AIE-based gold nanostar-berberine dimer nanocomposites for PDT and PTT combination therapy toward breast cancer.

We designed and synthesized three new berberine-based compounds, namely, pyridine-2,6-dimethyl-/2,2'-bipyridine-3,3'-dimethyl-tethered berberine dimers BD1 and BD2, and a tetrakis(4-benzyl)ethylene linked berberine tetramer BD4. We identified that the dimer BD2 and tetramer BD4, as well as 1,10-phenanthroline-2,9-dimethyl-linked berberine dimer BD3 previously reported by us, showed remarkable aggregation-induced emission (AIE) properties which endowed them with higher singlet oxygen (1O2) production ability than berberine. Of the four compounds, BD3 exhibits the lowest ΔEST energy with the highest 1O2 generation ability and thus was selected for further construction of AuNSs-BD3@HA (denoted as ABH, AuNSs = gold nanostars; HA = hyaluronic acid). The nanosystem of ABH shows a remarkable therapeutic effect toward breast cancer by combining photodynamic therapy (PDT) from BD3, photothermal therapy (PTT) from AuNSs, and the CD44-targeting capability of HA. The synergistically enhanced PDT and PTT induce superior cancer cell apoptosis/necrosis in vitro and anti-breast cancer activity in vivo. This study provides a new concept for PDT using natural product derivatives and their combination with PTT for efficient treatment of tumors.

Microenvironment-driven sequential ferroptosis, photodynamic therapy, and chemotherapy for targeted breast cancer therapy by a cancer-cell-membrane-coated nanoscale metal-organic framework.

Designing and developing nanomedicine based on the tumor microenvironment (TME) for effective cancer treatment is highly desirable. In this work, polyvinyl pyrrolidone (PVP) dispersed nanoscale metal-organic framework (NMOF) of Fe-TCPP (TCPP = tetrakis (4-carboxyphenyl) porphyrin) loaded with hypoxia-activable prodrug tirapazamine (TPZ) and coated by the cancer cell membrane (CM) is constructed (the formed nanocomposite denoted as PFTT@CM). Due to the functionalization with the homologous cancer cell membrane, PFTT@CM is camouflaged to evade the immune clearance and preferentially accumulates at the tumor site. Once internalized by cancer cells, PFTT@CM is activated by the TME through redox reaction and Fenton reaction between Fe3+ in nano-platform and endogenous glutathione (GSH) and hydrogen peroxide (H2O2) to promote GSH exhausting as well as •OH and O2 production, which triggers ferroptosis and dramatically enhances photodynamic therapy (PDT) efficacy. Subsequently, the PDT process mediated by TCPP and light would consume oxygen and aggravate tumor hypoxia to further activate the prodrug TPZ for cancer chemotherapy. As a consequence, the TME-driven PFTT@CM nano-platform not only demonstrated its TME modulation ability but also showed a sequential synergistic therapy, which eventually inhibited the cancer cell proliferation. This multimodal nano-platform is expected to shed light on the design of TME-activatable reaction to reinforce the synergistic therapeutic outcome and facilitate the development of effective cancer nanomedicine.

Convenient synthesis of zwitterionic calcium(II)-carboxylate metal organic frameworks with efficient activities for the treatment of osteoporosis.

Calcium supplementation is effective in alleviating the process of osteoporosis and the occurrence of osteoporotic fractures for people with long-term calcium deficiency. Herein, five water-stable calcium carboxylate compounds, that is, mononuclear coordination compound [Ca(Cbdcp)(H2O)6]·0.5H2O (1, H3CbdcpBr = N-(4-carboxybenzyl)-(3,5-dicarboxyl)pyridinium bromide), and metal organic frameworks (MOFs) {[Ca3(Dcbdcp)2(H2O)12]·2H2O}n (2, H4DcbdcpBr = N-(3,5-dicarboxybenzyl)-(3,5-dicarboxyl)pyridinium bromide), {[Ca(Cmdcp)(H2O)4]·3H2O}n (3, H3CmdcpBr = N-carboxymethyl-(3,5-dicarboxyl)pyridinium bromide), {[Ca(Cdcbp)]·2H2O}n (4, H3CdcbpBr = 3-carboxyl-(3,5-dicarboxybenzyl)-pyridinium bromide) and {[Ca0.5(Cmcp)]·2H2O}n (5, H2CmcpBr = N-carboxymethyl-(3-carboxyl)pyridinium bromide), were synthesized from the reaction of CaCl2 with five different kinds of zwitterionic carboxylate ligands in the presence of NaOH, respectively. Compounds 1-5 were characterized by Fourier-transform infrared (FTIR) spectroscopy, elemental analyses, single-crystal X-ray crystallography, and inductively coupled plasma mass spectrometry (ICP-MS). Compound 1 features a mononuclear structure and MOF 2 with a one-dimensional (1D) structure while MOFs 3 and 5 with 2D layer structures and MOF 4 showing a 3D structure. Compounds 1-5 exhibited good water stability and possessed considerable biocompatibility with primary mice osteoblasts. The in vitro ability of compounds 1-5 in regulating osteoblastic differentiation was studied via alkaline phosphatase (ALP) staining, alizarin red S (ARS) staining, and quantitative real-time polymerase chain reaction (qPCR). Among these 5 compounds, MOF 4 showed the overall best in vitro osteogenic effects. Then, we administrated MOF 4 intragastrically to bilaterally ovariectomized mice for 8 weeks and found that bone loss caused by ovariectomy (OVX) was significantly alleviated. Besides, MOF 4 administration showed no toxic effects in the main organs of the mice. Altogether, zwitterionic carboxylate ligands-based calcium compounds provide a new strategy for calcium agents development.

