Co-delivery of doxorubicin and shRNA of Beclin1 by folate receptor targeted pullulan-based multifunctional nanomicelles for combinational cancer therapy

Doxorubicin (DOX) is a widely-used effective antitumor agent. However, its clinical application is limited due to its side effects including anti-apoptotic defense of cancer cells caused by DOX-induced autophagy and deleterious effects in normal tissues. Therefore, in this study, a new folate (FA)-decorated amphiphilic bifunctional pullulan-based copolymer (named as FPDP) was developed as an efficient nano-carrier for the co-delivery of DOX and short hairpin RNA of Beclin1, a pivotal autophage-related gene, to enhance the anticancer effect of DOX by the blockade of the Beclin1 protein mediated autophagy process. In FPDP molecules, pullulan was modified with lipophilic desoxycholic acid for the formation of micelles, the introduced low molecular weight (1 kDa) branched polyethylenimine (PEI) was for shBeclin1 delivery, and folate (FA) was employed as the tumor-targeting group. FPDP micelles demonstrated an average diameter of 161.9 nm, good biocompatibility, applicable storage stability, excellent loading capacities for both DOX and shBeclin1 and a sustained drug release profile. In vitro cell culture experiments demonstrated that the uptake amount of FPDP/DOX micelles in folate receptor positive (FR⁺) HeLa cells was more than that in folate receptor negative (FR⁻) HepG2 cells, leading to significantly higher cytotoxicity against FR⁺ HeLa cells. The simultaneous co-delivery of shBeclin1 and DOX to HeLa cells with FPDP micelles led to efficient reduction in the expression level of Beclin1 as well as synergistic cell apoptotic induction. Furthermore, in vivo studies revealed superior antitumor efficacy of tumor-targeted FPDP/DOX/shBeclin1 in comparison with non-FR-targeted PDP micelles and free DOX. These results highlighted that co-delivery of DOX and shRNA of Beclin1 with FPDP micelles has the potential to overcome the limitations of DOX in clinical cancer therapy.

New folate receptor targeted nano-micelles enhanced the anticancer effect of doxorubicin by shBeclin1 with the blockade of the autophagy process.     

A novel biocompatible zwitterionic polyurethane with AIE effect for cell imaging in living cells

In this work, a novel and stable zwitterionic polymer (TPE-CB PUs) was prepared to realize a cellular imaging system. TPE was conjugated into the backbone of zwitterionic polyurethane, which could be well dispersed in aqueous solution and emitted strong blue fluorescence because the TPE segment was aggregated in the core of TPE-CB PUs micelles. More importantly, the TPE-CB PUs micelles showed significant stability in a large pH window and with different storage times. In addition, the micelles exhibited low cytotoxicity in HeLa cells and mainly distributed in the cytoplasm after being incubated with cells. The outstanding properties of TPE-CB PUs combining the merits of AIE and a zwitterionic segment highlight its potential for use as a cell imaging material with remarkable capability.

In this work, a novel and stable zwitterionic polymer (TPE-CB PUs) was prepared to realize a cellular imaging system.     

Dual-response CuS@MnO2 nanoparticles with activatable CT/MR-enhanced in vivo imaging guided photothermal therapy

Although photothermal therapy (PTT) has been extensively applied in the treatment of cancer using various types of nanomaterials, low penetration of excitation light, low nanoparticle concentration enrichment and abominable nanoparticle permeation still remain huge obstacles in cancer therapy. Herein, we synthesized stable cupric sulfide nanoparticles (CuS NPs) with small size, which after functionalization with a MnO₂ coating, were employed for diagnosing and treating tumors. After reacting with an RGD peptide, the nanoparticles were able to target and focus on tumor sites. Once the nanoparticles were enriched in tumors by RGD targeting, the MnO₂ coating decomposed to Mn²⁺ ions in the tumor microenvironment. Meanwhile, the decomposition of MnO₂ allowed the dispersion of aggregated CuS NPs to enter deep tumors, and a 1064 nm laser with powerful penetration was utilized to activate CuS NPs in deep tumors for PTT. More importantly, the generated Mn²⁺ ions were used for stimuli-enhanced T₁-weighted magnetic resonance imaging (T₁-MRI) and agminated CuS NPs in tumors were accepted for computed tomography (CT) imaging. It was found that these nanocomposites can accurately indicate tumor sites after being intravenously injected, and in vitro and in vivo experiments illustrated the tremendous potential of these nanoplatforms for use in imaging-guided PTT against HepG2 tumors.

