Nanogels exhibit potential application values in drug delivery systems because of their tunable properties and biocompatibility. In this study, multifunctional hyaluronic-based nanogels (HNPs), all-trans retinoid acid (ATRA)/aggregation-induced emission luminogen (AIEgen) fluorophores (TPENH 2)-grafted hyaluronic acid (HA) with disulfide bonds as linkers of (HA-ss-ATRA/TPENH 2), were successfully developed for doxorubicin hydrochloride (DOX) delivery. Besides, the controls of HA-ATRA/TPENH 2 were also developed for comparison. The HNPs with nanoscale particle sizes possessed an excellent DOX-loading capacity. As expected, the DOX-loaded HNPs exhibited the higher stability in a normal physiological environment (10 mM GSH), but rapidly disintegrated in the cancer microenvironment (20 mM GSH) according to an in vitro drug release study. The intracellular observation of HNPs by the fluorescence microscopy indicated that the self-fluorescent DOX-loaded HNPs with unique AIEgen characteristic transported DOX into the cancer cells and visibly accumulated within the cytoplasm. Importantly, the accumulation of DOX-loaded HNPs was largely increased due to the targeted reorganization of CD44 or LYCE-1 receptors by HA moieties on the surface of HNPs. Based on in vitro cytotoxicity analyses, the DOX-loaded HNPs displayed dramatically enhanced virulence to cancer cells compared to the controls and free DOX. This is the first study to achieve combined functionalities of targeted delivery, controllable release and real-time intracellular imaging on HA-base nanogels with enhanced antitumor efficiency. Therefore, the multifunctional HA-ss-ATRA/TPENH 2 HNPs have good potential to develop a novel drug delivery platform for the targeted delivery and controlled release of DOX to achieve enhanced antitumor efficiency as well as real-time intracellular imaging.
The function of retinoic acid-inducible gene-I (RIG-I) in viral replication is well documented, but its function in carcinogenesis and malignancies as well as relationship with microRNAs (miRNAs) remain poorly understood. miR-34a is an antioncogene in multiple tumors. In our study, RIG-I and miR-34a suppressed cell growth, proliferation, migration, and invasion in cervical cancer cells in vitro. miR-34a was validated as a new regulator of RIG-I by binding to its 3' untranslated region and upregulating its expression level. Furthermore, we revealed that RIG-I and miR-34a enhanced apoptosis, delayed the G1/S/G2 transition of the cell cycle, and inhibited the epithelial-mesenchymal transition process to modulate malignancies in cervical cancer cells. Phenotypic rescue experiments indicated that RIG-I mediates the effects of miR-34a in HeLa and C33A cells. These findings provide new insights into the mechanisms that underlie carcinogenesis and may provide new biomarkers for the diagnosis and therapy of cervical cancer.
The therapeutic effect of oxygen-concentration-dependent photodynamic therapy (PDT) can be diminished in the hypoxic environment of solid tumours, the effective solution to this problem is utilising hypoxic-activated bioreduction therapy (BRT). In this research, a biocompatible HA-C60/TPENH 2 nanogel which can specifically bind to CD44 receptor was developed for highly efficient PDT-BRT synergistic therapy. The nanogel was degradable in acidic microenvironments of tumours and facilitated the release of biological reduction prodrug tirapazamine (TPZ). Importantly, HA-C60/TPENH 2 nanogel produced reactive oxygen species and consumed oxygen content in the cell to activate TPZ, leading to higher cytotoxicity than the free TPZ did. The intracellular observation of nanogel indicated that the HA-C60/TPENH 2 nanogel was self-fluorescence for cell imaging. This study applied PDT-BRT to design smart HA-based nanogel with targeted delivery, pH response, and AIEgen feature for efficient cancer therapy.
Facile microwave synthesis, structural diversity and herbicidal activity of six novel alkaline-earth metal complexes (AECs) based on skeletal isomerization chlorophenoxyacetic acids.
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