Cisplatin-Cross-Linked DNA Origami Nanostructures for Drug Delivery Applications

Abstract

Biocompatible DNA origami nanostructures (DONs) attract significant interest as potential targeted drug carriers. Their sensitivity to various environmental triggers is beneficial as a drug release or decomposition mechanism, but it also hinders their stability; therefore, they require some extent of cross-linking. Using cisplatin, we demonstrate that a molecule can both act as a therapeutic and cross-linking agent for DONs. In this work, triangular two-dimensional DONs are loaded with ∼1000 cisplatin molecules per nanostructure as confirmed by ICP-MS and STEM-EDS. Time dependence of the loading shows a saturation point and gradual cisplatin release. Above ∼1000 cisplatin molecules loaded per nanostructure, structural distortion occurs as analyzed by AFM and gel electrophoresis. Cross-linking persists even after thermal treatment of cisplatin-loaded DONs above typical DON denaturing temperatures preventing complete separation into DON components (scaffold and staples). Cisplatin-loaded DON cytotoxicity is tested on FaDu cells and compared to that of free cisplatin using MTT assays. Nanomolar quantities of cisplatin-loaded DONs reduce cell viability to 50% after 48–72 h. Considering the low dose required of cisplatin-loaded DONs to exhibit cytotoxic behavior and the known tumor-targeting properties of DONs, this system can be a promising drug carrier for cancer therapy worthy of further exploration.

Facile preparation of toluidine blue-loaded DNA nanogels for anticancer photodynamic therapy

“…To prepare the self-assembled DNA nanogel, herring sperm DNA (hsDNA) segments (<50 bp) were selected as a model DNA since it is readily available and cost-effective and widely used for studying drug–DNA interactions ( Sirajuddin et al, 2013 ; Xiong et al, 2021 ). Cisplatin, a common chemotherapeutic drug that could also act as a crosslinker to build different nanoparticles ( Li et al, 2014 ; Zhang and Tung, 2017a ; Wang et al, 2021 ; Sala et al, 2022 ), was utilized to construct the DNA nanogel, as previously demonstrated ( Zhang and Tung, 2017b ). A simple mixing of cisplatin, TB, and hsDNA, followed by a heating and cooling process, generated the DNA/TB NG ( Figure 1A ).…”

Mechanics of Dynamic and Deformable DNA Nanostructures

“…There are several strategies for strengthening DNA, such as adding chemicals that can enhance DNA mechanics. For example, crosslinking molecules can improve the thermal stability of DNA structures, [126][127][128][129] and will likely enhance the stiffness and mechanical stability. This mechanical enhancement has not been explored yet.…”

“…Apart from photo-crosslinking, chemical crosslinking methods also have been developed. 128,129 Shih et al used polyethylene glycol (PEG) modified oligolysine-coated DNA nanostructures. With addition of glutaraldehyde, the structures can be crosslinked and show 400-fold higher resistance to nuclease as well as improved stability in low-salt environments.…”

Mechanics of dynamic and deformable DNA nanostructures

“…Chemical crosslinking methods also have been developed for structural reinforcement. 170,171 Anastassacos et al used polyethylene glycol (PEG) modied oligolysines for coating DNA nanostructures. With addition of glutaraldehyde, the structures were crosslinked and showed 400-fold higher resistance to nuclease as well as improved stability in low-salt environments.…”