Synthetic Conjugated Oligoelectrolytes Are Effective siRNA Transfection Carriers: Relevance to Pancreatic Cancer Gene Therapy

Abstract

Conjugated oligoelectrolyte COE-S6 contains an elongated conjugated core with three cationic charges at each termini of the internal core. As an analogue of bolaamphiphiles, these structural attributes lead to the formation of spherical nanoplexes with D h = 205 ± 5.0 nm upon mixing with small interfering RNA (siRNA). COE-S6/siRNA nanocomplexes were shown to be protective toward RNase, stimulate endosome escape, and achieve transfection efficiencies comparable to those achieved with commercially available LIP3000. Moreover, COE-S6/siRNA nanocomplexes enabled efficient silencing of the K-ras gene in pancreatic cancer cells and significant inhibition of cancer tumor growth with negligible in vitro toxicities. More importantly, cell invasion and colony formation of the Panc-1 cells were significantly inhibited, and apoptosis of the pancreatic cancer cells was also promoted. We also note that COE-S6 is much less toxic relative to commercial lipid formulations, and it provides optical signatures that can enable subsequent mechanistic work without the need to label nucleotides. COE-S6-based nanoplexes are thus a promising candidate as nonviral vectors for gene delivery.

Membrane-intercalating conjugated oligoelectrolytes

“…MICOEs may confer value-added functions to these systems, such as intrinsic fluorescence and membrane stabilisation, in areas such as drug delivery. 94…”

“…The COE-S6/siRNA nanocomplexes enabled efficient silencing of the K-ras gene in pancreatic cancer cells and significant inhibition of cancer cell growth with negligible in vitro toxicities. 94 5 Challenges and outlook…”

“…MICOEs may confer valueadded functions to these systems, such as intrinsic fluorescence and membrane stabilisation, in areas such as drug delivery. 94 A guided structural innovation of MICOEs to realize these new applications is highly desirable. Applications of MICOEs seem to be converging to more valuable fields, like diagnosis and therapeutics.…”

Building a Better Silver Bullet: Current Status and Perspectives of Non‐Viral Vectors for mRNA Vaccines

“…Available viral vectors for gene delivery include lentivirus, [26] adenovirus (AdV), [27] and adeno-associated viruses (AAV) [28] have been extensively used and reported for in vivo gene delivery; [29] however, the intrinsic disadvantages, including safety concerns on oncogenicity and immunogenicity, high cost, and low loading capacity of nucleic acid, hampered their clinical applications. [30] Thus, in recent several years, a growing interest in non-viral gene vectors, [31] including lipids, [19,32,33] polymers, [34][35][36]37] peptides, [38,39] and exosomes, [40][41][42] have been aroused among scientists as promising candidates for safe and versatile vaccine platforms.…”

Biodegradable Carbon Dioxide‐Derived Non‐Viral Gene Vectors for Osteosarcoma Gene Therapy

“…Vectors used to deliver genes typically can be categorized into viral and non‐viral vectors. [ 12,17 ] Viral vectors are mainly composed of lentiviruses (LVs), adenoviruses (AVs), and adeno‐associated viruses (AAVs), [ 12 ] while non‐viral vectors are mainly nano vectors consisting of cationic polymers, [ 18 ] lipids, [ 19 ] inorganic particles, [ 20 ] and their hybrid compositions. [ 17b,21 ] Due to the fragile nature, the successful delivery of negatively charged, high molecular weight, and unstable siRNA is highly challenging.…”