Abstract
A wider application of siRNA- and miRNA- based therapeutics is restricted by the currently available delivery systems. We have designed a new type of small molecule carrier (SMoC) system for siRNA modeled to interact with cell surface proteoglycans. This bifurcated SMoC has similar affinity for the model proteoglycan heparin to an equivalent polyarginine peptide and exhibits significant mRNA knockdown of protein levels comparable to lipofectamine and the previously reported linear SMoC.
Highlights
Small interfering RNAs, which are capable of catalytically silencing specific genes via the RNA interference (RNAi) pathway, are attractive candidates for therapeutics for a wide range of diseases including genetic disorders and cancer
The exact mechanism of cellular entry adopted by these polymers and peptides remains unclear, it is suggested that binding to cell surface proteoglycans such as heparan sulfate and chondroitin sulfate via their glycosaminoglycan (GAG) chains may be an initial internalization step, activating Rac1 and triggering subsequent rearrangement of the F-actin cytoskeleton leading to macropinocytosis initiation [18]
An efficient Small interfering RNAs (siRNA) transfection vector should tightly package the siRNA, bind to the cell surface so as to induce macropinocytosis, and escape from the endosome into the cytoplasm in order for the siRNA to act on the RNAi machinery and silence the target gene
Summary
Small interfering RNAs (siRNA), which are capable of catalytically silencing specific genes via the RNA interference (RNAi) pathway, are attractive candidates for therapeutics for a wide range of diseases including genetic disorders and cancer. Alnylam in partnership with Tekmira has developed two further LNP-based therapeutics, which are currently in clinical trials: ALNVSP in Phase II for liver cancer [7] and ALN-TTR01 for transthyretin-mediated amyloidosis which has completed Phase I trials [8] Another success for nanoparticles has been Calando’s CALAA-01, in which siRNA complexed by a cationic cyclodextrin polymer has demonstrated for the first time in humans that systemically delivered siRNA can silence genes [9], and is in Phase I clinical trials. Several studies have used heparin, a highly sulfated form of heparan sulfate, to estimate binding affinities of CPPs to cell surface GAGs, which were found to be in the micromolar to nanomolar range [19,20], while a more recent study shows evidence that CPPs are able to form clusters with multiple heparin chains [21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
