DNA Origami‐Enabled Engineering of Ligand–Drug Conjugates for Targeted Drug Delivery

Abstract

under the context that Brentuximab vedotin (Adcetris) for relapsed Hodgkin lymphoma [5,6] and T-DM1 (Kadcyla) for HER2 + metastatic breast cancer [7,8] received clinical approval from the Food and Drug Administration (FDA). The socalled "magic bullet," originally conceived by Paul Ehrlich, [9] are designed to combine the toxicity of small-molecule drugs with the targeting ability of antibodies to improve overall efficacy and therapeutic index. [10][11][12][13][14][15] Although conceptually straightforward, development of ADCs is encountered with several challenges including manageable toxicity, homogeneous conjugation and limited drug payload capacity. The balance between drug-to-antibody ratio (DAR) and targeting capability is mandatory for ADCs to reduce the attrition rate of drug candidates. Very high DAR ADCs may suffer decreased recognition to the target antigen. [16][17][18][19] Hence, it is highly desirable to develop ADCs with both high maximum tolerated doses and high selectivity. [20][21][22] Recently, the bloom of structural DNA nanotechnology [23,24] has demonstrated unprecedented precision on structural control, which enables predictable and programmable construction of complex nanostructures by exploiting intra-and inter-molecular Watson-Crick base-pairing. The programmability and addressability of DNA origami nanostructures (DONs) enable multiple desired functional moieties (such as therapeutic cargoes and tumor targeting ligands) with designer geometry and density. [25][26][27] Therefore, DONs have been increasingly employed for developing novel drug delivery systems [28,29] due to their versatile designability, high solubility, and intrinsic biocompatibility. [30][31][32][33][34][35][36][37] Moreover, certain types of DONs have been proven to be readily rapidly internalized by mammalian cells despite their negatively charged surface property. [38] We herein propose that DONs with certain framework [39] could serve as an ideal scaffold for ADCs analogues with exceptional control over targeting ligand density and drug loading contents for optimized antitumor efficacies and safety profile. [40] Specifically, we construct a new prostate cancer (PCa)specific drug delivery system by introducing different numbers of ligand 2-[3-(1,3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA) to a designed six-helical-bundle DNA origami nanostructure (6HB DON). DUPA has been demonstrated to be a high-affinity inhibitor (K i ≈ 0.02 × 10 −9 -0.1 × 10 −9 m) for prostate-specific membrane antigen (PSMA). [41] We incorporate this Effective drug delivery systems that can systematically and selectively transport payloads to disease cells remain a challenge. Here, a targeting ligandmodified DNA origami nanostructure (DON) as an antibody-drug conjugate (ADC)-like carrier for targeted prostate cancer therapy is reported. Specifically, DON of six helical bundles is modified with a ligand 2-[3-(1,3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA) against prostate-specific membrane antigen (PSMA), to serve as the antibody f...

Unraveling the interaction between doxorubicin and DNA origami nanostructures for customizable chemotherapeutic drug release

“…Its main mechanism of action takes place via type IIA DNA topoisomerase inhibition, but it also affects multiple other cellular processes through DNA intercalation and generation of reactive oxygen species (ROS) (31). The therapeutic potency of various DOX-loaded DNA origami nanostructures (DONs) has been demonstrated using in vitro and in vivo models in a number of reports (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42).…”

Protease-triggered bioresponsive drug delivery for the targeted theranostics of malignancy

“…Considerable achievements have also been made in PSA-mediated drug accumulation and efficacy improvement. Concretely, tumor lesions targeted delivery of PSA-specific motif-conjugated nanocomplexes carrying a variety of therapeutics either alone or in combination, mainly included DOX 181 , 182 , 183 , 184 , 185 , PTX 186 , DTX 187 , SN38 188 , camptothecin 189 , thapsigargin 190 , boron-containing reagents 191 , zinc chelator 192 , antibody-drug conjugates 193 , 194 , kinase inhibitors 195 , siRNA ( Fig. 7 ) 196 , 197 , 198 , 199 , 200 , miRNA 201 , oligonucleotide 202 , therapeutic proteins 203 , and chemotherapy-based combination regimens with molecular targeted therapy 204 , antibiotic therapy 205 , gene therapy 206 , 207 , and anti-inflammatory therapy 208 .…”

Recent Advances for Improving Functionality, Biocompatibility, and Longevity of Implantable Medical Devices and Deliverable Drug Delivery Systems

“…[81] DON are widely explored for DDS purposes, due to their biocompatibility, high solubility, and ability to be designed and tailored according to the need. Also, DON were proved to be uptaken by mammalian cells, [82] and also to be responsive for biostimuli. [81] However, DON have some limitations: the integrity of the nanostructure is hardly maintained under the physiological environment that is rich with enzymes.…”