DNA Trojan Horses: Self‐Assembled Floxuridine‐Containing DNA Polyhedra for Cancer Therapy

Abstract

Based on their structural similarity to natural nucleobases, nucleoside analogue therapeutics were integrated into DNA strands through conventional solid‐phase synthesis. By elaborately designing their sequences, floxuridine‐integrated DNA strands were synthesized and self‐assembled into well‐defined DNA polyhedra with definite drug‐loading ratios as well as tunable size and morphology. As a novel drug delivery system, these drug‐containing DNA polyhedra could ideally mimic the Trojan Horse to deliver chemotherapeutics into tumor cells and fight against cancer. Both in vitro and in vivo results demonstrate that the DNA Trojan horse with buckyball architecture exhibits superior anticancer capability over the free drug and other formulations. With precise control over the drug‐loading ratio and structure of the nanocarriers, the DNA Trojan horse may play an important role in anticancer treatment and exhibit great potential in translational nanomedicine.

Progress toward Understanding the Interactions between DNA Nanostructures and the Cell

“…The smallest DNA nanorectangles (32 nm × 12 nm) enter more cells than the longer and wider DNA nanorectangles (e.g., 64 nm × 24 nm) as well as the DNA nanotubes, although it is uncertain whether the differences in uptake among these structures are statistically significant. In 2017, Mou et al prepared fluorescently labeled DNA TDNs, dodecahedra, and buckyballs, and assessed their cellular uptake, keeping the total amounts of fluorophore added to the cells constant . By confocal imaging and flow cytometry, the authors observed that the DNA buckyballs (with a reported diameter of 84 nm) enter HeLa cells more abundantly than the other two smaller structures (with an estimated diameter of ≈16 nm for TDN and ≈55 nm for dodecahedron based on our analysis of their published atomic force microscopy (AFM) data).…”

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

“…[9] Thus far, by non-covalently or covalently loading chemotherapeutics onto DNAn anostructures,avariety of DNA-based DDSs have been constructed to deliver chemodrugs either in vitro or in vivo. [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. [11] Recently,w ep roposed as trategy that integrated nucleoside analogues (NAs) into DNAstrands and then assembled them into well-defined DNAn anostructures to construct precise nanomedicine.…”

Floxuridine Homomeric Oligonucleotides “Hitchhike” with Albumin In Situ for Cancer Chemotherapy

“…[2] Among these drug modules, therapeutic nucleoside and nucleobase analogues show inherent advantages for their excellent stability during DNA synthesis. [3] …”

“…[4] Recently, floxuridine was employed to construct fluoropyrimidine polymer (F10) and to pair with guanosine in a DNA polyhedral nanosystem for cancer therapy. [3c, 5] But, in spite of these advances, drug-incorporated oligonucleotides, consistent with natural oligonucleotides, face challenges in systemic delivery. [6] Conventional methods focus on chemical modifications with active targeting ligands and conjugation with nanoparticles which accumulate in the tumor by the EPR effect.…”

“…[10] It is also wellknown as a natural transporter of poorly water-soluble molecules (e.g., lipids and cholesterol) in plasma. [3d, 11] Remarkably, as a delivery carrier for chemotherapy, the biological safety of serum albumin outperforms most other carriers. [11] Therefore, various hydrophobic payloads, for instance, paclitaxel (Abraxane) and perflutren (Optison), have been designed to bond with albumin for cancer therapy and for contrast enhancement during ultrasound imaging.…”