Sequential Ag+/biothiol and synchronous Ag+/Hg2+ biosensing with zwitterionic Cu2+-based metal-organic frameworks.

Zwitterionic metal-organic frameworks (MOFs) of {[Cu(Cbdcp)(Dps)(H2O)3]·6H2O}n (MOF 1) and [Cu4(Dcbb)4(Dps)2(H2O)2]n (MOF 2) (H3CbdcpBr = N-(4-carboxybenzyl)-(3,5-dicarboxyl)pyridinium bromide; H2DcbbBr = 1-(3,5-dicarboxybenzyl)-4,4'-bipyridinium bromide; Dps = 4,4'-dipyridyl sulfide) quench the fluorescence of cytosine-rich DNA tagged with 5-carboxytetramethylrhodamine (TAMRA, emission at 582 nm, denoted as C-rich P-DNA-1) and yield the corresponding P-DNA-1@MOF hybrids. Exposure of these hybrids to Ag+ results in the release of the P-DNA-1 strands from the MOF surfaces as double-stranded, hairpin-like C-AgI-C (ds-DNA-1@Ag+) with the restoration of TAMRA fluorescence. The ds-DNA-1@Ag+ formed on the surface of 1 can subsequently sense biothiols cysteine (Cys), glutathione (GSH), and homocysteine (Hcy) due to the stronger affinity of mercapto groups for Ag+ that serves to unfold the ds-DNA-1@Ag+ duplex, reforming P-DNA-1, which is re-adsorbed by MOF 1 accompanied by quenching of TAMRA emission. Meanwhile, MOF 2 is also capable of co-loading a thymine-rich probe DNA tagged with 5-carboxyfluorescein (FAM, emission at 518 nm, denoted as T-rich P-DNA-2) to achieve synchronous sensing of Ag+ and Hg2+, resulting from the simultaneous yet specific ds-DNA-1@Ag+ and T-HgII-T duplex (ds-DNA-2@Hg2+) formation, as well as the distinctive emission wavelengths of TAMRA and FAM. Detection limits are as low as 5.3 nM (Ag+), 14.2 nM (Cys), 13.5 nM (GSH), and 9.1 nM (Hcy) for MOF 1, and 7.5 nM (Ag+) and 2.6 nM (Hg2+) for MOF 2, respectively. The sequential sensing of Ag+ and biothiols by MOF 1, and the synchronous sensing of Ag+ and Hg2+ by MOF 2 are rapid and specific, even in the presence of other mono- and divalent metal cations or other biothiols at much higher concentrations. Molecular simulation studies provide insights regarding the molecular interactions that underpin these sensing processes.

Experimental and theoretical validations of a one-pot sequential sensing of Hg2+ and biothiols by a 3D Cu-based zwitterionic metal-organic framework.

A zwitterionic three-dimensional (3D) metal-organic framework (MOF) of {[Cu(Cdcbp)(bipy)]·4H2O}n (1) has been synthesized and characterized (H3CdcbpBr = 3-carboxyl-(3,5-dicarboxybenzyl)-pyridinium bromide; bipy = 4,4'-bipyridine). MOF 1 exhibits a variety of structural traits, such as ligand conjugated, positively charged pyridinium center, and Cu(II) cations that collectively enable its efficient hybridization with the flexible, negatively charged, single-stranded, and thymine-rich (T-rich) DNA. The T-rich DNA is labeled with carboxyfluorescein (FAM) fluorescent probe (characterized as P-DNA), but the resultant MOF 1 - P-DNA hybrid (characterized as P-DNA@1) is non-emissive (off-state) because of the fluorescent quenching by MOF 1. The P-DNA@1 hybrid functions as an effective and selective sensor for Hg2+ due to the formation of rigid hairpin-like T-Hg2+-T double-stranded DNA (ds-DNA@Hg2+) which is subsequently ejected by MOF 1, triggering a recovery of the P-DNA fluorescence (on-state). Subsequent addition of biothiols further sequestrates Hg2+ from the ds-DNA@Hg2+ duplex driven by the stronger Hg-S coordination, thus release the P-DNA and, in turn, resorbed by MOF 1 to regain the initial hybrid (off-state). P-DNA@1 hybrid thus detects Hg2+ and biothiols sequentially via a fluorescence "off-on-off" mechanism. The limits of detection (LOD) for Hg2+, biothiols, including cysteine (Cys), glutathione (GSH) and homocysteine (Hcy) are 3.0, 14.2, 15.1 and 8.0 nM, respectively, with the detection time of 60 min for Hg2+, and instantaneous detection for all the three biothiols. The detection mechanism is further confirmed by circular dichroism (CD), fluorescence anisotropy (FA), binding constant and molecular simulation. This sequential detection of Hg2+ and biothiols counter-proofs the presence of each other and may shed light to the occurrence of related diseases, such as neurodegenerative disorders of Parkinson's disease (PD), and Alzheimer's disease (AD).

