Hyaluronic acid nanoparticles for targeted oral delivery of doxorubicin: Lymphatic transport and CD44 engagement.

The oral delivery of doxorubicin (DOX), an anti-cancer drug, encounters multiple hurdles such as limited gastrointestinal permeability, P-glycoprotein-mediated efflux, brief intestinal residence, and rapid degradation. This study introduced a novel approach utilizing hyaluronic acid (HA)-grafted fatty acid monoglycerides (HGD) to encapsulate DOX, forming HGD-DOX nanoparticles, aimed at enhancing its oral bioavailability. Drug encapsulated by HGD provided several advantages, including extended drug retention in the gastrointestinal tract, controlled release kinetics, and promotion of lymphatic absorption in the intestine. Additionally, HGD-DOX nanoparticles could specifically target CD44 receptors, potentially increasing therapeutic efficacy. The uptake mechanism of HGD-DOX nanoparticles primarily involved clathrin-mediated, caveolin-mediated and macropinocytosis endocytosis. Pharmacokinetic analysis further revealed that HGD significantly prolonged the in vivo residence time of DOX. In vivo imaging and pharmacodynamic studies indicated that HGD possessed tumor-targeting capabilities and exhibited a significant inhibitory effect on tumor growth, while maintaining an acceptable safety profile. Collectively, these findings position HGD-DOX nanoparticles as a promising strategy to boost the oral bioavailability of DOX, offering a potential avenue for improved cancer treatment.

Targeting NAD Metabolism: Rational Design, Synthesis and In Vitro Evaluation of NAMPT/PARP1 Dual-Target Inhibitors as Anti-Breast Cancer Agents.

The malignancy of breast cancer poses a global challenge, with existing treatments often falling short of desired efficacy. Extensive research has underscored the effectiveness of targeting the metabolism of nicotinamide adenine dinucleotide (NAD), a pivotal molecule crucial for cancer cell survival and growth, as a promising anticancer strategy. Within mammalian cells, sustaining optimal NAD concentrations relies on two key enzymes, namely nicotinamide phosphoribosyltransferase (NAMPT) and poly(ADP-ribose) polymer 1 (PARP1). Recent studies have accentuated the potential benefits of combining NAMPT inhibitors and PARP1 inhibitors to enhance therapeutic outcomes, particularly in breast cancer. In this study, we designed and synthesized eleven novel NAMPT/PARP1 dual-target inhibitors. Among them, compound DDY02 exhibited acceptable inhibitory activities against both NAMPT and PARP1, with IC50 values of 0.01 and 0.05 µM, respectively. Moreover, in vitro evaluations revealed that treatment with DDY02 resulted in proliferation inhibition, NAD depletion, DNA damage, apoptosis, and migration inhibition in MDA-MB-468 cells. These results posit DDY02, by targeting NAD metabolism through inhibiting both NAMPT and PARP1, as a promising lead compound for the development of breast cancer therapy.

Design, synthesis, and evaluation of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one derivatives: potent BRD4 inhibitors with anti-breast cancer activity.

BRD4 inhibitors have demonstrated promising potential in cancer therapy. However, their therapeutic efficacy in breast cancer varies depending on the breast cancer subtype, particularly in the treatment of TNBC. In this study, we designed and synthesized 94 derivatives of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one to evaluate their inhibitory activities against BRD4. Notably, compound DDT26 exhibited the most potent inhibitory effect on BRD4, with an IC50 value of 0.237 ± 0.093 µM. DDT26 demonstrated significant anti-proliferative activity against both TNBC cell lines and MCF-7 cells. Intriguingly, the phthalazinone moiety of DDT26 mimicked the PAPR1 substrate, resulting in DDT26 displaying a moderate inhibitory effect on PARP1 with an IC50 value of 4.289 ± 1.807 µM. Further, DDT26 was shown to modulate the expression of c-MYC and γ-H2AX, induce DNA damage, inhibit cell migration and colony formation, and arrest the cell cycle at the G1 phase in MCF-7 cells. Our findings present potential lead compounds for the development of potent anti-breast cancer agents targeting BRD4.

Self-Assembling Anchorage of Hyaluronic Acid on the Nanoparticle Surface Confers Superiority of Triple Negative Breast Cancer Treatment.

Triple-negative breast cancer (TNBC) has been listed as one of the most fatal diseases, and no effective targeting treatment is clinically available. Although CD44-targeting hyaluronic acid (HA) has been utilized as targeting ligands in many studies, no facile ways have been developed through HA self-assembly at the nanoparticle surface. Herein, we reported N-isopropylacrylamide-grafted chitosan-based nanoparticles self-assembling with HA (HA-NPs) through electrostatic forces and loaded with curcumin (CUR). The HA-NPs displayed pH-responsive properties due to the chemical modification of chitosan, and the preparation process was optimized by central composite design-response surface methodology. HA anchorage confers the vehicle with tumor-targeting capability. HA-NPs displayed more robust effects of inhibiting TNBC primary tumor growth than free CUR and a plain counterpart but without increased systemic cytotoxicity. In addition, in vivo pharmacokinetic studies showed that HA-NPs significantly increased the in vivo residence time of free CUR and improved the bioavailability of CUR. These findings suggested that chitosan-based HA-NPs may provide a feasible and unique strategy to achieve CD44 targeting and enhance its efficacy in vivo for the treatment of advanced TNBC.