A stable multifunctional nanoplatform with superior biocompatibility and excellent targeting function was synthesized for MR/CT image guided PTT treatment, for potential application in clinical cancer treatment.     

Synthesis and photophysical properties of benzoxazolyl-imidazole and benzothiazolyl-imidazole conjugates

Materials that have higher fluorescence emission in the solid state than molecules in solution have recently been paid more attention by the scientific community due to their potential applications in various fields. In this work, we newly synthesized benzoxazolyl-imidazole and benzothiazolyl-imidazole conjugates, which show aggregation-induced emission (AIE) features in their solid and aggregate states. It was found that oxygen and sulfur substitutions can dramatically influence the molecular structures and polarities of the dyes, leading to different degrees of the AIE phenomenon. The benzothiazolyl-imidazole molecule has lower polarity compared to that of benzoxazolyl-imidazole; therefore, the dye bearing a benzothiazolyl group shows higher emission intensity and dual emission in aqueous solution. Theoretical calculation results suggest that the benzothiazolyl-imidazole molecules might have electrostatic interactions between sulfur and nitrogen atoms, explaining the experimental observations of lower critical aggregation concentration and photophysical properties both in solution and in the solid state. The theoretical calculations agree with the experimental data, thus demonstrating a potent strategy to gain a deep understanding of the structure–property relationships to design solid-state fluorescent materials.

The effect of heteroatoms on the structural and photophysical properties of donor-π-acceptor molecules, comprising imidazole and benzoxazolyl as well as imidazole and benzothiazolyl units, was investigated.     

Assessment of in vitro cytotoxicity of imidazole ionic liquids and inclusion in targeted drug carriers containing violacein

Violacein (Viol) is a pigment produced by several Gram-negative bacteria with many bioactivities, such as anticancer, virucide, and antiparasitic. However, violacein is insoluble under physiological conditions preventing its potential therapeutic uses. Surface-active ionic liquids (SAILs) based on the cation 1-alkylimidazolium ([C_nHim]) with n = 10 to 16 alkyl carbon side chain lengths and acetate, bromide, methanesulfonate (S) or trifluoroacetate (F) as counterions were synthesized and screened to dissolve Viol in micellar aqueous media and for toxicological studies on the human lung carcinoma A549 cell line. Screening allowed the selection of 1.5 × 10⁻³% (w/v) [C₁₆Him]-S because it combines low cytotoxicity with 71.5% cell viability and good interaction with 95.2% of the violacein kept in micellar solution for at least 48 h. [Viol-([C₁₆Him]-S)] complex was used to develop an efficient hybrid solid lipid nanoparticle (SLN) carrier based on myristyl myristate and poloxamer 188 and tailored with folate to target cancer cells. Cellular SLN uptake was evaluated with fluorescent DiOC₁₈ on A549, HCT-116, and HeLa cell lines expressing or not the folate receptor. The results showed fivefold incorporation of Viol nanoparticles in HCT-116 and HeLa cell cultures, displaying a high level of folate receptor. Biophysical characterization of the hybrid solid lipid carrier containing Viol was performed by dynamic light scattering, Fourier transform infrared, X-ray diffraction and X-ray photoelectron spectroscopies, and by transmission electron and cryo-transmission microscopies.

Violacein (Viol) is a pigment produced by several Gram-negative bacteria with many bioactivities, such as anticancer, virucide, and antiparasitic.     

