Dual Functional Microcapsule based on Monodisperse Short PEG Amphiphile for Drug Encapsulation and Protein Affinity Controlled Release.

A short monodisperse poly(ethylene glycol) (PEG) and a neutral organic rotamer conjugate TEG-BTA-2 amphiphile was designed for the construction of a stimuli-responsive switchable self-assembled structure for drug encapsulation by noncovalent interaction and targeted controlled delivery. A short PEG, tetraethylene glycol (TEG) was covalently attached with a neutral organic rotamer benzothiazole dye (BTA-2) affording the neutral TEG-BTA-2 (<500 D). The TEG-BTA-2 is self-assembled into a microsphere in an aqueous medium, but remarkably undergoes morphology change switching to a rice-like microcapsule for curcumin encapsulation. Curcumin-loaded microcapsules were stable in an aqueous solution, however, were noticed disintegrating upon the addition of BSA protein. This is possibly due to an interaction with BSA protein leading to a protein affinity-controlled curcumin release in a neutral PBS buffer. Moreover, cell internalization of the neutral amphiphile TEG-BTA-2 into A549 cells was observed by fluorescence microscopy, providing an opportunity for application as a molecular vehicle for targeted drug delivery and monitoring.

Improving In Vivo Tumor Accumulation and Efficacy of Platinum Antitumor Agents by Electronic Tuning of the Kinetic Lability.

The impact of kinetic lability or reactivity on in vitro cytotoxicity, stability in plasma, in vivo tumor and tissue accumulation, and antitumor efficacy of functional platinum(II) (Pt) anticancer agents containing a O˄O ß-diketonate leaving ligand remain largely unexplored. To investigate this, we synthesized Pt complexes [(NH3 )2 Pt(L1-H)]NO3 and [(DACH)Pt(L1-H)]NO3 (L1=4,4,4-trifluoro-1-ferrocenylbutane-1,3-dione, DACH=1R,2R-cyclohexane-1,2-diamine) containing an electron deficient [L1-H]- O˄O leaving ligand and [(NH3 )2 Pt(L2-H)]NO3 and [(DACH)Pt(L2-H)]NO3 (L2=1-ferrocenylbutane-1,3-dione) containing an electron-rich [L2-H]- O˄O leaving ligand. While all four complexes have comparable lipophilicity, the presence of the electron-withdrawing CF3 group was found to dramatically enhance the reactivity of these complexes toward nucleophilic biomolecules. In vitro cellular assays revealed that the more reactive complexes have higher cellular uptake and higher anticancer potency as compared to their less reactive analogs. But the scenario is opposite in vivo, where the less reactive complex showed improved tissue and tumor accumulation and better anticancer efficacy in mice bearing ovarian xenograft when compared to its more reactive analog. Finally, in addition to demonstrating the profound but contrasting impact of kinetic lability on in vitro and in vivo antitumor potencies, we also described the impact of kinetic lability on the mechanism of action of this class of promising antitumor agents.

Development of a Highly In Vivo Efficacious Dual Antitumor and Antiangiogenic Organoiridium Complex as a Potential Anti-Lung Cancer Agent.

While the phenomenal clinical success of blockbuster platinum (Pt) drugs is highly encouraging, the inherent and acquired resistance and dose-limiting side effects severely limit their clinical application. To find a better alternative with translational potential, we synthesized a library of six organo-IrIII half-sandwich [(η5-CpX)Ir(N∧N)Cl]+-type complexes. In vitro screening identified two lead candidates [(η5-CpXPh)Ir(Ph2Phen)Cl]+ (5, CpXPh = tetramethyl-phenyl-cyclopentadienyl and Ph2Phen = 4,7-diphenyl-1,10-phenanthroline) and [(η5-CpXBiPh)Ir(Ph2Phen)Cl]+ (6, CpXBiPh = tetramethyl-biphenyl-cyclopentadienyl) with nanomolar IC50 values. Both 5 and 6 efficiently overcame Pt resistance and presented excellent cancer cell selectivity in vitro. Potent antiangiogenic properties of 6 were demonstrated in the zebrafish model. Satisfyingly, 6 and its nanoliposome Lipo-6 presented considerably higher in vivo antitumor efficacy as compared to cisplatin, as well as earlier reported IrIII half-sandwich complexes in mice bearing the A549 non-small lung cancer xenograft. In particular, complex 6 is the first example of this class that exerted dual in vivo antiangiogenic and antitumor properties.

