Morphology and Phase Compositions of FePt and CoPt Nanoparticles Enriched with Noble Metal.

The article reveals for the first time the features of nanoparticle morphology, phase compositions, and their changes when heating FePt and CoPt nanoalloys. Nanoparticles were obtained by co-reduction of precursor solution mixtures with hydrazine hydrate. The features were found by a complex of methods of X-ray diffraction (in situ XRD and X-ray scattering), TEM HR, and cyclic voltammetry. In addition, adsorbometry results were obtained, and the stability of different nanocluster structures was calculated by the molecular dynamics method. There were only FCC solid solutions in the X-ray patterns of the FePt and CoPt nanoalloys. According to XRD, in the case of nanoparticle synthesis with Fe and Co content less than 10 at. %, the composition of solid solutions was close to or practically equal to the composition of the as-synthesized nanoparticles quantified by inductively coupled plasma optical emission spectrometry. For systems synthesis with Fe and Co content greater than the above, the solubility limits (SLs) of Fe and Co in Pt were set 11.4 ± 0.7 at. % and 17.5 ± 0.6 at. %, respectively. Therefore, there were non-registered XRD extra-phases (XRNDPh-1) in the systems when CFe,Co ≥ SL. This statement was supported by the results of TEM HR and X-ray scattering: the smallest nanocrystals (1-2 nm) and amorphous particles were found, which qualitatively agreed with the sorbometry and SAXS results. Molecular dynamics calculations of stability for FePt and CoPt alloys claimed the structures of the most stable phase corresponded to phase diagrams (A1 and L12). Specific peculiarities of the morphology and compositions of the solid solutions of nanoalloys were established: structural blockiness (domain) and composition heterogeneity, namely, platinum enrichment of internal (deep) layers and homogenization of the nanoalloy compositions at relatively low temperatures (130-200 °C). The suggested model of the formation of nanoalloys during the synthesis, qualitatively, was compliant with the results of electrochemical deposition of FePt films on the surface of various electrodes. When nanocrystals of solid solutions (C(Fe, Co) < SL) were heated above specific temperatures, there were phase transformations with the formation of two-phase regions, with solid solutions enriched with platinum or iron (non-registered XRD phase XRNDPh-2). The newly formed phase was most likely intermetallic compounds, FePt3, CoPt3. As a result of the study, the model was developed, taking into account the nanoscale of the particles: XRDPh (A1, FeaPt1-a) → XRDPh (A1, Fem×a-xPtm-m×a+x) + XRNDPh-2 (Fen×a+yPtn-n×a-y) (here, m + n = 1, m ≤ 1, n ≤ 1).

Synthesis and Biological Properties of EGFR-Targeted Photosensitizer Based on Cationic Porphyrin.

Photodynamic therapy (PDT) in oncology is characterized by low invasiveness, minimal side effects, and little tissue scarring. Increasing the selectivity of PDT agents toward a cellular target is a new approach intended to improve this method. This study is devoted to the design and synthesis of a new conjugate based on meso-arylporphyrin with a low-molecular-weight tyrosine kinase inhibitor, Erlotinib. A nano-formulation based on Pluronic F127 micelles was obtained and characterized. The photophysical and photochemical properties and biological activity of the studied compounds and their nano-formulation were studied. A significant, 20-40-fold difference between the dark and photoinduced activity was achieved for the conjugate nanomicelles. After irradiation, the studied conjugate nanomicelles were 1.8 times more toxic toward the EGFR-overexpressing cell line MDA-MB-231 compared to the conditionally normal NKE cells. The IC50 was 0.073 ± 0.014 µM for the MDA-MB-231 cell line and 0.13 ± 0.018 µM for NKE cells after irradiation for the target conjugate nanomicelles.

An injectable PEG-like conjugate forms a subcutaneous depot and enables sustained delivery of a peptide drug.

