Solid-phase supported design of carriers for therapeutic nucleic acid delivery

Abstract

Nucleic acid molecules are important therapeutic agents in the field of antisense oligonucleotide, RNA interference, and gene therapies. Since nucleic acids are not able to cross cell membranes and enter efficiently into cells on their own, the development of efficient, safe, and precise delivery systems is the crucial challenge for development of nucleic acid therapeutics. For the delivery of nucleic acids to their intracellular site of action, either the cytosol or the nucleus, several extracellular and intracellular barriers have to be overcome. Multifunctional carriers may handle the different special requirements of each barrier. The complexity of such macromolecules however poses a new hurdle in medical translation, which is the chemical production in reproducible and well-defined form. Solid-phase assisted synthesis (SPS) presents a solution for this challenge. The current review provides an overview on the design and SPS of precise sequence-defined synthetic carriers for nucleic acid cargos.

The Multifaceted Histidine-Based Carriers for Nucleic Acid Delivery: Advances and Challenges

“…Lipopeptide or lipid-peptide hybrid carriers form micelles alone and in complex with nucleic acids ( Table 5 ). Since the earliest report of lipid-peptide hybrids, these hybrids have evolved into an important area for polymeric carriers [ 77 ], in part because of their ability to increase the stability and/or the half-life of the polyplexes in the bloodstream [ 78 , 79 , 80 ].…”

Differentially Branched Ester Amine Quadpolymers with Amphiphilic and pH-Sensitive Properties for Efficient Plasmid DNA Delivery

“…With further knowledge of precise desired polymer structures, solid phase synthesis of alternating copolymers is an option that has been utilized in the synthesis of precisely defined polymers for gene delivery. 59 Degradation rate of polymers could also play a role in the differences in transfection, as differences in constituent monomers can affect the specific degradation rate. 18 The total possible solution space for BEAQs that may be highly effective for gene delivery is vast, as there are many diacrylate, side-chain amino, and end-capping amino monomers available that have been shown to yield linear polymers effective for transfection of diverse cell types.…”

Microparticle Depots for Controlled and Sustained Release of Endosomolytic Nanoparticles

“…1,24,31 This pervasive challenge has led to the widespread development of synthetic nucleic acid carriers that enhance cellular uptake and promote endosomal escape of associated cargo. 4,36,66 Our group, and others, have recently utilized pH-responsive, endosomolytic polymer nanoparticles (NPs) to enhance the cytosolic delivery and activity of siRNA and immunostimulatory 5¢triphosphate RNA. 19,24,31,46 These NPs are assembled using amphiphilic diblock copolymers that selfassemble into micelles with a cationic dimethylaminoethyl methacrylate (DMAEMA) corona for electrostatic complexation of nucleic acids, and a pHresponsive, endosomolytic core comprising DMAE-MA, butyl methacrylate (BMA), and propylacrylic acid (PAA) ( Fig.…”