Abstract
In this study, we report pH-responsive metal-based biopolymer nanoparticles (NPs) for tumor-specific chemotherapy. Here, aminated hyaluronic acid (aHA) coupled with 2,3-dimethylmaleic anhydride (DMA, as a pH-responsive moiety) (aHA-DMA) was electrostatically complexed with ferrous chloride tetrahydrate (FeCl2/4H2O, as a chelating metal) and doxorubicin (DOX, as an antitumor drug model), producing DOX-loaded Fe-based hyaluronate nanoparticles (DOX@aHA-DMA/Fe NPs). Importantly, the DOX@aHA-DMA/Fe NPs improved tumor cellular uptake due to HA-mediated endocytosis for tumor cells overexpressing CD44 receptors. As a result, the average fluorescent DOX intensity observed in MDA-MB-231 cells (with CD44 receptors) was ~7.9 × 102 (DOX@HA/Fe NPs, without DMA), ~8.1 × 102 (DOX@aHA-DMA0.36/Fe NPs), and ~9.3 × 102 (DOX@aHA-DMA0.60/Fe NPs). Furthermore, the DOX@aHA-DMA/Fe NPs were destabilized due to ionic repulsion between Fe2+ and DMA-detached aHA (i.e., positively charged free aHA) in the acidic environment of tumor cells. This event accelerated the release of DOX from the destabilized NPs. Our results suggest that these NPs can be promising tumor-targeting drug carriers responding to acidic endosomal pH.
Highlights
IntroductionThe biological or physical properties of metal molecules have inspired the development of various bioactive nanoparticles (e.g., bacteria-killing nanoparticles and tumor-targeting nanoparticles) [1,2] and the development of simple biomimetic particles
Hyaluronic acid (HA, Mw = 4.8 kDa), adipic acid dihydrazide (ADH), N,N 0 -dicyclohe xylcarbodiimide (DCC), N-hydroxysuccinimide (NHS), dimethyl sulfoxide (DMSO), triethylamine (TEA), 2,3-dimethylmaleic anhydride (DMA), sodium hydroxide (NaOH), ferrous chloride tetrahydrate (FeCl2 ·4H2 O), doxorubicin hydrochloride (DOX), formaldehyde, and triton X-100 were purchased from Sigma-Aldrich
The zeta potential values of DOX@HA/Fe NPs, DOX@aminated hyaluronic acid (aHA)-DMA0.36 /Fe NPs, and DOX@aHADMA0.60 /Fe NPs at pH 6.8 were shifted to −7.2 mV, −4.3 mV, and −0.5 mV, respectively. These results reveal that the degradation of DMA moieties in DOX@aHA-DMA0.36 /Fe NPs
Summary
The biological or physical properties of metal molecules have inspired the development of various bioactive nanoparticles (e.g., bacteria-killing nanoparticles and tumor-targeting nanoparticles) [1,2] and the development of simple biomimetic particles. Metal-containing biopolymer nanocomposites have been actively designed for engineering multifunctional drug carriers with specific biological functions and tunable hyperstructures [1,2,3]. It is interesting to note that the combination of biopolymers reactive to specific stimuli (light, temperature, pH, etc.) and Fe can contribute to the development of stimuli-responsive drug delivery systems [4,5,6,7,8,9]
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