Fabrication and Optical Characterization of VO2-Based Thin Films Deposited on Practical Float Glass by Magnetron Sputtering and Professional Annealing.

In this paper, VO2 thin films with good optical properties are fabricated on practical float glass by magnetron sputtering and a professional annealing method. The near-infrared switching efficiency (NIRSE) of the prepared film reaches 39% (@2000 nm), and its near-infrared energy modulation ability (ΔTir) reaches 10.9% (780-2500 nm). Further, the highest integral visible transmittance Tlum is 63%. The proposed method exhibits good reproducibility and does not cause any heat damage to the magnetron sputtering machine. The crystalline structure of the VO2 film is characterized by X-ray diffraction (XRD). The lattice planes (011) and (-211) grow preferentially (JCPDS 65-2358), and a large number of NaV2O5 crystals are detected simultaneously. The microstructures are characterized by scanning electron microscopy (SEM), and a large number of long sheet crystals are identified. The phase transition temperature is significantly reduced by an appropriate W doping concentration (Tc = 29 °C), whereas excessive W doping causes distortion of the thermal hysteresis loop and a reduction in the NIRSE. Oxygen vacancies are created by low pressure annealing, due to which the phase transition temperature of VO2 film decreases by 8 °C. The addition of an intermediate SiO2 layer can prevent the diffusion of Na+ ions and affect the preparation process of the VO2 thin film.

Signal enhancing strategies in aptasensors for the detection of small molecular contaminants by nanomaterials and nucleic acid amplification.

Small molecular contaminants (such as mycotoxins, antibiotics, pesticide residues, etc.) in food and environment have given rise to many biological and ecological toxicities, which has attracted worldwide attention in recent years. Meanwhile, due to the advantages of aptamers such as high specificity and stability, easy synthesis and modification, as well as low cost and immunogenicity, various aptasensors for the detection of small molecular contaminants have been flourishing. An aptasensor as a whole is composed of an aptamer-based target recognizer and a signal transducer, which are fields of concentrated research. In the practical detection applications, in order to achieve the quantitative detection of small molecular contaminants at low abundance in real samples, a large number of signal enhancing strategies have been utilized in the development of aptasensors. Recent years is a vintage period for efficient signal enhancing strategies of aptasensors by the aid of nanomaterials and nucleic acid amplification that are applied in the elements for target recognition and signal conversion. Therefore, this paper meticulously reviews the signal enhancing strategies based on nanomaterials (including the (quasi-)zero-dimensional, one-dimensional, two-dimensional and three-dimensional nanomaterials) and nucleic acid amplification (including enzyme-assisted nucleic acid amplification and enzyme-free nucleic acid amplification). Furthermore, the challenges and future trends of the abovementioned signal enhancing strategies for application are also discussed in order to inspire the practitioners in the research and development of aptasensors for small molecular contaminants.

Significant optical force enhancements of nanostructure with balanced gain and loss.

In this paper, we theoretically analyze the optical force between a pair of active and passive plasmonic core-shell nanoparticles (NPs). The optical force between the NPs can be either attractive or repulsive near the critical point while the passive dimer provides only attractive force. We reveal that the reversal of attractive or repulsive force is determined by the relative phase of electric dipole (ED) modes, which can be strongly affected by the gain and loss coefficient κ. Compared with the passive dimer with the same size, the active-passive dimer can exhibit a very high repulsive force (about two orders of magnitude) while remaining the same order magnitude attractive force when the value of coefficient is 0.345. Interestingly, we find that the position of the maximum repulsive force occurs near the critical point. We also investigate the influence of variations in geometrical parameters of the dimer and polarization angle on the force. Finally, the numerical results demonstrate that when the dimer is illuminated by a laser beam, the attractive and repulsive forces can also be achieved. The manipulation of optical force can find potential in optical sorting and transport of NPs.

Color-dependent unidirectional scattering of a plasmonic heterodimer investigated by a dipole-dipole interference model.

In this paper, we employ an interference model of two separated electric dipoles to study the color-dependent unidirectional scattering of a plasmonic heterodimer consisting of a pair of gold and silver disks of the same size. The dipole moments in such a dipole-dipole interference model are numerically obtained by a multipole decomposition method. It shows that the power difference between the different scattering directions predicted by the dipole-dipole interference model agrees well with that calculated by the full wave simulation. The dipole-dipole interference model indicates that the scattering directionality of the heterodimer is intimately related to its geometrical parameters, including the height and radius of the disk as well as the distance between two disks. We further show that the color routing of such a heterodimer is also maintained when an electric or magnetic dipole source is positioned in the center of the heterodimer. Finally, we propose an approach to enhance bidirectional scattering by arranging the heterodimer in a line and then the main lobe beamwidth can be reduced to about 26 deg for the right scattering and 29 deg for the left scattering. Our results may be used in designing integrated plasmonic nanocircuits that demand light guiding and routing in nanoscale.