18-ß-glycyrrhetinic acid-loaded polymeric nanoparticles attenuate cigarette smoke-induced markers of impaired antiviral response in vitro.

Tobacco smoking is a leading cause of preventable mortality, and it is the major contributor to diseases such as COPD and lung cancer. Cigarette smoke compromises the pulmonary antiviral immune response, increasing susceptibility to viral infections. There is currently no therapy that specifically addresses the problem of impaired antiviral response in cigarette smokers and COPD patients, highlighting the necessity to develop novel treatment strategies. 18-ß-glycyrrhetinic acid (18-ß-gly) is a phytoceutical derived from licorice with promising anti-inflammatory, antioxidant, and antiviral activities whose clinical application is hampered by poor solubility. This study explores the therapeutic potential of an advanced drug delivery system encapsulating 18-ß-gly in poly lactic-co-glycolic acid (PLGA) nanoparticles in addressing the impaired antiviral immunity observed in smokers and COPD patients. Exposure of BCi-NS1.1 human bronchial epithelial cells to cigarette smoke extract (CSE) resulted in reduced expression of critical antiviral chemokines (IP-10, I-TAC, MIP-1α/1ß), mimicking what happens in smokers and COPD patients. Treatment with 18-ß-gly-PLGA nanoparticles partially restored the expression of these chemokines, demonstrating promising therapeutic impact. The nanoparticles increased IP-10, I-TAC, and MIP-1α/1ß levels, exhibiting potential in attenuating the negative effects of cigarette smoke on the antiviral response. This study provides a novel approach to address the impaired antiviral immune response in vulnerable populations, offering a foundation for further investigations and potential therapeutic interventions. Further studies, including a comprehensive in vitro characterization and in vivo testing, are warranted to validate the therapeutic efficacy of 18-ß-gly-PLGA nanoparticles in respiratory disorders associated with compromised antiviral immunity.

Doxorubicin loaded thermostable nanoarchaeosomes: a next-generation drug carrier for breast cancer therapeutics.

Breast cancer has a poor prognosis due to the toxic side effects associated with high doses of chemotherapy. Liposomal drug encapsulation has resulted in clinical success in enhancing chemotherapy tolerability. However, the formulation faces severe limitations with a lack of colloidal stability, reduced drug efficiency, and difficulties in storage conditions. Nanoarchaeosomes (NA) are a new generation of highly stable nanovesicles composed of the natural ether lipids extracted from archaea. In our study, we synthesized and characterized the NA, evaluated their colloidal stability, drug release potential, and anticancer efficacy. Transmission electron microscopy images have shown that the NA prepared from the hyperthermophilic archaeon Aeropyrum pernix K1 was in the size range of 61 ± 3 nm. The dynamic light scattering result has confirmed that the NA were stable at acidic pH (pH 4) and high temperature (70 °C). The NA exhibited excellent colloidal stability for 50 days with storage conditions at room temperature. The cell viability results have shown that the pure NA did not induce cytotoxicity in NIH 3T3 fibroblast cells and are biocompatible. Then NA were loaded with doxorubicin (NAD), and FTIR and UV-vis spectroscopy results have confirmed high drug loading efficiency of 97 ± 1% with sustained drug release for 48 h. The in vitro cytotoxicity studies in MCF-7 breast cancer cell lines showed that NAD induced cytotoxicity at less than 10 nM concentration. Fluorescence-activated cell sorting (FACS) results confirmed that NAD induced late apoptosis in nearly 92% of MCF-7 cells and necrosis in the remaining cells with cell cycle arrest at the G0/G1 phase. Our results confirmed that the NA could be a potential next-generation carrier with excellent stability, high drug loading efficiency, sustained drug release ability, and increased therapeutic efficacy, thus reducing the side effects of conventional drugs.

Elucidating shape-mediated drug carrier mechanics of hematite nanomaterials for breast cancer therapeutics.

