How to Tackle the Challenge of siRNA Delivery with Sequence‐Defined Oligoamino Amides

Abstract

RNA interference (RNAi) as a mechanism of gene regulation provides exciting opportunities for medical applications. Synthetic small interfering RNA (siRNA) triggers the knockdown of complementary mRNA sequences in a catalytic fashion and has to be delivered into the cytosol of the targeted cells. The design of adequate carrier systems to overcome multiple extracellular and intracellular roadblocks within the delivery process has utmost importance. Cationic polymers form polyplexes through electrostatic interaction with negatively charged nucleic acids and present a promising class of carriers. Issues of polycations regarding toxicity, heterogeneity, and polydispersity can be overcome by solid-phase-assisted synthesis of sequence-defined cationic oligomers. These medium-sized highly versatile nucleic acid carriers display low cytotoxicity and can be modified and tailored in multiple ways to meet specific requirements of nucleic acid binding, polyplex size, shielding, targeting, and intracellular release of the cargo. In this way, sequence-defined cationic oligomers can mimic the dynamic and bioresponsive behavior of viruses.

Synthesis and Evaluation of Chloroquine‐Containing DMAEMA Copolymers as Efficient Anti‐miRNA Delivery Vectors with Improved Endosomal Escape and Antimigratory Activity in Cancer Cells

“…However, polyplexes are usually taken up by cells via endocytosis, which leads to entrapment of miRNA in the endosomes and lysosomes where it is subject to enzymatic degradation. Hence, strategies to enhance endosomal escape and ensure effective release of therapeutic miRNA into the cytosol are urgently needed . Among the various endosomal escape strategies, pH‐sensitive polycations such as PEI and virus‐derived or bacteria‐derived proteins and peptides have been widely employed as methods to disrupt endosomal membrane and to facility cytoplasmic delivery .…”

“…Hence, strategies to enhance endosomal escape and ensure effective release of therapeutic miRNA into the cytosol are urgently needed. [23][24][25][26] Among the various endosomal escape strategies, pH-sensitive polycations such as PEI and virus-derived or bacteria-derived proteins and peptides have been widely employed as methods to disrupt endosomal membrane and to facility cytoplasmic delivery. [27] Similarly, chloroquine (CQ) has been used as a chemical endosomal agent to improve in vitro transfection of polyplexes.…”

Cross‐Linkable Polyion Complex Micelles from Polypept(o)ide‐Based ABC‐Triblock Copolymers for siRNA Delivery

“…[7] In order to bypass these adverse effects, carrier systems can be intrinsically stabilized to keep structural integrity until reaching the site of action. [8,9] In this respect, the most common techniques are hydrophobic stabilization [10,11] and bioreversible cross-linking (mostly disulfide-mediated). [12,13] These three major tasks of PIC micelles, i) cargo shielding from the biological environment, ii) intrinsic stabilization, and (iii) complexing properties, can be accomplished by ABC triblock copolymers, where block A builds up the shielding and surrounding corona, block B and C display core functionalities.…”

Monitoring integrity and localization of modified single-stranded RNA oligonucleotides using ultrasensitive fluorescence methods

“…Combined with the progress that has been made in the delivery of oligonucleotides, some of them are already approved for market access and numerous candidates are currently under investigation in clinical trials for treatment of a variety of different diseases[2, 3]. Delivery can be accomplished in both the double or single-stranded configuration[4].…”

“…Oligonucleotide therapeutics have gained in importance over the last decades as they can be utilized to interfere with almost every cellular process by simply selecting the appropriate sequence and format[ 1 ]. Combined with the progress that has been made in the delivery of oligonucleotides, some of them are already approved for market access and numerous candidates are currently under investigation in clinical trials for treatment of a variety of different diseases[ 2 , 3 ]. Delivery can be accomplished in both the double or single-stranded configuration[ 4 ].…”