Light-Triggered, Self-Immolative Nucleic Acid-Drug Nanostructures

Tan, Xuyu; Li, Ben B.; Lu, Xueguang; Jia, Fei; Santori, Clarissa; Menon, Priyanka; Li, Hui; Zhang, Bohan; Zhao, Jean J.; Zhang, Ke

doi:10.1021/jacs.5b00795

Cited by 190 publications

(159 citation statements)

References 39 publications

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“…This stands in contrast to previously observed resistance of DNA-displaying micellar nanoparticles against degradation by certain DNases. 31,32,45 We assume that this lack of specificity toward the substrate duplex–either three-dimensionally arranged on a densely packed micelle corona or free in solution–originates in the relatively small size and very high catalytic activity of RNase A, whose processing rate is diffusion-controlled. 46,47 However, the 2′-fluoro modification of ribose provided a suitable means to render the nanoparticles inert against nucleolytic degradation.…”

Section: ■ Resultsmentioning

confidence: 99%

Self-Transfecting Micellar RNA: Modulating Nanoparticle Cell Interactions via High Density Display of Small Molecule Ligands on Micelle Coronas

Roloff¹,

Nelles²,

Thompson³

et al. 2017

Bioconjugate Chem.

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The intracellular delivery of synthetic nucleic acids represents a major challenge in biotechnology and in biomedicine. Methods to deliver short, double-stranded RNA to living cells are of particular interest because of the potential to engage the RNA interference machinery and to regulate mRNA expression. In this work, we describe novel RNA-polymer amphiphiles that assemble into spherical micellar nanoparticles with diameters of ca. 15–30 nm and efficiently enter live cells without transfection reagents. Each micelle consists of approximately 100 RNA strands forming a densely packed corona around a polymeric core. Importantly, the surface-displayed RNA remains accessible for hybridization with complementary RNA. Chemical modification of the termini of hybridized RNA strands enabled the display of small organic moieties on the outer surface of the micelle corona. We found that some of these modifications can have a tremendous impact on cellular internalization efficiencies. The display of hydrophobic dabcyl or stilbene units dramatically increased cell uptake, whereas hydrophilic neutral hydroxy or anionic phosphate residues were ineffective. Interestingly, neither of these modifications mediated noticeable uptake of free RNA oligonucleotides. We infer that their high density display on micellar nanoparticle surfaces is key for the observed effect; achieved with local effective surface concentrations in the millimolar range. We speculate that weak interactions with cell surface receptors that are amplified by the multivalent presentation of such modifications may be responsible. The installation of small molecule ligands on nanomaterial surfaces via hybridization of chemically modified oligonucleotides offers a simple and straightforward way to modulate cellular uptake of nanoparticles. Biological functionality of micellar RNA was demonstrated through the sequence-specific regulation of mRNA expression in HeLa cells.

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Section: ■ Resultsmentioning

confidence: 99%

Self-Transfecting Micellar RNA: Modulating Nanoparticle Cell Interactions via High Density Display of Small Molecule Ligands on Micelle Coronas

Roloff¹,

Nelles²,

Thompson³

et al. 2017

Bioconjugate Chem.

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“…Another example of how the auxiliary segment can influence assembly is provided by Zhang and co-workers, who developed light-triggered nucleic acid–drug amphiphiles (Figure 17a). 198 With CPT as the primary drug, these DNA drug amphiphiles were seen to form either spherical or cylindrical nanostructures depending on the length of the DNA strand. A short segment (5 base pairs) gave spherical structures, whereas a longer sequence (20 base pairs) led to the formation of rigid rods 53 ± 14 nm in length.…”

Section: Small Molecule Sapdsmentioning

confidence: 99%

Self-assembling prodrugs

et al. 2017

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Covalent modification of therapeutic compounds is a clinically proven strategy to devise prodrugs with enhanced treatment efficacies. This prodrug strategy relies on modified drugs that possess advantageous pharmacokinetic properties and administration routes over their parent drug. Self-assembling prodrugs represent an emerging class of therapeutic agents capable of spontaneously associating into well-defined supramolecular nanostructures in aqueous solutions. The self-assembly of prodrugs expands the functional space of conventional prodrug design, providing a possible pathway to more effective therapies as the assembled nanostructure possesses distinct physicochemical properties that can be tailored to specific administration routes and disease treatment. In this review, we will discuss the various types of self-assembling prodrugs in development, providing an overview of the methods used to control their structure and function and, ultimately, our perspective on their current and future potential.

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“…An intriguing strategy has been developed by Zhang and coworkers, who exploited the properties of spherical nucleic acids (SNAs) [120,121] to create DNA–drug amphiphiles [122]. SNAs, which are normally based on a DNA shell around a solid core such as a gold nanoparticle, have been shown to have exceptional cellular uptake properties [123] and stability towards enzymatic degradation [124].…”

Section: Supramolecular Nanostructures Formed By Amphiphilic Prodrugsmentioning

confidence: 99%

“…Representative TEM images of the spherical nanostructure formed by DNA 5 –CPT in phosphate-buffered saline (PBS) (CB) and the rod-like structure formed by DNA 20 –CPT in PBS with 5 mM MgCl 2 (D). Adapted from from ref [177], copyright 2015 American Chemical Society.…”

Section: Figurementioning

confidence: 99%

Building nanostructures with drugs

2016

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The convergence of nanoscience and drug delivery has prompted the formation of the field of nanomedicine, one that exploits the novel physicochemical and biological properties of nanostructures for improved medical treatments and reduced side effects. Until recently, this nanostructure-mediated strategy considered the drug to be solely a biologically active compound to be delivered, and its potential as a molecular building unit remained largely unexplored. A growing trend within nanomedicine has been the use of drug molecules to build well-defined nanostructures of various sizes and shapes. This strategy allows for the creation of self-delivering supramolecular nanomedicines containing a high and fixed drug content. Through rational design of the number and type of the drug incorporated, the resulting nanostructures can be tailored to assume various morphologies (e.g. nanospheres, rods, nanofibers, or nanotubes) for a particular mode of administration such as systemic, topical, and local delivery. This review covers the recent advances in this rapidly developing field, with the aim of providing an in-depth evaluation of the exciting opportunities that this new field could create to improve the current clinical practice of nanomedicine.

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Light-Triggered, Self-Immolative Nucleic Acid-Drug Nanostructures

Cited by 190 publications

References 39 publications

Self-Transfecting Micellar RNA: Modulating Nanoparticle Cell Interactions via High Density Display of Small Molecule Ligands on Micelle Coronas

Self-Transfecting Micellar RNA: Modulating Nanoparticle Cell Interactions via High Density Display of Small Molecule Ligands on Micelle Coronas

Self-assembling prodrugs

Building nanostructures with drugs

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