Raymond Schiffelers | University Medical Center Utrecht (original) (raw)

Uploads

Papers by Raymond Schiffelers

The 15th Journées Scientifiques of the Groupe Thematique de Recherche sur les Vecteurs provided a... more The 15th Journées Scientifiques of the Groupe Thematique de Recherche sur les Vecteurs provided an overview of the various aspects of drug delivery systems. Copolymers of poly(lactic acid) (PLA) and poly(epsilon-caprolactone) (PCL) could be functionalized allowing the introduction of poly(ethylene) glycol side chains and ligands. Coupling of bispecific antibodies to radioactive compounds and carbohydrates to tris-(hydroxymethyl) acrylamidomethane telomers increased cell specificity. New polyhydroxy alkanoate polymers, used to prepare nanoparticles, were discussed. Promising results of a new helper lipid in the transfection of cells, fluorinated glycerophosphoethanolamine, were discussed, as was the ability of HIV protein R fragments to condensate and deliver nucleic acids. Spontaneously lysing strains of Shigella and Escherichia were reported to stably transfect cells for periods of up to 2 months. Coupling of lipid anchors to peptides allowed display at liposome surfaces, generating antibody responses to the exposed peptide loops. Long-circulating liposomes co-encapsulating synergistically acting antibiotics, showed high therapeutic efficacy in models of drug-resistant pneumonia. A long-circulating system consisting of nanoparticles with a hydrophobic core increased delivery of lipid soluble photosensitizers to tumors. Heparin was reported to be bioavailable after oral administration by use of encapsulation into nanoparticles. This review aims to show the most promising or furthest developed drug delivery systems presented at the meeting.

Ter herinnering aan mijn moeder tested in clinically relevant rat models of serious K. pneumoniae... more Ter herinnering aan mijn moeder tested in clinically relevant rat models of serious K. pneumoniae infections. Both the clinically encountered problems of a low susceptibility of the bacteria as well as lack of adequate host defense were addressed.

IDrugs: the investigational drugs journal

The Drug Delivery - Select Biosciences Inaugural Summit, held in London, included topics covering... more The Drug Delivery - Select Biosciences Inaugural Summit, held in London, included topics covering recent advances in delivery systems for the controlled release of small-molecule drugs and larger biologicals, particularly nucleic acids, peptides and proteins. This conference report highlights selected presentations on image-guided drug delivery; the delivery of nucleic acids, peptoids, peptides and proteins; and formulation and solubility research. Technological approaches discussed include polymeric nanomedicines, nucleic acid-based therapeutics, the solid-dose injector Glide SDA, polyamino acid-based nanocarriers, polylactide glycolic acid microspheres, and enhanced biopharmaceutical products such as CriticalMix and CriticalSorb, PolyPEG, microspheres and cell-penetrating peptides.

European Journal of Cancer, 2014

Current topics in medicinal chemistry

Journal of Extracellular Vesicles, 2012

Current topics in medicinal chemistry, 2012

IDrugs : the investigational drugs journal, 2009

Current Signal Transduction Therapy, 2011

ABSTRACT Conventional treatment of cancer is accompanied by severe systemic side effects. As an a... more ABSTRACT Conventional treatment of cancer is accompanied by severe systemic side effects. As an alternative, targeting only deregulated intracellular pathways that cause proliferation, migration and metastasis are emerging in the field of cancer therapy. Kinase inhibitors are one appealing class of drugs that target specific intracellular pathways. However, kinase inhibitors are not specific in terms of tissue or cellular distribution, and kinase inhibitor therapy can cause serious side effects that are dose-limiting or reason to withdraw the compound from clinical testing. This review will highlight how the selectivity of kinase inhibitors can be improved via a different type of targeted therapy, i.e. by using drug delivery systems that are capable of directing kinase inhibitors specifically to tumor cells. We will explain how so-called nanomedicines obtain specificity for tumor cells and how other mechanisms can contribute to the guiding of the drug delivery system into the tumor tissue. EGFR and VEGFR are two classes of receptor tyrosine kinases that are highly deregulated in almost all cancers, and several effective kinase inhibitors targeted to these pathways have entered the clinic. We will focus on the inhibition of these pathways by analyzing the strategies that combine these kinase inhibitors with drug delivery systems to obtain enhanced tumor-selective effects.

Peptide-based gene delivery systems are composed of synthetic (20 amino acid) peptides derivatize... more Peptide-based gene delivery systems are composed of synthetic (20 amino acid) peptides derivatized with a targeting oligosaccharide or a polyethylene glycol chain (PEG) 1,2. Ad-mixtures of the glycopeptide and PEG-peptide conjugates were used to form DNA condensates that were stabilized by glutaraldehyde cross-linking through formation of a di-Schiffs base. The degree of metabolic stability is directly related to the degree of glutaraldehyde crosslinking, with metabolic half-lives in mouse liver ranging from 2 hours to 3 days 3.In the present study we demonstrate that the metabolic half-life of cross-linked peptide DNA condensates in liver can be significantly extended following reduction of Schiff-bases. Zeta potential analysis revealed that electro positive peptide-DNA condensates became electro neutral upon reaction with glutaraldehyde when forming Schiff-bases. Reduction with borane dimethylamine complex led to the formation of electro positive particles due to the formation of secondary amines.Reductively stabilized cross-linked DNA condensates demonstrated a liver half life of 5 days. Comparison of identical formulations composed of either L or D-amino acids failed to further increase in the metabolic half-life of either reduced or non-reduced crosslinked peptide-DNA condensates.The results suggest that reversal of di-Schiffs bases on cross-linked DNA condensates contribute to the metabolic half-life of peptide-DNA condensates in vivo. However, the route of metabolism for reduced cross-linked D-peptide DNA condensates remains unclear since these formulations should neither undergo cross-linking reversal nor proteolytic cleavage to release DNA.

Molecular Therapy, 2004

Gene therapy, in principle, can be applicable to the management and cure of a variety of diseases... more Gene therapy, in principle, can be applicable to the management and cure of a variety of diseases, but efficient and targeted delivery of the therapeutic gene to the disease site has been a formidable challenge. Local delivery of genes has some limited utility. But development of a delivery vector that provides tissue and cell targeted gene delivery from systemic administration

International Journal of Pharmaceutics, 2008

Tumor cells have long been the primary target cell type of liposomes for anticancer therapy. At p... more Tumor cells have long been the primary target cell type of liposomes for anticancer therapy. At present, it appears that tumor growth and metastasis is facilitated by interactions between tumor cells and supporting cells. These supporting cells consist of adaptive and innate immune cells, endothelial cells, pericytes, fibroblasts, stromal and mesenchymal cells. Insight into the activity of these cells and communication between these cells has provided new tactics for targeting alternative cell types in tumor treatment and offered new drug classes that could be used to modulate the activity of these supporting cells. Here, we provide an overview of liposomal systems that have been designed to target supporting cells in tumor tissue and therapeutic results of these systems.