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

Abstract

Osteosarcoma often occurs in children and adolescents with high invasiveness and high mortality. Polo‐like kinase 1 (PLK1) overexpressed in most tumors promotes cancer cell proliferation and transformation. PLK1 is considered as a therapeutic target for osteosarcoma. RNA interference‐based therapies are employed to combat osteosarcoma through silencing PLK1 gene expression. However, the treatment results remain unsatisfactory due to the lack of a safe and efficient nonviral gene vector. To tackle this hurdle, biodegradable and CO2‐derivative cationic poly(vinylcyclohexene carbonates) (CPCHCs) are used as gene vectors to perform a siPLK1 therapeutic strategy for osteosarcoma treatment. Of those CPCHCs, CPCHC60 demonstrates the most excellent performance in gene transfection efficiency, endo‐lysosome escaping, biodegradability, and biosafety. With the treatment of CPCHCs/siRNA nanoparticles, the expression level of PLK1 gene in osteosarcoma cells is significantly down‐regulated. Subsequently, cells are arrested in the G2/M phase and subsequently dead in the form of apoptosis, resulting in significant tumor regression both in vitro and in vivo. This study brings a new insight into the development of superior nonviral gene vectors for practical cancer treatment. Based on the results, the resulting nanoparticle‐based gene drug formation is considered to have a highly successful chance in further translational nanomedicine applications.

Recent Advances in Engineering Carriers for siRNA Delivery

“…For example, our group synthesized CO 2 ‐based cationic poly(vinylcyclohexene carbonates) (CPCHCs) with a charge density of 46%, 60%, and 70%. [ 23 ] On the basis of gene transfection efficiency, endo‐lysosome escaping, biodegradability, and biosafety, CPCHCs with a charge density of 60% was chosen as an optimal siRNA carrier. Upon loading PLK1 target siRNA, such siRNA‐loaded‐CPCHCs further resulted in significant tumor regression both in vitro and in vivo.…”

“…To address the abovementioned hurdles, various nanocarriers, such as lipids, cationic polymers, polymer-inorganic hybrid NPs, nanogels, and nucleic acid NPs, have been successfully designed and created in order to deliver vulnerable siRNA into targeting cells (Figure 1a). [19][20][21][22][23] To deliver the loaded siRNA molecules into target cells, an ideal carrier is considered to exhibit abilities to overcome the mentioned extracellular and intracellular barriers (Figure 1b,c). In this context, common carrier design criteria to circumvent the biological barriers when delivering the loaded siRNA payloads will be introduced first.…”

“…To address the abovementioned hurdles, various nanocarriers, such as lipids, cationic polymers, polymer‐inorganic hybrid NPs, nanogels, and nucleic acid NPs, have been successfully designed and created in order to deliver vulnerable siRNA into targeting cells (Figure 1a). [ 19–23 ]…”

Post-polymerization functionalization of aliphatic polycarbonates using click chemistry

“…Among the different cationic polycarbonates, ones with 60% amine moieties showed the best results (Scheme 5c). 62 Since the development of an effective process for the copolymerization of limonene oxide (LO), a bio-mass-derived monomer and CO 2 by Coates and coworkers, 68 significant progress has been achieved in the post-polymerization functionalization of this polymeric material. 69 Bio-based poly (limonene carbonate)s have been functionalized to provide antibacterial polymers, heat processing-grade polymeric materials, and seawater soluble polymers.…”

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.…”