Hemocompatibility assessment of two siRNA nanocarrier formulations.
OBJECTIVE
Since the discovery of RNAi and its therapeutic potential, carrier systems have been developed to deliver small RNAs (particularly siRNA) for modulation of gene expression at the post-transcriptional level. An important factor determining the fate and usability of these systems in vivo is interaction with blood components, blood cells, and the immune system. In this study, a lipid-based and a polymer-based carrier system containing siRNA have been investigated in vitro in terms of their hemocompatibility.


METHODS
The nanocomplexes studied were Angiplex, a targeted lipid-based system, and pHPMA-MPPM polyplex, a formulation based on a cationic polymer. siVEGFR-2 was encapsulated in both carriers and activation of platelets, coagulation, and complement cascade as well as induction of platelet aggregation were evaluated in vitro.


RESULTS
Both systems had been shown before to cause significant silencing in vitro. Our findings indicated that pHPMA-MPPM polyplex triggered high platelet activation and aggregation although it did not stimulate coagulation substantially. Angiplex, on the other hand, provoked insignificant activation and aggregation of platelets and activated coagulation minimally. Complement system activation by Angiplex was in general low but stronger than pHPMA-MPPM polyplex.


CONCLUSIONS
Taken together, these in vitro assays may help the selection of suitable carriers for systemic delivery of siRNA in early preclinical investigations and reduce the use of laboratory animals significantly.
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
Afrouz
A
Yousefi
Marianne
M
Lauwers
Reka
R
Nemes
Thijs
T
van Holten
Negar
N
Babae
Mark
M
Roest
Gert
G
Storm
Raymond
R
Schiffelers
Enrico
E
Mastrobattista
D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects; D002412:Cations / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008689:Methacrylates / Q000737:chemistry; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010974:Platelet Aggregation / Q000187:drug effects; D011108:Polymers / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry*
D002412:Cations; D004337:Drug Carriers; D008055:Lipids; D008689:Methacrylates; D011108:Polymers; D034741:RNA, Small Interfering; C032802:hydroxypropyl methacrylate