Rapid sequential detection of Hg2+ and biothiols by a probe DNA-MOF hybrid sensory system.

A one-dimensional (1D) metal-organic framework (MOF) of [Cu(Cdcbp)(H2O)2·2H2O]n (1, H3CdcbpBr = 3-carboxyl-(3,5-dicarboxybenzyl)-pyridinium bromide) has been synthesized and characterized. MOF 1 features a cationic Cu2+ center, conjugated tricarboxylate ligand bearing positively charged pyridinium and uncoordinated carboxylate groups within its skeleton. These features enable MOF 1 to tightly adsorb thymine rich (T-rich) single-stranded DNA (ss-DNA) probe labeled with carboxyfluorescein (FAM) (denote as P-DNA) through π-stacking, electrostatic interactions and/or hydrogen bonding to give a hybrid complex (denote as P-DNA@1), and quenches its fluorescence via a photo-induced electron transfer (PET) process. The formed P-DNA@1 hybrid can thus function as a sensing platform for the detection of Hg2+, driven by the formation of hairpin-like double-stranded DNA (ds-DNA@Hg2+) with a T-Hg-T coordination motif, and subsequently dissociated into the solution due to its more rigid nature than ss-DNA, leading to the recovery of FAM fluorescence. In the presence of biothiols, including cysteine (Cys), homocysteine (Hcy) and glutathione (GSH), the strong coordination interaction between Hg2+ and the mercapto function serves to sequestrate the Hg2+ from the ds-DNA@Hg2+ duplex. The released ss-DNA, in turn, are re-adsorbed by MOF 1, leading to the formation of the initial P-DNA@1 state with fluorescence quenching. As such, P-DNA@1 detects Hg2+ and biothiols Cys/Hcy/GSH in sequence with detection limits of (2.3 ±â€¯0.8) nM and (29.6 ±â€¯0.1) nM/(19.8 ±â€¯0.5) nM/(10.2 ±â€¯0.1) nM. The sensing process is efficient and selective with instantaneous response time. The detection mechanism was further validated by circular dichroism (CD), and simulation studies using Molecular Operating Environment (MOE) package.

Phenanthroline-linked berberine dimer and fluorophore-tagged DNA conjugate for the selective detection of microRNA-185: Experimental and molecular docking studies.

A phenanthroline (phen) tethered berberine dimer 1 is synthesized and further conjugated with carboxyfluorescein (FAM)-labeled single-stranded probe DNA (P-DNA) to give P-DNA@1. The mutual interaction of these two components triggers the fluorescence quenching of FAM, and the non-emissive P-DNA@1, in turn, functions as a sensor to detect cancer-associated microRNA-185 (miRNA-185), characterized by the FAM fluorescence recovery. The results show that P-DNA@1 is capable of detecting miRNA-185 in 2 min with the detection limit of 0.2 nM. The detection mechanism was supported by fluorescence anisotropy, binding constant and molecular docking study. Competing experiments further indicate that P-DNA@1 exhibits a high selectivity for miRNA-185 thus has a good potential in the diagnosis of related cancer at the early stage.

Experimental and computational investigation of a DNA-shielded 3D metal-organic framework for the prompt dual sensing of Ag+ and S2.

We herein report an efficient Ag+ and S2- dual sensing scenario by a three-dimensional (3D) Cu-based metal-organic framework [Cu(Cdcbp)(bpea)] n (MOF 1, H3CdcbpBr = 3-carboxyl-(3,5-dicarboxybenzyl)-pyridinium bromide, bpea = 1,2-di(4-pyridinyl)ethane) shielded with a 5-carboxytetramethylrhodamine (TAMRA)-labeled C-rich single-stranded DNA (ss-probe DNA, P-DNA) as a fluorescent probe. The formed MOF-DNA probe, denoted as P-DNA@1, is able to sequentially detect Ag+ and S2- in one pot, with detection limits of 3.8 nM (for Ag+) and 5.5 nM (for S2-), which are much more lower than the allowable Ag+ (0.5 µM) and S2- (0.6 µM) concentration in drinking water as regulated by World Health Organization (WHO). The detection method has been successfully applied to sense Ag+ and S2- in domestic, lake, and mineral water with satisfactory recoveries ranging from 98.2 to 107.3%. The detection mechanism was further confirmed by molecular simulation studies.