Metallic nanomaterials have gained significant attention in cancer therapy as potential nanocarriers due to their unique properties at the nanoscale. However, nanomaterials face several drawbacks, including biocompatibility, stability, and cellular uptake. Hematite (α-Fe2O3) nanoparticles are emerging as promising nano-carriers to reduce adverse outcomes of conventional chemotherapeutics. However, the shape-mediated drug carrier mechanics of hematite nanomaterials are not raveled. In this study, we tailored hematite nanoparticles in ellipsoidal (EHNP) and spherical (SHNP) shapes with excellent biocompatibility and efficient drug encapsulation and release. We elucidate that EHNP exhibits higher cellular uptake than SHNP. With effective cellular internalization, the cisplatin-loaded EHNP showed excellent cytotoxicity with an IC50 value of 200 nM compared to the cisplatin-loaded SHNP. The flow cytometry cell sorting (FACS) analysis showed a four-fold increase in cell death by arresting the cells at the G0/G1 and G1 phases for cis-EHNP compared to cis-SHNP. The results show that ellipsoidal-shaped hematite nanoparticles can act as attractive nanocarriers with improved therapeutic efficacy in cancer therapy.

Liquid-Liquid Phase Separation (LLPS)-Driven Fibrilization of Amyloid-ß Protein.

Amyloid-ß [Aß(1-40)] aggregation into a fibrillar network is one of the major hallmarks of Alzheimer's disease (AD). Recently, a few studies reported that polyphosphate (polyP), an anionic biopolymer that participates in various cellular physiological processes in humans, induces fibrilization in many amyloidogenic proteins [ 2020 Alzheimer's Disease Facts and Figures; John Wiley and Sons Inc., 2020; Tanzi, R. E.; Bertram, L. Cell 2005, 120, 545-555; Selkoe, D. J. Proc. Natl. Acad. Sci. U.S.A. 1995, 275, 630-631; and Rambaran, R. N.; Serpell, L. C. Prion 2008, 2, 112-117]. However, the role of polyP in Aß(1-40) fibrilization and the underlying mechanism are unclear. In this study, we report experimental investigations on the role of polyP in the fibrilization kinetics of Aß(1-40). It is found that polyP exhibits a dual effect depending upon the pH value. At pH = 7 (neutral), polyP inhibits amyloid fibrilization in a dose-dependent manner similar to negatively charged nanoparticles. On the contrary, at pH = 3 (acidic), polyP accelerates amyloid fibrilization kinetics via liquid-liquid phase separation (LLPS), wherein the protein-rich droplets contain mature fibrils. In the parameter space spanned by concentrations of Aß(1-40) and polyP, a phase diagram is constructed to demark the domain where LLPS is observed at pH = 3. Characterization of the protein aggregates, secondary structure content in the aggregates, and cell viability studies in the presence of aggregates are discussed at both pH values. This study reveals that anionic biopolymers can modulate amyloid fibrilization kinetics, linked to neurodegenerative diseases, depending upon their local concentrations and pH.

Anisotropic and Amphiphilic Mesoporous Core-Shell Silica Microparticles Provide Chemically Selective Environments for Simultaneous Delivery of Curcumin and Quercetin.

Porous silica materials are often used for drug delivery. However, systems for simultaneous delivery of multiple drugs are scarce. Here we show that anisotropic and amphiphilic dumbbell core-shell silica microparticles with chemically selective environments can entrap and release two drugs simultaneously. The dumbbells consist of a large dense lobe and a smaller hollow hemisphere. Electron microscopy images show that the shells of both parts have mesoporous channels. In a simple etching process, the properly adjusted stirring speed and the application of ammonium fluoride as etching agent determine the shape and the surface anisotropy of the particles. The surface of the dense lobe and the small hemisphere differ in their zeta potentials consistent with differences in dye and drug entrapment. Confocal Raman microscopy and spectroscopy show that the two polyphenols curcumin (Cur) and quercetin (QT) accumulate in different compartments of the particles. The overall drug entrapment efficiency of Cur plus QT is high for the amphiphilic particles but differs widely between Cur and QT compared to controls of core-shell silica microspheres and uniformly charged dumbbell microparticles. Furthermore, Cur and QT loaded microparticles show different cancer cell inhibitory activities. The highest activity is detected for the dual drug loaded amphiphilic microparticles in comparison to the controls. In the long term, amphiphilic particles may open up new strategies for drug delivery.