The Power of Kinetic Inertness in Improving Platinum Anticancer Therapy by Circumventing Resistance and Ameliorating Nephrotoxicity.

Even in the modern era of precision medicine and immunotherapy, chemotherapy with platinum (Pt) drugs remains among the most commonly prescribed medications against a variety of cancers. Unfortunately, the broad applicability of these blockbuster Pt drugs is severely limited by intrinsic and/or acquired resistance, and high systemic toxicity. Considering the strong interconnection between kinetic lability and undesired shortcomings of clinical Pt drugs, we rationally designed kinetically inert organometallic Pt based anticancer agents with a novel mechanism of action. Using a combination of in vitro and in vivo assays, we demonstrated that the development of a remarkably efficacious but kinetically inert Pt anticancer agent is feasible. Along with exerting promising antitumor efficacy in Pt-sensitive as well as Pt-resistant tumors in vivo, our best candidate has the ability to mitigate the nephrotoxicity issue associated with cisplatin. In addition to demonstrating, for the first time, the power of kinetic inertness in improving the therapeutic benefits of Pt based anticancer therapy, we describe the detailed mechanism of action of our best kinetically inert antitumor agent. This study will certainly pave the way for designing the next generation of anticancer drugs for effective treatment of various cancers.

Potent Ruthenium-Ferrocene Bimetallic Antitumor Antiangiogenic Agent That Circumvents Platinum Resistance: From Synthesis and Mechanistic Studies to In Vivo Evaluation in Zebrafish.

Emergence of resistance in cancer cells and dose-limiting side effects severely limit the widespread use of platinum (Pt) anticancer drugs. Multi-action hybrid anticancer agents that are constructed by merging two or more pharmacophores offer the prospect of circumventing issues of Pt drugs. Herein, we report the design, synthesis, and in-depth biological evaluation of a ruthenium-ferrocene (Ru-Fc) bimetallic agent [(η6-p-cymene)Ru(1,1,1-trifluoro-4-oxo-4-ferrocenyl-but-2-en-2-olate)Cl] and its five analogues. Along with aquation/anation chemistry, we evaluated the in vitro antitumor potency, Pt cross-resistance profile, and in vivo antiangiogenic properties. A structure activity analysis was performed to understand the impact of Fc, CF3, and p-cymene groups on the anticancer potency of the Ru-Fc hybrid. Finally, in addition to assessing cellular uptake and intracellular distribution, we demonstrated that the Ru-Fc hybrid binds to nucleophilic biomolecules and produces reactive oxygen species, which causes mitochondrial dysfunction and induces ER stress, leading to poly(ADP-ribose) polymerase-mediated necroptotic cell death.

A BOPHY based fluorescent probe for Hg2+via NTe2 chelation.

A BOPHY-based organotellurium-containing probe was synthesized and characterized via single crystal XRD for the selective and sensitive detection of Hg2+ over other metal ions. The probe detects Hg2+ in less than 1 s with a 2.5-fold enhancement in fluorescent intensity. Due to the chalcogenophilicity of mercury, Hg2+ was facilely trapped in the NTe2 chelating cavity of the probe. The probe can detect Hg2+ in the nanomolar range (62 nM) and it showed reversibility with S2- ions. The sensitivity of the probe for the detection of Hg2+ was confirmed in living HeLa cells.

Enhancement of patterned triboelectric output performance by an interfacial polymer layer for energy harvesting application.