Unveiling the effect of 11-MUA coating on biocompatibility and catalytic activity of a gold-core cerium oxide-shell-based nanozyme

The biocompatibility and catalytic activity of nanomaterials exhibiting biological enzyme-like functions (nanozymes) are controlled by shape, size, composition, and surface capping molecules. Although synthesis of multifunctional nanozymes for multiple applications has shown tremendous attraction among researchers worldwide, often their biocompatibility is compromised. In this work, we report the replacement of CTAB by 11-MUA from the surface of a Au-core CeO₂-shell NP-based nanozyme studied for exhibiting multiple enzyme-like activities such as peroxidase, catalase, and superoxide dismutase. We compared the biocompatibility and enzyme-like activities of CTAB coated Au-core CeO₂-shell NPs (CSNPs) before and after 11-MUA coating. The catalytic reaction mechanism of peroxidase-like activity of CTAB coated CSNPs was found to be the “Random Bi–Bi”, which also remained unaltered after removal of surface CTAB with 11-MUA. The other kinetic parameters, K_m and V_max values, of 11-MUA coated CSNPs were found to be comparable to the CTAB coated NPs.

Replacement of CTAB and CeO₂ nanoparticle layer by 11-MUA from the surface of Au core-CeO₂ shell nanoparticle.     

In vivo study of a novel,safe, rapid,and targeted red carbon dot probe for recognition of tumors with high expression of folate enzyme

Carbon dots (CDS) have been proved to be a type of ideal biological imaging probe. They have the advantages of spontaneous fluorescence, anti-photobleaching, good biocompatibility and easy surface decoration, and are receiving special attention from researchers. The early imaging diagnosis of tumors has always been a practical means of clinical diagnosis. Finding an efficient and low-toxicity tumor probe is the continuous goal of tumor clinical diagnosis and treatment. Therefore, this article uses the modifiable properties of the surface structure of carbon dots, and at the same time, uses the characteristics of tumors with high expression of folate receptors (FR) that can specifically take up folic acid (FA) to construct folic acid carbon dot conjugates (FA–CDs) to achieve targeted tumor uptake. Firstly, CCK8 toxicity tests proved that FA–DCCDs had good biocompatibility and were almost non-toxic. Further, confocal cell imaging experiments, microplate quantitative experiments and flow cytometry experiments proved that FA–CDs were selective and more easily absorbed by tumor cells with high expression of folate receptors, and bare carbon dots could be absorbed into cells without selectivity. Through in vivo experiments, the law of injection of bare CDs into the body was explored, which proved that they had no obvious accumulation and had high distribution in the liver and kidneys. FA–CDs was applied to the targeted imaging of a mouse tumor model in vivo for the first time, which proved again that the carbon point coupled with folic acid had selectivity for tumor cells with high expression of FR receptors, which provided a basis for tumor drug research and early clinical diagnosis of tumors.

Carbon dots (CDS) have been proved to be a type of ideal biological imaging probe.     

Bamboo leaf-based carbon dots for efficient tumor imaging and therapy

In this study, carbon dots synthesized from bamboo leaf cellulose were used simultaneously as a staining agent and for doxorubicin delivery to target cancer cells. Owing to their nontoxic properties, the production of carbon dots from bamboo leaves is a green approach involving optimized application of bamboo tree waste. For multifunctional applications, the carbon dots were modified with 4-carboxybenzylboronic acid and doxorubicin to improve target specificity and drug delivery to HeLa tumor cells. The resulting modified carbon dots were characterized using different analytical techniques, which showed that they were biocompatible, nontoxic, and highly stable over a wide range of pH values and at high ionic strengths. Furthermore, in vitro confocal microscopy studies demonstrated their blue fluorescence and cellular pathway for entering HeLa cells via folate receptor-mediated endocytosis. Cell viability data and flow cytometry results also confirmed the selective uptake of the carbon dots by HeLa cells, which significantly enhanced cell cytotoxicity.

In this study, carbon dots synthesized from bamboo leaf cellulose were used simultaneously as a staining agent and for doxorubicin delivery to target cancer cells.     

An Au@Ag nanocube based plasmonic nano-sensor for rapid detection of sulfide ions with high sensitivity

Based on the localized surface plasmon resonance (LSPR) technology, a novel plasmonic nanosensor with high sensitivity and high selectivity was prepared for the detection of trace sulfide ions on an individual Au@Ag nanoparticle. Furthermore, it could be used to monitor the sulfurization on an individual Au@Ag nanoparticle surface observed under dark-field microscopy (DFM).

