Project

Screening for molecular adjuvants to enhance cytoplasmic delivery of small interfering RNA in cancer cells

Duration
01 January 2016 → 31 December 2018
Funding
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Biomarker discovery and evaluation
    • Drug discovery and development
    • Medicinal products
    • Pharmaceutics
    • Pharmacognosy and phytochemistry
    • Pharmacology
    • Pharmacotherapy
    • Toxicology and toxinology
    • Other pharmaceutical sciences
Keywords
adjuvants cancer cells
 
Project description

Cancer remains one of the most attractive disease targets for RNA interference (RNAi)-based
therapeutics. To facilitate in vivo delivery of small interfering RNA (siRNA) to cancer cells, they are
typically formulated into nanoparticles (nanomedicines). The latter are designed to overcome the
many extra- and intracellular barriers encountered en route to the intracellular site-of-action (i.e.
the cytosol). Unfortunately, nanomedicines are internalized by tumor cells via endocytosis, leading
to their sequestration in lysosomes and allowing only marginal fractions of the internalized dose to
be delivered into the cell cytoplasm. Escape from endosomes and lysosomes is thus regarded as one
of the most prominent bottlenecks in macromolecular drug delivery. In this project, we propose a
screening approach to identify small molecules that are able to stimulate cytosolic siRNA delivery in
cancer cells. To this end, a phenotypic high-throughput screening methodology will be used to
select hit compounds which will be subjected to subsequent high content secondary screening. The
latter will be optimized to probe for the intracellular mechanism of action, responsible for the
observed improvements in intracellular siRNA delivery. Importantly, the project aims to evaluate to
what extent the observed effects are selective for cancer cells. This strategy might thus be an
important dose-sparing approach, maximizing the therapeutic effect of a single dose while
mitigating off-target toxicity.