Efficient, pH‐Triggered Drug Delivery Using a pH‐Responsive DNA‐Conjugated Gold Nanoparticle

Abstract

Over the past two decades, DNA has been demonstrated as a powerful, versatile building material in the construction of a wide range of functional nanostructures, nanodevices, molecular nanomachines, and nanowalkers, [1][2][3] which have broad potential applications in computing, nanoelectronic devices, biosensing, and intelligent drug delivery. [1][2][3][4] In particular, multiple DNA conjugated gold nanoparticles (DNA-GNPs) have recently emerged as an important class of nanomaterials for biodiagnosis and nanomedicine, due to a number of very attractive properties, including sharp melting transitions on binding to complementary DNA, enhanced target binding affi nity, high stability in high salt buffer, low/non-toxicity, resisting nuclease degradation, and effi cient uptake by some 50 different cell lines. [ 5 ] Polyvalent DNA-GNP conjugates have been used sucessfully in gene regulation, [ 6 ] and delivery of small molecule drugs [ 7 , 8 ] at the cellular level. To date, most DNA-GNP systems reported have simply used DNA as drug carrier, where the drug release was achieved by drug-DNA passive dissociation, [ 7 , 8 ] lacking stimuli responsive release which is important for effi cient drug delivery. Moreover, most GNP-DNA systems exibited limited stability in biological fl uids, showing a significant increase of carrier size in cell culture media (due to the non-specifi c adsorption of serum proteins), and could aggregate on cellular surfaces, which can limit their potential for in vivo applications. [5][6][7][8] On the other hand, pH is well-known to play a key role in many biological functions. Unlike healthy tissues which usually have a normal physiological pH of ∼ 7.4, disease regions such as tumors and intracellular endosomal/lysosomal compartments often exhibit abnormally high local acidities. [ 9 ] Therefore pH can be exploited as a useful strategy for cancer targeting. A proton-fuelled DNA nanomachine (PF-DNA) made of a single-stranded (ss) DNA of four stretches of cytosine ( C )-rich sequences ( i -motif domain), [ 10 ] fi rst proposed by Liu et al. [ 11 ] appears well-suited for cancer targeting. It can produce rapid, highly reversible conformational switches between a four-stranded i -motif structure at weakly acidic pH ( < 6.0) and random coil at higher pH ( > 6.4). [ 11 ] Previously, we and others have harnessed this pH-dependent conformational changes and successfully constructed several pH-responsive DNA nanostructures and nanodevices. [ 12 ] Herein, we report that this PF-DNA can be employed for effective delivery and pH-triggered release of doxorubicin (DOX), a model anticancer drug widely used in clinical treatment of various cancers, leukemia and Hodgkin's lymphoma, and also in drug delivery research (see Supporting Information (SI), Figure S1 for the number of drug delivery papers using DOX). Besides, being a DNA intercalator, DOX can be conveniently loaded to the PF-DNA system by simple mixing, avoiding the use of chemical conjugation or encapsulation steps which may affect its bioavailabilit...

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