Based on the localized surface plasmon resonance (LSPR) technology, a novel plasmonic nanosensor with high sensitivity and high selectivity was prepared for the detection of trace sulfide ions on an individual Au@Ag nanoparticle.     

pH-responsive curcumin-based nanoscale ZIF-8 combining chemophotodynamic therapy for excellent antibacterial activity

Antimicrobial photodynamic therapy (aPDT) is a highly attractive therapy due to its advantages of being a non-antibiotic procedure for reducing drug-resistant microbes. Curcumin (CCM) has been considered as a natural photosensitizer for PDT with prominent antibacterial, antifungal, and anti-proliferative activity. However, its excellent biological and pharmacological activities are limited because of its low solubility, rapid metabolization and instability. Herein, we reported a promising agent based on CCM-incorporated into zeolitic imidazolate framework-8 (ZIF@CCM). The as-prepared nanoparticle exhibited high drug loading capability (11.57%) and drug loading encapsulation (82.76%). Additionally, ZIF@CCM displayed a pH-responsive drug release behavior and chemophotodynamic therapy for excellent antibacterial activity. The underlying mechanism elucidated that Zn²⁺ released from ZIF-8 increased the permeability of the bacterial cell membrane with leakages of K⁺. The overproduction of extracellular ROS further resulted in the disrupted bacterial cell membrane and distorted bacterial morphology. Thus, ZIF@CCM-mediated photodynamic activation might be a promising treatment strategy for microbial inactivation.

Schematic illustration of the preparation of ZIF@CCM and its application for photodynamic antibacterial response.     

Tuning the fluorescence based on the combination of TICT and AIE emission of a tetraphenylethylene with D–π–A structure

A simple D–π–A structured tetraphenylethylene with two electron-rich methyloxy groups and two electron withdrawing cyano groups, which features both twisted intramolecular charge-transfer (TICT) and aggregation-induced emission (AIE) properties, namely TPEOMeCN has been prepared. The emission of TPEOMeCN examined in various solvents is dependent on the polarities of solvents, which indicates the TICT character. The emission intensity of the compound also enhances with the increasing water fraction in H₂O–DMSO mixtures, demonstrating the typical AIE property. Excitingly, the TICT and AIE emission could be observed separately or simultaneously by adjusting the water fraction or viscosity of the solvent. Encouragingly, the combined emission of the TPEOMeCN derived from this single molecule could be readily tuned via regulating the viscosity of the system, resulting in a broad emission peak which covers the visible spectrum (400–700 nm). This work provides a general strategy for designing molecules combining TICT emission and AIE for application as full-color emitters.

The combination of the TICT and AIE properties in a tetraphenylethylene based molecule with D–π–A structure is observed by simply adjusting the viscosity of the solvent.     

Aggregation-induced emission compounds based on 9,10-diheteroarylanthracene and their applications in cell imaging

Four centrosymmetric 9,10-diheteroarylanthracene (DHA) derivatives, including 9,10-dithienylanthracene (DTA), 9,10-difurylanthracene (DFA), 9,10-di-(N-t-butyloxycarboryl-2-pyrryl)anthracene (DBPA), and 9,10-dipyrrylanthracene (DPA) have been synthesized and characterized. All of these DHA derivatives displayed distinct aggregation-induced emission (AIE) behaviors except for DBPA, which showed typical aggregation-caused quenching (ACQ) properties. Their crystal structures exhibited nonplanar conformations on account of the intramolecular torsional effects and intramolecular interactions in rigid molecules. The investigation of the effects of the anthracene core and the side heterocyclic units on the AIE properties demonstrated that the heterocycle moiety is the key factor for the AIE features. These DHA AIEgens exhibited excellent bioimaging performance under physiological conditions.

