Rene van Nostrum
Nanoparticles engineering for drug delivery
Nanomedicines is a multidisciplinary field of research, which encompasses elements of medicine, biology, chemistry, and materials science. In the Department of Pharmaceutics, we focus on the development of polymeric nanoparticles that are suitable for the site specific delivery and controlled release of drugs, which also include proteins, peptides, and nucleic acids. Important parameters are biocompatibility, degradability and (colloidal) stability of the nanoparticles in time under physiological conditions.
Asymmetric flow field flow fractionation (AF4)
The study of nanoparticles and their stability in complex biological fluids (like blood or serum) requires sophisticated equipment that allows non-destructive separation of the mixture combined with sensitive analysis. AF4 meets those high demands, and we have recently acquired state-of-the-art and temperature controlled apparatus coupled to an array of detectors (MALLS, DLS, RI, UV/vis and fluorescence). Thereby, we will be able to predict the behavior of nanoparticles in complex biological media with the aim to preselect formulations before testing them in animal models, and thus to reduce the use of testing animals.
People involved: Mies van Steenbergen (technician)
Nanogels for Peptide and Protein Delivery
Therapeutic proteins or peptides are highly biodegradable and therefore need either local administration, or prolonged administration to maintain sufficient concentrations at the target site. Moreover, targets of therapeutic peptides and proteins are often inside cells of specific (diseased) tissues, where the active molecules interfere with, activate or inactivate certain biological processes to treat the disease. Therefore, these sensitive compounds needs a delivery system to carry them to and inside the target cells, and should subsequently be released.
One of the projects, in collaboration with Dr. Tina Vermonden of our department, aims at the development of nanogels based on dextran or hyaluronic acid in which therapeutic proteins and peptides (incl. antigens for cancer immunotherapy) are actively loaded and fixed. The chemical fixation is designed such that the connections are broken once the nanoparticles are taken up by the target cells, and thus the drug is released. Currently we are collaborating with Prof. Niels Bovenschen from UMCU aiming at the intracellular delivery of the cytotoxic protein Granzyme B for cancer treatment using these nanogels.
People involved: students.
Polymeric and mixed micelles for delivery of hydrophobic drugs and photosensitizers
Many drugs belong to the so-called BCS class II or IV drugs, i.e. those that have low solubility in water. Such drugs are difficult to formulate, and one of the approaches is to solubilize drugs in polymeric micelles. Such drug loaded micelles are suitable for intravenous administration, but to allow the micelles acting as a true drug carrier throughout the body, the inherent instability of micelles should be overcome.
This project aims at the stabilization of drug-loaded polymeric micelles by enhancing physical interactions (inbetween polymer molecules and/or between polymer and drug molecules), or by chemical crosslinking of the micelles (possibly together with the drugs). The approaches to stabilize the micelles are chosen such that it allows controlled release of the drug molecules by applying an internal or external trigger.
One of the applications that we aim for is photodynamic therapy of cancer and atherosclerosis, for which photosensitive molecules need to be delivered to the target site (tumor tissue or atherosclerotic lesions). Those photosensitive molecules require irradiation by light to become active, which provide another mechanism of targeting by local activation.
In another application, we work at the development of mixed micelles for oral delivery of hydrophobic drugs, especially vitamin K. For this, maintaining (colloidal) stability at gastric pH, and allowing controlled release and uptake at the intestines, are the main challenges to overcome.
- Thijs Rooimans, Ph.D. candidate
- Xiangjie Su, Ph.D. candidate
- Yan Wang, Ph.D. candidate
- Barbara Mesquita (Ph.D. candidate) in collaboration with Dr. Sabrina Oliviera.
Polyesters such as polylactic acid, polyglycolic acid, or copolymers of them, are very frequently used in biomaterials research, because of its safety and biocompatibility. Drug loaded microspheres and nanoparticles are used for local or systemic administration where sustained release of the drug is required for prolonged action. Especially therapeutic peptides and proteins can benefit from such sustained release approach, since these sensitive biomolecules are rapidly degraded in the body when injected as such at once.
Unfortunately, the current generation of polyesters, like the ones mentioned above, are not most suitable for the delivery of peptides and proteins, because degradation of the polymers results in formation of acid degradation products that locally decreases the pH, and can cause denaturation of the protein. Also, peptides and proteins contain functional groups that are reactive towards the ester bonds which can cause chemical modification of the peptide/protein, as has been investigated in great detail in our laboratory. Both denaturation and modification can be detrimental to the activity of the drug, or can cause immunogenic responses.
In our laboratory, we have developed polyesters that are more hydrophilic than the state-of-the-art ones, and thereby show lower degrees of unwanted side effects as mentioned above. Moreover, these new polyesters show a larger window of degradation rates, which makes them wider applicable. We not only aim at the delivery of therapeutic peptides or proteins, but also at the controlled release of antibiotics.
People involved: Mengshan Liu, Ph.D. candidate
Absorption of proteins into nanogels by electrostatic interactions is being used in our laboratory as a means to achieve very high loading efficiency and capacity, see topic above: Nanogels for Peptide and Protein Delivery.
In a project financed by NWO-TTW and the kidney foundation, in collaboration with Dr. Karin Gerritsen of the Utrecht Medical Center, we develop polymeric materials that can absorb high amounts of urea. These absorbents will be integrated into wearable artificial kidneys.
People involved: Piet Driest (postdoc)
An antibubble is reverse of a bubble, i.e., a water droplet is surrounded by an air film inside a bulk liquid. The presence of an air-shell in this unusual physical object suggests extraordinary applications, e.g., an exceptional stability of the core, and on-demand, triggered and guided release of the active compounds. However, to fully exploit the advantageous controlled-release properties of antibubbles it is necessary to produce them with a core-shell morphology and this remains a big challenge.
