DNA Origami Delivery System for Cancer Therapy with Tunable Release Properties

Abstract

In the assembly of DNA nanostructures, the specificity of Watson-Crick base pairing is used to control matter at the nanoscale. Using this technology for drug delivery is a promising route toward the magic bullet concept, as it would allow the realization of complex assemblies that co-localize drugs, targeting ligands and other functionalities in one nanostructure. Anthracyclines' mechanism of action in cancer therapy is to intercalate DNA, and since DNA nanotechnology allows for such a high degree of customization, we hypothesized that this would allow us to tune the DNA nanostructures for optimal delivery of the anthracycline doxorubicin (Dox) to human breast cancer cells. We have tested two DNA origami nanostructures on three different breast cancer cell lines (MDA-MB-231, MDA-MB-468, and MCF-7). The different nanostructures were designed to exhibit varying degrees of global twist, leading to different amounts of relaxation in the DNA double-helix structure. By tuning the nanostructure design we are able to (i) tune the encapsulation efficiency and the release rate of the drug and (ii) increase the cytotoxicity and lower the intracellular elimination rate when compared to free Dox. Enhanced apoptosis induced by the delivery system in breast cancer cells was investigated using flow cytometry. The findings indicate that DNA origami nanostructures represent an efficient delivery system for Dox, resulting in high degrees of internalization and increased induction of programmed cell death in breast cancer cells. In addition, by designing the structures to exhibit different degrees of twist, we are able to rationally control and tailor the drug release kinetics.

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

“…Through the utilization of various nanoformulations, many of the issues associated with the use of free drugs have been addressed via tunable release of therapeutics, enhanced pharmacokinetic and pharmacodynamic profiles, modifications for superior targeted delivery, and ease of incorporation of multiple agents with differing solubility profiles [16][17][18]. Tunable release has been a major component of the recent boom in nanomedicine research, as stimuli-responsive carriers are optimized to release payload only upon certain cues either intracellularly or within the microenvironment of tumors and can potentially lower systemic toxicity of chemotherapeutic agents [19][20][21]. Commonly utilized triggers for payload release include a slightly acidic pH in the microenvironment, overexpression of specific enzymes, localized hyperthermia, and increased levels of glutathione within the cell [22][23][24][25][26][27].…”

Nanodiagnostics: a new frontier for veterinary and medical sciences

“…The DNA robot was an elegant model system which has shown great potential for uses as a smart drug. The DNA nanotechnology science has also been used as carriers for Doxorubicin (anticancer drug) (Jiang et al, 2012;Zhao et al, 2012). This showed increased potency of Doxorubicin as compared to normal medication.…”

Drug delivery systems based on nucleic acid nanostructures

“…Similar tubes as generated for immunostimulation were harnessed for cancer therapy [79]. In this study two types of DNA origami tubes were employed that were smaller than the one applied for immunostimulation.…”

“…3D models of (A) straight nanotube (S-Nano), using 10.5 bp per turn twist density and (B) twisted nanotube (T-Nano), having 12 bp/turn. Reproduced with permission from [79]. dependent manner.…”