Four centrosymmetric 9,10-diheteroarylanthracene (DHA) derivatives, including 9,10-dithienylanthracene (DTA), 9,10-difurylanthracene (DFA), 9,10-di-(N-t-butyloxycarboryl-2-pyrryl)anthracene (DBPA), and 9,10-dipyrrylanthracene (DPA) have been synthesized and characterized.     

Application of nanosonosensitizer materials in cancer sono-dynamic therapy

Sonodynamic therapy (SDT) is a novel non-invasive treatment for cancer combining low-intensity ultrasound and sonosensitizers. SDT activates sonosensitizers through ultrasound, releasing energy and generating reactive oxygen species to kill tumor cells. Compared with traditional photodynamic therapy (PDT), SDT is a promising anti-cancer therapy with the advantages of better targeting, deeper tissue penetration, and higher focusing ability. With the development and broad application of nanomaterials, novel sonosensitizers with tumor-targeting specificity can deliver to deep tumors and enhance the tumor microenvironment. In this review, we first review the mechanisms of sonodynamic therapy. In addition, we also focus on the current types of sonosensitizers and the latest design strategies of nanomaterials in sonosensitizers. Finally, we summarize the combined strategy of sonodynamic therapy.

Sonodynamic therapy (SDT) is a novel non-invasive treatment for cancer combining low-intensity ultrasound and sonosensitizers.     

Methyl-restricted rotor rotation on the stator produces high-efficiency fluorescence emission: a new strategy to achieve aggregation-induced emission

At present, we have realized that the aggregation-induced emission (AIE) achieves the purpose of fluorescence enhancement by restricting rotations to reduce intermolecular or intramolecular energy loss. Based on this idea, we synthesized a novel fluorene-based fluorescent compound with a restricted rotor rotation on the stator through the Suzuki coupling reaction. The luminescence effect was evaluated by comparing its fluorescence intensity with that of the control compound. Finally, theoretical calculations showed that the presence of methyl groups hindered the thermal rotation of the fluorenyl groups. Thus, the results indicated that the fluorescence of this compound was better than that of the control compound. A new synthetic pathway for high-efficiency AIE-based fluorescent luminogens has been developed.

At present, we have realized that the aggregation-induced emission (AIE) achieves the purpose of fluorescence enhancement by restricting rotations to reduce intermolecular or intramolecular energy loss.     

Aggregation-induced emission spectra of triphenylamine salicylaldehyde derivatives via excited-state intramolecular proton transfer revealed by molecular spectral and dynamics simulations

Aggregation-induced emission (AIE) spectra accompanied by excited state intramolecular proton transfer (ESIPT) for two triphenylamine salicylaldehyde derivatives (namely, TS and TS-OMe) are investigated by performing molecular spectral and dynamics simulations associated with the hybrid quantum mechanics/molecular mechanics (QM/MM) at the quantum level of the time-dependent density functional theory. The simulated emission spectral peaks and Stokes'' shifts are in good agreement with the experimental results for both TS and TS-OMe. Furthermore, the AIE spectral mechanisms are well explained to be associated with the ESIPT processes for both TS and TS-OMe monomers in the aggregated crystal state, while the AIE spectra mechanism for the TS-OMe (TS) dimer is accompanied by intermolecular charge-transfer excitation process. Besides, the TS dimers also contributed to the AIE mechanisms in the crystal with the intermolecular charge-transfer from one monomer to another. In addition, the TS dimers are contributed to the AIE mechanisms in the crystal with the intermolecular charge-transfer from one monomer to another. On the other hand, simulated emission spectra for both the TS and TS-OMe monomers in acetonitrile solution are involved in mixed emission with and without the ESIPT process, as interpreted by nonadiabatic molecular dynamics simulation. It is also briefly addressed that the emission spectra in the solution are weak and enhanced in the crystal. The present study provides a great physical insight into the design of highly efficient AIE compounds.

The emission spectra of triphenylamine salicylaldehyde derivatives are weak in solution and strong in the crystal, as interpreted by molecular spectral and dynamics simulations.     