Germanium nanospheres for ultraresolution picotensiometry of kinesin motors.

Kinesin motors are essential for the transport of cellular cargo along microtubules. How the motors step, detach, and cooperate with each other is still unclear. To dissect the molecular motion of kinesin-1, we developed germanium nanospheres as ultraresolution optical trapping probes. We found that single motors took 4-nanometer center-of-mass steps. Furthermore, kinesin-1 never detached from microtubules under hindering load conditions. Instead, it slipped on microtubules in microsecond-long, 8-nanometer steps and remained in this slip state before detaching or reengaging in directed motion. Unexpectedly, reengagement and thus rescue of directed motion was more frequent. Our observations broaden our knowledge on the mechanochemical cycle and slip state of kinesin. This state and rescue need to be accounted for to understand long-range transport by teams of motors.

Rapid Dissolution of Amyloid ß Fibrils by Silver Nanoplates.

Plaques of amyloid beta (Aß) protein are associated with neurodegenerative diseases, and preventing their formation and dissolution of plaques are essential to the development of therapeutics. In this study, silver triangular nanoplates (AgTNPs) are shown to dissolve mature Aß fibrils because of their plasmonic photothermal property. Mature Aß fibrils treated with AgTNPs under near-infrared (NIR)-illuminated conditions are dissolved in less than 1 h, while an equal concentration of silver spherical nanoparticles took about 70 h. The concentration of the fibrils decreased from 10 to 0.3 µM upon treating the amyloid fibrils with AgTNPs under NIR. AgTNPs are also shown to prevent the formation of Aß fibrils by selective binding to the positively charged amyloidogenic sequence of the Aß monomer. The kinetics of inhibition by AgTNPs follows the predictions of the detailed kinetic model (Ramesh et al., Langmuir 2018, 34, 4004-4012). The kinetics of dissolution and inhibition are characterized by Congo red/ThT assay, transmission electronic microscopy, atomic force microscopy, and attenuated total reflectance Fourier transform-infrared spectroscopy. Cell viability studies on SH-SY5Y and BE-(2)-C cells using 3-[4,5-dimethy-lthi-azol-2-yl]-2,5-diphenyl-tetrazdium bromide and lactate dehydrogenase assay show that the viability of the cells increased from 33 to 70% on treating the cells with AgTNP-incubated Aß fibrils compared to the mature Aß fibrils. The study provides new insights to design plasmonic nanoparticle-based therapeutics to cure neurodegenerative diseases.

Phospholipid stabilized gold nanorods: towards improved colloidal stability and biocompatibility.

Biocompatible and colloidally stable gold nanorods (GNRs) with well-defined plasmonic properties are essential for biomedical and theranostic applications. The as-synthesized GNRs using the seed-mediated method are stabilized by the surfactant, cetyltrimethylammonium bromide (CTAB), which is known for its cytotoxicity in many cell lines. Biocompatible GNRs synthesized using known protocols exhibit some extent of cytotoxicity and colloidal instability because of the incomplete removal of CTAB. We report a facile method for the efficient removal of CTAB molecules with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) phospholipid molecules, which are naturally present in cell membranes. The kinetics of the ligand exchange process is studied using surface-enhanced Raman scattering (SERS) and corroborated with matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. From colloidal stability studies using dynamic light scattering (DLS) and UV-Vis spectroscopy, the optimal lipid concentration and duration required for the successful ligand exchange of CTAB by DMPC are reported. Using thermogravimetric analysis, the surface concentration of DMPC on colloidally stable GNRs is found to be approximately 9 molecules per nm2. The 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays show that the surface-modified DMPC-GNRs have significantly better biocompatibility than those of CTAB-GNRs. Studies on the ligand exchange, colloidal stability and biocompatibility of DMPC-GNRs with aspect ratios ranging from 2.2 to 4.2 demonstrate the robustness of the proposed method. The results provide insights into the important factors to be considered while designing biocompatible GNRs suitable for applications in nanomedicine.