Efficaciously scavenging waste mechanical energy from the environment is an emerging field in the self-powered and self-governing electronics systems which solves battery limitations. It demonstrates enormous potential in various fields such as wireless devices, vesture, and portable electronic devices. Different surface textured PET triboelectric nanogenerators (TENGs) were developed by the laser pattern method in the previous work, with the line textured TENG device showing improved performance due to a larger surface contact area. Here, a polyethylene oxide (PEO) and polyvinyl alcohol (PVA) coated line patterned PET-based TENG was developed for the conversion of mechanical energy into useful electric energy. The PEO layer boosted the TENG output to 4 times higher than that of the PA6-laser patterned PET TENG device (our previous report) and 2-fold higher than that of a pristine line patterned TENG. It generated an open-circuit voltage, short circuit current, and instantaneous power density of 131 V, 2.32 µA, and 41.6 µW cm-2, respectively. The as-fabricated device was tested for 10 000 cycles for reliability evaluation, which shows no significant performance degradation. In addition, the device was deployed to power 10 LEDs with high intensity. Thus, this device can be used for ambient mechanical energy conversion and to power micro and nano-electronic devices.

A Comparative Study of Compressible and Conductive Vertically Aligned Carbon Nanotube Forest in Different Polymer Matrixes for High-Performance Piezoresistive Force Sensors.

In the present scenario, conducting and lightweight flexible polymer nanocomposites rival metallic and inorganic semiconducting materials as highly sensitive piezoresistive force sensors. Herein, we explore the feasibility of vertically aligned carbon nanotube (VACNT) nanocomposites impregnated in different polymer matrixes, envisioned as highly efficient piezoresistors in sensor applications. Polymer nanocomposites are selectively designed and fabricated using three different polymer matrixes, i.e., polydimethylsiloxane (PDMS), polyurethane (PU), and epoxy resins with ideal reinforcement of VACNTs to enhance the thermal stability, conductivity, compressibility, piezoresistivity, and sensitivity of these nanocomposites. To predict the best piezoresistive force sensor, we evaluated the structural, optical, thermal, electrical, mechanical, and piezoresistive properties of the nanocomposites using field-emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), Raman spectroscopy, thermogravimetric analysis (TGA), I-V measurements, compressive stress-strain measurements, hysteresis, sensitivity, and force studies. The results demonstrate that the PDMS/VACNT nanocomposite is capable of sustaining large force with almost complete recovery and enhanced sensitivity, thereby fulfilling the desirable need for a highly efficient conductive and flexible force sensor as compared to PU/VACNT and epoxy/VACNT nanocomposites.

Green synthesis of near-infrared absorbing eugenate capped iron oxide nanoparticles for photothermal application.

Nanomaterials exhibit different interesting physical, chemical, electronic and magnetic properties that can be used in a variety of biomedical applications such as molecular imaging, cancer therapy, biosensing, and targeted drug delivery. Among various types of nanoparticles, super paramagnetic iron oxide nanoparticles (SPIONs) have emerged as exogenous contrast agents for in vitro and in vivo deep tissue imaging. Here, we propose a facile, rapid, non-toxic, and cost-effective single step green synthesis method to fabricate eugenate (4-allyl-2-methoxyphenolate) capped iron oxide nanoparticles (E-capped IONPs). The magnetic E-capped IONPs are first time synthesized using a medicinal aromatic plant, Pimenta dioica. The Pimenta dioica leaf extract was used as a natural reducing agent for E-capped IONPs synthesis. The crystalline structure and size of the synthesized spherical nanoparticles were confirmed using the x-ray diffraction and electron microscopic images respectively. In addition, the presence of the functional groups, responsible for capping and stabilizing the synthesized nanoparticles, were identified by the Fourier transform infra-red spectrum. These nanoparticles were found to be safe for human cervical cancer (HeLa) and human embryonic kidney 293 (HEK 293) cell lines and their safety was established using MTT[3-(4, 5-Dimethylthiazol-2-yl)-2, 5-Diphenyltetrazolium Bromide] assay. These green synthesized E-capped IONPs display a distinct absorbance in the tissue transparent near-infrared (NIR) wavelength region. This property was used for the NIR photothermal application of E-capped IONPs. The results suggest that these E-capped IONPs could be used for deep tissue photothermal therapy along with its application as an exogenous contrast agent in biomedical imaging.