Preparation and photodynamic antibacterial/anticancer effects of ultralong-lifetime room-temperature phosphorescent N-doped carbon dots

Room-temperature phosphorescent (RTP) N-doped carbon-dots (CNDs) featuring eco-friendliness, low cost and high biocompatibility, are ideal photodynamic antibacterial and anticancer nanomaterials. However, the existing CNDs are limited by low singlet oxygen (¹O₂) quantum yield, which has become a bottleneck in the development of CNDs. One basic reason is the short T₁-state exciton lifetime of CNDs. Herein, triethylenetetramine hexaacetic acid was used to synthesize CNDs via a one-step hydrothermal method. CNDs are characterized with low toxicity, high biocompatibility and ultralong-lifetime RTP (URTP). In addition to the URTP (average lifetime 414 ms) under solid conditions, CNDs even had URTP (average lifetime 320 ms) in a water environment. The ultralong T₁ exciton lifetime largely extends the collision time between T₁ state excitons and O₂ and prolongs the energy transfer time, not only improving the quantum yield (0.63) of singlet oxygen (¹O₂) in solution, but also facilitating the photodynamic antibacterial and anticancer effects.

The URTP CNDs largely extends the collision time between T₁ state exciton and O₂, which improve quantum yield of singlet oxygen (¹O₂) in solutions, facilitating the photodynamic antibacterial and anticancer effects.     

DNA–affibody nanoparticle delivery system for cisplatin-based breast cancer chemotherapy

Cisplatin is the most widely used anticancer drug, but its side effects limit the maximum systemic dose. To circumvent the side effects, a DNA tetrahedron–affibody nanoparticle was prepared by combination of a DNA chain with cisplatin via interstrand crosslinks or adducts. Each nanocarrier can bind ∼68 molecules of cisplatin. This cisplatin nanoparticle exhibited high selectivity and inhibition for breast cancer HER2 overexpressing cells BT474 and lower toxicity in MCF-7 cells with low HER2 expression. The nano-drug inhibited the growth of BT474 cells by 94.57% at 512 nM (containing 33.3 μM cisplatin), which was higher than that of cisplatin (82.9%, 33.3 μM).

The novel nano-drug cisplatin-DNA tetrahedron-affibody has high specificity, high efficacy, and low toxicity for the treatment of HER2-overexpressing breast cancers.     

Polymer encapsulated clinical ICG nanoparticles for enhanced photothermal therapy and NIR fluorescence imaging in cervical cancer

Photothermal therapy (PTT) is a popular tumor therapy method, which is based on efficient photothermal nanoagents (PTNs). Clinical Indocyanine Green (ICG), as a Food and Drug Administration (FDA) approved agent, is an often-used PTN, meanwhile it is also a good near-infrared (NIR) fluorescence contrast agent. However, the further applications of ICG in biomedical fields are limited due to its poor stability. In this study, ICG was encapsulated by the amphiphilic polymer poly(styrene-co-maleic anhydride) (PSMA) to form ICG@PSMA nanoparticles. Furthermore, optical and thermal characteristics of ICG@PSMA nanoparticles were studied in detail. Strong NIR fluorescence and excellent photothermal properties of ICG@PSMA nanoparticles under 808 nm laser irradiation were measured. Besides, favorable biocompatibility of ICG@PSMA nanoparticles was demonstrated on a human cervical cancer cell line (HeLa) via cell viability studies. Hence, ICG@PSMA nanoparticles were further applied to enhanced PTT of living HeLa cells under 808 nm excitation, and a high PTT efficiency of ∼70% was obtained. The novel ICG nanoparticles as a promising PTT nanoplatform could offer an opportunity for further tumour treatments.

PSMA encapsulated Clinical ICG to form ICG@PSMA nanoparticles. ICG@PSMA nanoparticles showed strong NIR fluorescence and excellent photothermal properties.     

Aggregation induced emission by pyridinium–pyridinium interactions

Non-covalent intermolecular interactions between pyridinium subunits in a crystal-state are an efficient means to accomplish aggregation induced emission and avoid aggregation caused quenching.

Non-covalent intermolecular pyridinium–pyridinium and pyridinium–arene-π system interactions result in aggregation induced emission (AIE).