Multicomponent Polymerization toward Cationic Polymers for Efficient Gene Delivery

Abstract

A new class of cationic polymers containing tertiary amine, thioether, and hydroxyl groups are prepared via a catalyst‐free, multicomponent polymerization method using dithiol, formaldehyde, and di‐sec‐amine with a ratio of 1:2:1, to access a library of water‐soluble polymers with well‐defined structures and suitable molecular weights (Mw ranging from 5000 to 8000 Da) in high yields (up to 90%). Such polycations are demonstrated to be promising nonviral gene delivery vectors with high transfection efficiency (up to 3.5‐fold of PEI25k) and low toxicity with multiple functionalities: 1) efficient gene condensation by tertiary amine groups; 2) reactive oxygen species scavenging by thioether groups; and 3) positive charge shielding by hydroxyl groups. Both the thioether and hydroxyl groups are contributed to reduce the cytotoxicity of the polycations by tuning the oxidative stress and preventing the undesired serum binding. The optimized polycations can achieve high transfection efficiency under the serum conditions, indicating the great potential as a nonviral gene delivery vector candidate for clinical application.

Well-Defined pH-Responsive Self-Assembled Block Copolymers for the Effective Codelivery of Doxorubicin and Antisense Oligonucleotide to Breast Cancer Cells

“…Of note, uptake of nanocomplex of cationic polymers with genes by MCF-7 cells via endocytosis has been reported in literature. 66,67 In this work, because the PDMAEMA block involved in GTI2040/DOX-SAN has a pKa value of 7.5 and exhibits a remarkable buffering capacity in acidic endo-lysosomes, the co-delivery system may enable endosomal escape through the proton sponge mechanism. 58,59 Moreover, due to the dynamic equilibrium between the free polymer chains and GTI2040/DOX-SAN nanocomplex, the intercalation between free cationic polymers and negatively charged endosomal membrane likely can cause destabilization, permeability, and hole formation within the lipid layer, leading to endosomal escape.…”

Synthesis of ionizable lipopolymers using split-Ugi reaction for pulmonary delivery of various size RNAs and gene editing

“…[29][30][31][32][33] While diverse libraries of cationic polymers are being synthesized to enable delivery across extrahepatic tissues, the therapeutic index remains limited for clinical development. [34][35][36][37] Moreover, the dispersity inherent to polymers presents further challenges for scale up and reproducibility. To this end, we hypothesized that a rapid high-throughput method of derivatization of PEI that results in unprecedent structural diversity of PEI based ionizable lipopolymers and further formulation optimization can result in resolving these long-standing issues.…”

Aliphatic Quaternary Ammonium Functionalized Nanogels for Gene Delivery

“…However, concerns with the use of viruses, including the high production cost, and risk of immunogenicity and induced oncogenic transformations have led researchers to search for non-viral gene vectors [5,6]. Until now, cationic polymers (e.g., poly(ethyleneimine), polylysine, and cationic polysaccharides) [7][8][9] and cationic lipids (e.g., Lipofectin TM and LipofectAMINE TM ) [10][11][12][13] were the most investigated classes of synthetic materials for gene delivery. Cationic polymers usually contain primary, secondary, and/or tertiary amino groups and provide a positive charge through the presence of protonated amines, which mediates complex formation with anionic gene molecules through electrostatic interactions [14].…”