Endothelial-specific delivery of siRNA by novel SAINT-based lipoplexes
|PhD ceremony:||Mr N.G.J. (Niek) Leus|
|When:||October 08, 2014|
|Supervisor:||prof. dr. G. (Ingrid) Molema|
|Co-supervisor:||dr. J.A.A.M. (Jan) Kamps|
|Where:||Academy building RUG|
|Faculty:||Medical Sciences / UMCG|
Since its discovery, RNA interference (RNAi) has emerged as one of the most powerful tools to study gene regulation and function, and has great potential to become an effective therapeutic strategy for various diseases, including (chronic) inflammatory diseases and cancer. For therapeutic application, siRNA (an important component of the RNAi pathway) needs to be protected during circulation and delivered to the desired tissue and into the target cell in order to achieve therapeutic effects. Progress towards clinical application of siRNA-based interventions is still hampered by inadequate and ineffective delivery into target cells or tissues. This thesis focuses on the development of cationic amphiphilic SAINT-C18-based lipoplexes (called SAINTarg and SAINTPEGarg) suitable for efficient and endothelial-specific siRNA delivery in vivo.
Microvascular endothelial cells at the site of inflammation are both active regulators of, and participants in acute and chronic inflammatory processes. Therefore, endothelial-specific siRNA delivery presents a promising strategy for anti-inflammatory interventions aiming at silencing disease-associated genes involved in the pathophysiology of acute or chronic inflammation.
The studies described in this thesis have yielded novel SAINT-based carriers including anti-VCAM-1-SAINTarg, anti-E-selectin- and anti-VCAM-1-SAINTPEGarg that all showed functional in vitro siRNA delivery, and that we optimized for in vivo siRNA delivery into inflammation-activated endothelial cells. Even though anti-VCAM-1-SAINTPEGarg/PEG2% containing VE-cadherin specific siRNA selectively and extensively accumulated in VCAM-1 expressing postcapillary venules in lungs of TNFα-challenged mice, no down-regulation of VE-cadherin gene expression was found. Consequently, the current antibody-SAINTPEGarg formulation still has to be improved in order to enable in vivo applications.