Abstract
i-motif is cytosine (C)-rich oligonucleotide (ODN) which shows pH-responsive structure change in acidic condition. Therefore, it has been utilized for the trigger of intercalated drug release, responding to environmental pH change. In this study, 2.76 molecules of i-motif binding ODNs (IBOs) were conjugated to each hyaluronic acid (HA) via amide bond linkages. Synthesis of HA-IBO conjugate (HB) was confirmed by FT-IR and agarose gel electrophoresis with Stains-All staining. After hybridization of HB with i-motif ODN (IMO), it was confirmed that doxorubicin (DOX) could be loaded in HB-IMO hybrid structure (HBIM) with 65.6% of drug loading efficiency (DLE) and 25.0% of drug loading content (DLC). At pH 5.5, prompt and significant DOX release from HBIM was observed due to the disruption of HBIM hybrid structure via i-motif formation of IMO, contrary to pH 7.4 condition. Then, HBIM was complexed with low molecular weight polyethylenimine (PEI1.8k), forming positively charged nanostructures (Z-average size: 126.0 ± 0.4 nm, zeta-potential: 16.1 ± 0.3 mV). DOX-loaded HBIM/PEI complexes displayed higher anticancer efficacy than free DOX in A549 cells, showing the potential for pH-responsive anticancer drug delivery systems.
Highlights
It was reported that specific cytosine (C)-rich oligonucleotide (ODN) can form non-canonical structures called i-motif, which are tetramer structures of cytosine-rich sequences constructed by parallel-stranded duplex of C·CH+ pairing in low pH conditions [1,2]
Prior to conjugation of ODNs to hyaluronic acid (HA), hybridization and denaturation behavior of i-motif ODN (IMO) and i-motif binding ODNs (IBOs) were investigated by ethidium bromide (EtBr) binding assay
Hybridization and denaturation of IMO and IBO were further examined by measuring EtBr fluorescence change (Figure 1B)
Summary
It was reported that specific cytosine (C)-rich oligonucleotide (ODN) can form non-canonical structures called i-motif, which are tetramer structures of cytosine-rich sequences constructed by parallel-stranded duplex of C·CH+ (protonated C) pairing in low pH conditions [1,2]. Intercalated DOX can be released from IMO-IBO hybrid structure in acidic conditions by disruption of the hybrid structure via i-motif formation of IMO [5]. I-motif formation caused AuNP to release DOX by disintegrating the intercalation and to aggregate itself, improving PTT efficiency [8]. In another case, i-motif was grafted on exosome using biotin-streptavidin interaction to deliver DOX by intercalation in their double-stranded structure. DOX release from exosome was triggered by the formation of i-motif, disintegrating double-stranded DNA structure [9]. Hybridization of HB and IMO (HBIM formation), DOX loading and pH-responsive release of HBIM structure were examined. Anticancer activity of DOX-loaded HBIM/PEI was investigated
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