DNA Origami as a Carrier for Circumvention of Drug Resistance

Abstract

Although a multitude of promising anti-cancer drugs have been developed over the past 50 years, effective delivery of the drugs to diseased cells remains a challenge. Recently, nanoparticles have been used as drug delivery vehicles due to their high delivery efficiencies and the possibility to circumvent cellular drug resistance. However, the lack of biocompatibility and inability to engineer spatially addressable surfaces for multi-functional activity remains an obstacle to their widespread use. Here we present a novel drug carrier system based on self-assembled, spatially addressable DNA origami nanostructures that confronts these limitations. Doxorubicin, a well-known anti-cancer drug, was noncovalently attached to DNA origami nanostructures through intercalation. A high level of drug loading efficiency was achieved, and the complex exhibited prominent cytotoxicity not only to regular human breast adenocarcinoma cancer cells (MCF 7), but more importantly to doxorubicin-resistant cancer cells, inducing a remarkable reversal of phenotype resistance. With the DNA origami drug delivery vehicles, the cellular internalization of doxorubicin was increased, which contributed to the significant enhancement of cell-killing activity to doxorubicin-resistant MCF 7 cells. Presumably, the activity of doxorubicin-loaded DNA origami inhibits lysosomal acidification, resulting in cellular redistribution of the drug to action sites. Our results suggest that DNA origami has immense potential as an efficient, biocompatible drug carrier and delivery vehicle in the treatment of cancer.

DNA origami based assembly of gold nanoparticle dimers for surface-enhanced Raman scattering

“…Such structures have been typically assembled by folding a long 'scaffold' strand of viral single-stranded DNA (ssDNA) using multiple short ssDNA 'staple' strands; however, they can also be assembled without the use of a scaffold [5][6][7] . The strength of this technique has been demonstrated in a number of applications including control and study of molecular transport in cells [8][9][10] , drug delivery systems 11 , as platforms for single-molecule chemical reactions 12,13 , rulers for super-resolution microscopy 14,15 as well as nanopore biosensors [16][17][18] . Furthermore, the double helical structure of DNA offers the possibility of unique binding sites with a regular spacing of B7 nm (21 bp) along the helix and B3 nm perpendicular to the helical axis 19 which makes DNA origami perfectly suited as a platform for the assembly of multicomponent nanostructures 20,21 .…”

Self-assembled, aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics

“…Recent biotechnological advancements have led to a variety of targeted drug transport (TDT) strategies based on aptamer-drug conjugates or aptamer-nanomaterial assemblies (11,12,(18)(19)(20)(21)27). However, these strategies have unique limitations that could hamper the transition to clinical application, including (i) complicated design, laborious and uneconomical bulky preparation of myriad ssDNA as building blocks to construct sophisticated nucleic acid-based nanomaterials, or laborious and inefficient preparation of aptamer-drug conjugates (9,11,14,15,17,18); (ii) limited drug payload capacity and the attendant high cost, hampering production scale-up (9,11,14,15,17,18,20,27); (iii) poor biodegradability, causing chronic accumulation of nanomaterials in vivo (28, 29); and (iv) limited universality by the requirement of specific aptamer for drug loading (20).However, we have designed and engineered a DNA nanostructure able to circumvent these limitations. Specifically, we report an aptamer-tethered DNA nanotrain (aptNTr), which is a long linear DNA nanostructure self-assembled simply from two relatively short DNA building blocks upon initiation of aptamertethered trigger probes, through a hybridization chain reaction (8) (Fig.…”

“…A theranostic (4) platform with targeted and efficient drug transport would solve these problems, and, by its programmability, DNA nanotechnology has been used for the rational assembly of one-, two-, and three-dimensional nanostructures (5)(6)(7)(8), which have been further studied for biomedical applications, including the passive targeted transport of theranostic agents (9)(10)(11)(12)(13)(14)(15)(16)(17). In addition, aptamers, as specific recognition elements, have been studied for active targeted transport of conventional chemotherapeutic drugs (11,12,(18)(19)(20)(21).…”

3D DNA Crystals and Nanotechnology

“…One potential application that has already been explored with DNA origami constructs is as a drug delivery vehicle. Anti-cancer drugs, such as doxorubicin, can be intercalated into DNA origami designs and used to improve drug efficacy in cell culture models [72,73]. DNA crystals may be suitable for similar use, but with the potential of drugs beyond just small molecule intercalators.…”