With the advent of microfluidic systems, an incredible development has been witnessed in efficient production of small and uniform droplets, bubbles, particles, etc. The project, which is a collaboration with Dr. Albert Poortinga at TU/e and Dr. Akmal Nazir at UAEU, aims at producing small and stable core-shell antibubbles, through microfluidic technology. Furthermore, the potential triggered release properties will also be studied. This will require the design of core-shell antibubbles stabilized by particles that impart the antibubbles with triggered-release properties.
People involved: Rabia Zia (Ph.D. candidate)
List of key publications
- Y. Wang, M.H. Fens, N.C.H. van Kronenburg, Y. Shi, T. Lammers, M. Heger, C.F. van Nostrum, W.E. Hennink, Magnetic beads for the evaluation of drug release from polymeric micelles in biological media, J. Controlled Release, 349 (2022), 954-962.
- R. Zia, A. Nazir, A.T. Poortinga, C.F. van Nostrum, Advances in antibubble formation and potential applications, Adv. Coll. Interf. Sci., 305 (2022), 102688.
- M. Liu, S. Thijssen, C.F. van Nostrum, W.E. Hennink, J. Garssen, L.E.M. Willemsen, Inhibition of cow’s milk allergy development in mice by oral delivery of β-lactoglobulin derived peptides loaded PLGA nanoparticles is associated with systemic whey-specific immune silencing, Clin. Exp. Allergy, 52 (2022),137-148.
- T. Rooimans, T.C. Minderhoud, N. Leal, M. Rodriquez, F. Sun, C. Oussoren, T.K. Slot, M van der Ham, G.E.P.J. Janssens, M. de Sain, L.M. Akkermans, R.H.J. Houwen, T.J. de Koning, W.E. Hennink, H. Vromans, C.F. van Nostrum, P.M. van Hasselt, Improved vitamin K uptake from orally administered mixed micelles under bile deficient conditions in rats, Gastroenterology, 161 (2021), 1056-1059.
- Y. Liu, M.H.A.M. Fens, R.B. Capomaccio, D. Mehn, L. Scrivano, S. Oliveira, W.E. Hennink, C.F. van Nostrum, Correlation between in vitro stability and circulation kinetics of dithiolane crosslinked poly(ε-caprolactone)-based micelles loaded with a photosensitizer, J. Controlled Release, 328 (2020), 942-951.
- J.A.W. Jong, Y. Guo, D, Hazenbrink, S. Doukaa J. van der Zwan, K. Houben, K.C. Scheiner, R. Dalebout, M.C. Verhaar, R. Smakman, W.E. Hennink, C.F. van Nostrum, K.G.F. Gerritsen, A Ninhydrin-type Urea Sorbent for Regeneration of Kidney Dialysate, Macromol. Biosci. (2020), 1900396.
- N. Kordalivand, E. Tondini, C.Y. Lau, T. Vermonden, E. Mastrobattista, W.E. Hennink, F. Ossendorp, C.F. van Nostrum, Cationic Synthetic Long Peptide-Loaded Nanogels: An Efficient Therapeutic Vaccine formulation for induction of T-cell Responses, J. Controlled Release, 315 (2019), 114-125.
- J.W.H. Wennink, Y. Liu, P. Makinen, F. Setaro, A. de la Escosura, M Bourajjaj, J. Lappalainen, L.Holappa, J.B. van den Dikkenberg, M. al Fartousi, P. Trohopoulos, S. Yla-Herttuala, T. Torres, W.E.Hennink, C.F. van Nostrum, Macrophage Selective Photodynamic Therapy by Meta-Tetra(hydroxyphenyl)chlorin Loaded Polymeric Micelles: a Possible Treatment for Cardiovascular Diseases, Eur. J. Pharm. Sci., 107 (2017), 112-125.
- D. Li, F. Sun, M. Bourajjaj, Y. Chen, E.H. Pieters, J. Chen, J.B. van den Dikkenberg, M.G.M. Camps, F. Ossendorp, T. Vermonden, W.E. Hennink, C.F. van Nostrum, Strong in vivo antitumor responses induced by antigen immobilized in nanogels via reducible bonds, Nanoscale, 8 (2016), 19592-19604.
- F. Sun, P.M. van Hasselt, W.E. Hennink, C.F. van Nostrum, A Mixed Micelle Formulation for Oral Delivery of Vitamin K, Pharm. Res., 33 (2016), 2168-2179.
- M. Shirangi, M. Najafi, D. Rijkers, R.J. Kok, W.E. Hennink, C.F. van Nostrum, Inhibition of octreotide acylation inside PLGA microspheres by derivatization of the amines of the peptide with a self immolative protecting group, Bioconj. Chem. (2016), DOI: 10.1021/acs.bioconjchem.5b00598
- Y. Shi, R. van der Meel, B. Theek, E. Oude Blenke, E.H.E. Pieters, M.H.A.M. Fens, J. Ehling, R.M. Schiffelers, G. Storm, C.F. van Nostrum, T. Lammers, W.E. Hennink, Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via Π–Π Stacking Stabilized Polymeric Micelles, ACS nano 9 (2015), 3740–3752.
- C.F. van Nostrum, Covalently cross-linked amphiphilic block copolymer micelles, Soft Matter, 7 (2011), 3246-3259.
- C.J.F. Rijcken, O. Soga, W.E. Hennink, C.F. van Nostrum, Triggered destabilization of polymeric micelles and vesicles by changing core polarity: a new tool for drug delivery, J. Controlled Release, 120 (2007), 131-148.