishing a network of scientists skilled in the use of smart nanocarriers and boosting their careers, the consortium hopes that these researchers will one day be able to apply this technology in the musculoskeletal area. Gerjo van Osch and Laura Creemers, who jointly coordinated the project respectively on behalf of Erasmus MC, University Medical Centre Rotterdam and UMC Utrecht, discuss its outcomes further.
What would you say are the main limitations of current treatment options for chronic lower back pain and osteoarthritis?
Van Osch: The treatments currently available only address the symptoms and not the disease itself. Patients’ options are mainly painkillers, exercise and weight loss. The latter actually does improve the clinical symptoms a little. In osteoarthritis the symptoms can be resolved permanently by replacing the joint with a prosthesis, but even this is a salvage treatment and does not address the disease itself. Moreover, prostheses have a limited lifespan, which means that only patients over 60 years of age are eligible for this treatment. In the case of chronic lower back pain caused by intervertebral disc degeneration, disc prosthesis development is still in its infancy and has had little success so far. This leaves patients only with physiotherapy, weight loss, exercise and psychological therapy to learn to cope with the pain. In the US, many opiate addictions are related to chronic lower back pain.
What makes your approach particularly innovative in this regard?
Van Osch: Osteoarthritis and lower back pain are chronic diseases characterised by tissue degeneration. Besides inhibiting this degeneration, we aim to regenerate the affected tissues. The novelty in our approach is the use of local drug delivery with novel generations of drug delivery carriers. Rather than using oral medication or intravenous injection that make the drug end up everywhere in the body, we aim for local injection with degradable biomaterial carriers loaded with the drugs. The carriers developed in TargetCaRe consist of nanoparticles and hydrogels that have advanced properties and allow for the passive release of drugs. These properties include layers to deliver several drugs at the same time, particle materials that make drug release faster in conditions of disease (also called triggered release), and particles with targeting molecules making them attack the right tissue. The latter is important especially in osteoarthritis, as different tissues in the joint are known to respond differently to different types of drugs and have a different role in disease. For example, anti-inflammatory drugs should be delivered to the inflamed synovium of the joint capsule and mainly handle pain, while drugs that stimulate repair should be delivered to the degenerated cartilage.
Could you tell us more about the treatment process?
Creemers: The treatment would consist of a local nanocarrier injection which will inhibit inflammation and/or stimulate regeneration in the joint or intervertebral disc. The active drugs are delivered over several days or weeks. Injection into the intervertebral disc will be done under radiographic guidance, while injection into the articular joint could even be done by general practitioners.
What were the main difficulties you faced in achieving your objectives and how did you overcome them?
Van Osch: One difficulty was that some of the innovative nanocarriers took a longer time to be developed than anticipated, so these could not be tested by the other consortium partners in their in vitro and in vivo models. We overcame this problem by developing many different carriers, and several were in fact ready in due time for experiments. This way the early-stage researcher (ESR) could still be trained as planned in multiple disciplines. Another obstacle is that ESRs are only paid for 3 years, which in many EU countries is too short to produce a thesis. This was resolved in most cases by hiring these ESRs in related projects at their institutions for the remaining time. Also, the ITN budget does not provide much room for in vivo work. We selected the most promising carriers to ensure optimal use of animals.
Speaking of which, what are the results of your in vivo tests? How did you proceed to evaluate the effectiveness of your method?
Creemers: A hydrogel carrier releasing the oligonucleotide anti miR221 showed improved regeneration in a mouse model of a local cartilage defect. PLGA nanoparticles releasing hyaluronic acid showed preliminary promising effects in a mouse model of osteoarthritis. The nanoghosts, small vesicles prepared from mesenchymal stem cells, demonstrated uptake by cells and good tolerability in similar animal models. However, the effect on joint integrity still needs to be analysed.
Have you been following up on this research since the end of the project? How so?
Creemers: As mentioned, many ESRs got extended contracts to finish their PhD research. Most of them have now graduated. Collaborations between partners are ongoing and ESRs are still communicating and even visiting other partners’ labs for the final experiments. Partners are continuing or planning to continue working on the most promising methods developed in the project. Some partners have already found grants to achieve this (typically bilateral collaborations) and new grants are being written to follow up on our work as well.
How soon do you think patients could hope to benefit from this new treatment, and to what benefits?
Creemers: Our drug delivery systems are mostly in very early stages of development. Although we have had some promising results, more extensive animal testing is required before these treatments can be taken to the patient, for further validation and dosage optimisation. The subsequent use of large animal models is also required. As the latter implies many official regulatory tests to demonstrate safety, we estimate that it will take at least 10 years before one of the novel treatments can be made available to patients. The hydrogel with the oligonucleotide stimulating regeneration may be one of the first treatments to be applied, as the gel is already in clinical studies. Also, the nanoghosts are already being taken to the clinic for cancer treatment and therefore the regulatory route to the osteoarthritis and chronic lower back pain patient can be relatively short. Other nanocarriers such as multilayered nanocarriers may need an additional few years of further validation in vitro and in small animal models.