Robbert Jan Kok

Drug Targeting & Pharmacokinetics
Dr RJ Kok (UU)
Dr. R.J. Kok

Robbert Jan Kok is Associate Professor in the Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS). He is an expert in drug targeting and pharmacokinetics. The primary goal of his research is to improve drug action and safety by nanomedicines and drug delivery formulations. 
Dr Kok obtained his PharmD (1992) and PhD (1998) at Groningen University. After his PhD in Drug targeting to the Kidney he studied drug targeting in various disease areas such as chronic inflammation and cancer. He joined Utrecht University as Assistant Professor at the Department of Pharmaceutics in 2006 and became associate professor in 2009.

RESEARCH
Research in the Kok group is dedicated to the development of better and safer drugs by improving their biodistribution and by promoting their uptake in target cells. Rather than to rely on passive processes like diffusion, on can employ receptor-mediated endocytosis as a gateway for cell-specific uptake. Organs like liver and kidney express a wide range of such transporter proteins that are involved in the clearance of endogenous and exogenous compounds. The Kok group exploits these clearance pathways for cellular drug targeting to the kidney. Similarly, one can exploit membrane transporters for drug targeting to cancer cells, endothelial cells and many other cell types. A wide range of “nanocarrier” systems is at hand to achieve cell-specific targeting, ranging from drug-peptide conjugates to lipid- and polymer-based nanoparticles. biodistribution of nanocarriers and relative expression levels of target receptor. Equally important however is the medicinal chemistry of the nanomedicine since both drug, linker and carrier play a pivotal role in stability, biocompatibility and drug release. Synthesis, characterization and in vitro evaluation are the first stages of this type of interdisciplinary research. In a different approach, one can tailor the therapeutic profile of drugs towards a more focused tissue-specific action by localized drug delivery depots. Biopharmaceutical and pharmacological aspects are carefully considered in the selection of nanocarriers, e.g. Next, once in vitro proof-of-concept is obtained, biopharmaceutical and preclinical evaluation in animal models demonstrate the improved therapeutic index of nanomedicine based drugs. 

PROJECTS 
NANOMEDICINES FOR THE KIDNEY

One of the unique features of the kidney is its high capacity to recover nutrients and xenobiotics from the renal ultrafiltrate. We exploit the transporter proteins expressed by proximal tubular cells or other renal cell types for targeted drug delivery to the kidney. Drug-carrier conjugates and drug-loaded nanoparticles are made with anti-fibrotic and anti-inflammatory drugs,  and studied for cellular uptake in pharmacological activity in cell culture and animal models of renal disease.
People involved:
Haili Shi, targeted nanomedicines for polycystic kidney disease
Shima Gholizadeh, nanoparticles for targeting glomerular disease 

LIPID-BASED DELIVERY SYSTEMS FOR BIOPHARMACEUTICALS 
Formulation of biopharmaceutical drugs like proteins and nucleic acids is often hampered by poor encapsulation efficiency and low release rates. This projects aims at improving nanomedicine formulations of plant-derived toxins and interfering RNAs by novel encapsulation strategies, while improving target-site availability by incorporation of  triggered release modalities.
People involved:
Maria Carreira de Matos, lipid-based carrier systems for cytotoxic biopharmaceuticals
Dr. Nataliia Beztsinna, Imaging of the fate of nanomedicines

LIPOSOMAL FORMULATIONS FOR ANTI-INFLAMMATORY DRUGS
This project is dedicated to improving the therapeutic availability of well-known anti-inflammatory drugs by nanoparticle formulations. Nanoparticles can localized in inflamed tissues by enhanced permeability, while therapeutic availability can be improved by triggered release via focused heat- or ultrasound stimuli. 
People involved:
Amr Alaarg, Liposomal formulations for atherosclerosis
Dr. Daiki Omata, Temperature-sensitive liposomes for arthritis treatment 

POLYMERIC MICROSPHERES FOR LOCALIZED DRUG DELIVERY 
Drug-loaded polymeric microspheres can be embedded in biomaterials and thus can contribute to a localized drug action within the vicinity of an stent or implant. Different formulations with either small molecule drugs or biopharmaceutical proteins are prepared by emulsification processes or by membrane-sieving or microfluidic techniques. 
People involved:
Louan Chen, bronchotracheal stents
Karina Scheiner, diabetes reverting implants

SELECTED PUBLICATIONS

  1. Falke LL, van Vuuren SH, Kazazi-Hyseni F, Ramazani F, Nguyen TQ, Veldhuis GJ, Maarseveen EM, Zandstra J, Zuidema J, Duque LF, Steendam R, Popa ER, Kok RJ, Goldschmeding R. Local therapeutic efficacy with reduced systemic side effects by rapamycin-loaded subcapsular microspheres. Biomaterials. 2015 Feb;42:151-60. 
  2. Van der Meel R, Vehmeijer LJC, Kok RJ, Storm G, and van Gaal EVB. Ligand-targeted particulate nanomedicines undergoing clinical evaluations: current status. Advanced Drug Delivery Reviews 65, 1284-1298, 2013.
  3. Harmsen S, Dolman MEM, Nemes Z, Lacombe M, Szokol B, Pató J, Kéri G, Őrfi L, Storm G, Hennink WE, Kok RJ. Development of a cell-selective and Intrinsically active multikinase inhibitor bioconjugate. Bioconjugate Chemistry 22(4):540-5 (2011).
  4. Dolman ME, Harmsen S, Storm G, Hennink WE, Kok RJ. Drug targeting to the kidney: Advances in the active targeting of therapeutics to proximal tubular cells. Advanced Drug Delivery Reviews 62(14):1344-57 (2010).
  5. Prakash J, de Borst MH, Lacombe M, Opdam F, Klok PA, van Goor H, Meijer DK, Moolenaar F, Poelstra K, Kok RJ. Inhibition of Renal Rho Kinase Attenuates Ischemia/Reperfusion-Induced Injury. J Am Soc Nephrol 19(11):2086-2097 (2008).