Stressing the Role of DNA as a Drug Carrier: Synthesis of DNA–Drug Conjugates through Grafting Chemotherapeutics onto Phosphorothioate Oligonucleotides

Abstract

To stress the role of deoxyribonucleic acid (DNA) as a drug carrier, an efficient conjugation strategy in which chemotherapeutics can be grafted onto a phosphorothiolated DNA backbone through the reaction between the phosphorothioate group (PS) and a benzyl bromide group is proposed. As a proof of concept, benzyl‐bromide‐modified paclitaxel (PTX) is employed to graft onto the DNA backbone at the PS modification sites. Due to the easy preparation of phosphorothiolated DNA at any desired position during its solid‐phase synthesis, diblock DNA strands containing both normal phosphodiester segment (PODNA) and phosphorothiolate segment (PSDNA) are directly grafted with a multitude of PTXs without using complicated and exogenous linkers. Then, the resulting amphiphilic PODNA‐blocked‐(PSDNA‐grafted PTX) conjugates (PODNA‐b‐(PSDNA‐g‐PTX)) assemble into PTX‐loaded spherical nucleic acid (SNA)‐like micellar nanoparticles (PTX‐SNAs) with a high drug loading ratio up to ≈53%. Importantly, the PODNA segment maintains its molecular recognition property and biological functions, which allows the as‐prepared PTX‐SNAs to be further functionalized with tumor‐targeting aptamers, fluorescent probe strands, or antisense sequences. These multifunctional PTX‐SNAs demonstrate active tumor‐targeting delivery, efficient inhibition of tumor growth, and the reversal of drug resistance both in vitro and in vivo for comprehensive antitumor therapy.

A Camptothecin‐Grafted DNA Tetrahedron as a Precise Nanomedicine to Inhibit Tumor Growth

“…[10] However, previously reported DNA-based DDSs still lack the control in precisely tuning the number and type of loaded drug molecules. [16] Although PS conjugation provides anew way to effectively synthesize DDCs,hydrophilicities of which usually alter after drug conjugation and their assemblies are lack of control in morphology and reproducibility.Therefore,how to balance the drug loading and hydrophilicity of the DDCs to retain their capability of programmable self-assembly remains as am ajor challenge in the synthesis of precise DNA-based nanomedicine. [12] Despite the advances in precise control over composition and morphology,t his strategy is strictly limited to NAsthat can be converted into phosphoramidte for solidphase synthesis.T oe xpand the drug scope that can be precisely loaded on DNA, it is unmet to develop new strategies for the DDC synthesis.B ased on the fact that phosphorothioate group in PS-modified DNA( PS-DNA) is ag ood nucleophile and more reactive than phosphodiester group,f unctional molecules such as fluorescent dyes, [13] proteins, [14] gold nanoparticles, [15] have been conjugated onto DNAs trands at PS sites.P articularly,a fter modifying the chemodrug with electrophile moiety,weonce showed that PS-DNAc ould be efficiently grafted with am ultitude of paclitaxels and subsequently self-assemble into am icellular nanodrug.…”

“…[12] Despite the advances in precise control over composition and morphology,t his strategy is strictly limited to NAsthat can be converted into phosphoramidte for solidphase synthesis.T oe xpand the drug scope that can be precisely loaded on DNA, it is unmet to develop new strategies for the DDC synthesis.B ased on the fact that phosphorothioate group in PS-modified DNA( PS-DNA) is ag ood nucleophile and more reactive than phosphodiester group,f unctional molecules such as fluorescent dyes, [13] proteins, [14] gold nanoparticles, [15] have been conjugated onto DNAs trands at PS sites.P articularly,a fter modifying the chemodrug with electrophile moiety,weonce showed that PS-DNAc ould be efficiently grafted with am ultitude of paclitaxels and subsequently self-assemble into am icellular nanodrug. [16] Although PS conjugation provides anew way to effectively synthesize DDCs,hydrophilicities of which usually alter after drug conjugation and their assemblies are lack of control in morphology and reproducibility.Therefore,how to balance the drug loading and hydrophilicity of the DDCs to retain their capability of programmable self-assembly remains as am ajor challenge in the synthesis of precise DNA-based nanomedicine.…”

A Camptothecin‐Grafted DNA Tetrahedron as a Precise Nanomedicine to Inhibit Tumor Growth

“…Based on the fact that phosphorothioate group in PS‐modified DNA (PS‐DNA) is a good nucleophile and more reactive than phosphodiester group, functional molecules such as fluorescent dyes, proteins, gold nanoparticles, have been conjugated onto DNA strands at PS sites. Particularly, after modifying the chemodrug with electrophile moiety, we once showed that PS‐DNA could be efficiently grafted with a multitude of paclitaxels and subsequently self‐assemble into a micellular nanodrug . Although PS conjugation provides a new way to effectively synthesize DDCs, hydrophilicities of which usually alter after drug conjugation and their assemblies are lack of control in morphology and reproducibility.…”

DNA‐Guided Assembly of Molecules, Materials, and Cells

“…Then DNA‐fluorophore hybrid structures were placed into photonic crystal cavities at selected positions to digitally tune the light emission intensities, with which they have generated an image mimicking Van Gogh's The Starry Night (Figure b) . Zhang and co‐workers grafted an anticancer small molecule drug (paclitaxel) onto ssDNAs, which formed a micellar structure with hydrophobic paclitaxel residing inside the core and hydrophilic DNA protruding outward serving as the shell (Figure c) . The molecular recognition capability of DNA shell remained available to load functional moieties such as targeting ligands.…”

“…c) Paclitaxel‐grafted DNA self‐assembled into micellar particles for cancer therapy. Reproduced with permission . Copyright 2019, John Wiley & Sons Inc. d) Conductive polymer was placed and routed on a DNA origami template.…”