Nanoparticles engineering for drug delivery
Dr. Cornelus F. van Nostrum
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.
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 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.
- Neda Kordalivand, PhD-student
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.
- Feilong Sun, Ph.D. student
- Yanna Liu, Ph.D. student
- Mahsa Bagheri, Ph.D. student
- Thijs Rooimans, Ph.D. student
- Xiangjie Su, Ph.D. student
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.
- Jeffrey Ritsema, Ph.D. student
- Lucia Martinez Jothar, Ph.D. Student
- Mengshan Liu, Ph.D. Student
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.
- Sjaak Jong, Ph.D. student
- Yong Guo, postdoc
List of key publications
- J.A.W. Jong, M.E. Moret, M.C. Verhaar, W.E. Hennink, K.G.F. Gerritsen, C.F. Van Nostrum, Effect of substituents on the reactivity of ninhydrin with urea, Chem. Select., 3 (2018), 1224-1229.
- A.I. Kostadinova, J. Middelburg, M. Ciulla, J. Garssen, W.E. Hennink, L.M.J. Knippels, C.F. van Nostrum, L.E.M. Willemsen, PLGA nanoparticles loaded with beta-lactoglobulin-derived peptides modulate mucosal immunity and may facilitate cow's milk allergy prevention, Eur. J. Pharmacology, 818 (2018), 211–220.
- 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.