René 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 and Antoinette van den Dikkenberg (technicians)

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: Rioyana Pratiwi (Ph.D. candidate).

Antibubbles

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 allows extraordinary applications, e.g., an exceptional stability of the core, and on-demand, triggered and guided release of the active compounds. 
Interestingly, antibubbles are sensitive to surfactants including bile acids, which make them pop in, for example, intestinal fluids while being stable in the gastric environment. The fine-tuning of bile-sensitivity allows precise intestinal delivery of sensitive drugs. The outer air-water interface can be designed such that antibubbles can be made sensitive to other triggers such as pH or ultrasound.  
The project, which sprouts from a collaboration with Dr. Albert Poortinga at TU/e and Dr. Akmal Nazir at UAEU, aims at producing small and stable core-shell antibubbles. Furthermore, the potential triggered release properties are studied. This will require the design of core-shell antibubbles stabilized by particles that impart the antibubbles with triggered-release properties.
People involved: students

Polymeric absorbents

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 financially supported by the kidney foundation, in collaboration with Dr. Karin Gerritsen of the University Medical Center and Dr. Akbar Asadi Tashvigh (WUR), we develop porous polymeric materials that can absorb high amounts of urea. These absorbents will be integrated into wearable artificial kidneys.
People involved: Martijn Ekhart (Ph.D. candidate).

Polymeric 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.
People involved: collaboration with Dr. Sabrina Oliviera
 

List of key publications

  1. 1.    A.T. Poortinga, C.F. van Nostrum, Microbubble-encapsulation of actives for controlled release and its application to the taste-masking of acetaminophen, Int. J. Pharmaceutics 672 (2025), 125309.
    2.    B. Mesquita, A. Singh, C. Prats Masdeu, N. Lokhorst, E.R. Hebels, M. van Steenbergen, E. Mastrobattista, M. Heger, C.F. van Nostrum, S. Oliveira, nanobody-mediated targeting of zinc phthalocyanine by polymer micelles as nanocarriers, Int. J. Pharm., 655 (2024), 124004.
    3.    R. Zia, A.T. Poortinga, A. Nazir, M. Ayyash, C.F. van Nostrum, Preparation of acid-responsive antibubbles from CaCO3-based Pickering emulsions, J. Coll. Interf. Sci., 652B (2023), 2054-2065.
    4.    M. Liu, C.Y. Lau,  I. Trillo Cabello, J. Garssen, L.E.M. Willemsen, W.E. Hennink, C.F. van Nostrum, Intracellular trafficking of PLGA nanoparticles and the release of a loaded peptide via live cell imaging of dendritic cells by Förster Resonance Energy Transfer fluorescence, Pharmaceuticals, 16 (2023), 818.
    5.    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.
    6.    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.
    7.    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.
    8.    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.
    9.    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.
    10.    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.
    11.    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.
    12.    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.
    13.    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.
    14.    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.
    15.    C.F. van Nostrum, Covalently cross-linked amphiphilic block copolymer micelles, Soft Matter, 7 (2011), 3246-3259.
    16.    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.