Many biologics have a short plasma half-life, and their conjugation to polyethylene glycol (PEG) is commonly used to solve this problem. However, the improvement in the plasma half-life of PEGylated drugs' is at an asymptote because the development of branched PEG has only had a modest impact on pharmacokinetics and pharmacodynamics. Here, we developed an injectable PEG-like conjugate that forms a subcutaneous depot for the sustained delivery of biologics. The PEG-like conjugate consists of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) conjugated to exendin, a peptide drug used in the clinic to treat type 2 diabetes. The depot-forming exendin-POEGMA conjugate showed greater efficacy than a PEG conjugate of exendin as well as Bydureon, a clinically approved sustained-release formulation of exendin. The injectable depot-forming exendin-POEGMA conjugate did not elicit an immune response against the polymer, so that it remained effective and safe for long-term management of type 2 diabetes upon chronic administration. In contrast, the PEG conjugate induced an anti-PEG immune response, leading to early clearance and loss of efficacy upon repeat dosing. The exendin-POEGMA depot also showed superior long-term efficacy compared to Bydureon. Collectively, these results suggest that an injectable POEGMA conjugate of biologic drugs that forms a drug depot under the skin, providing favorable pharmacokinetic properties and sustained efficacy while remaining non-immunogenic, offers significant advantages over other commonly used drug delivery technologies.

Genetically Engineered Nanoparticles of Asymmetric Triblock Polypeptide with a Platinum(IV) Cargo Outperforms a Platinum(II) Analog and Free Drug in a Murine Cancer Model.

The development of platinum(Pt)-drugs for cancer therapy has stalled, as no new Pt-drugs have been approved in over a decade. Packaging small molecule drugs into nanoparticles is a way to enhance their therapeutic efficacy. To date, there has been no direct comparison of relative merits of the choice of Pt oxidation state in the same nanoparticle system that would allow its optimal design. To address this lacuna, we designed a recombinant asymmetric triblock polypeptide (ATBP) that self-assembles into rod-shaped micelles and chelates Pt(II) or enables covalent conjugation of Pt(IV) with similar morphology and stability. Both ATBP-Pt(II) and ATBP-Pt(IV) nanoparticles enhanced the half-life of Pt by ∼45-fold, but ATBP-Pt(IV) had superior tumor regression efficacy compared to ATBP-Pt(II) and cisplatin. These results suggest loading Pt(IV) into genetically engineered nanoparticles may yield a new generation of more effective platinum-drug nanoformulations.

High-efficiency KYW acousto-optic Q-switch for a Ho:YAG laser.

A new, to the best of our knowledge, type of acousto-optic Q-switch was developed using slow shear acoustic mode in potassium yttrium tungstate (KYW) crystal. Two Q-switch configurations were created: one for vertical and one for horizontal light polarization, both providing over 50% diffraction efficiency at a wavelength of 2.1 µm and an RF driving power below 8 W. The laser-induced damage threshold of the KYW crystal was found to equal 650 MW/cm2. Operation of a nanosecond periodically pulsed Ho:YAG laser emitting 15 mJ pulses at 2.1 µm with the KYW Q-switch is reported.

Polyethylene Glycol-Like Brush Polymer Conjugate of a Protein Drug Does Not Induce an Antipolymer Immune Response and Has Enhanced Pharmacokinetics than Its Polyethylene Glycol Counterpart.

Protein therapeutics, except for antibodies, have a short plasma half-life and poor stability in circulation. Covalent coupling of polyethylene glycol (PEG) to protein drugs addresses this limitation. However, unlike previously thought, PEG is immunogenic. In addition to induced PEG antibodies, ≈70% of the US population has pre-existing anti-PEG antibodies. Both induced and preexisting anti-PEG antibodies result in accelerated drug clearance, reduced clinical efficacy, and severe hypersensitivity reactions that have limited the clinical utility of uricase, an enzyme drug for treatment for refractory gout that is decorated with a PEG corona. Here, the authors synthesize a poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) conjugate of uricase that decorates the protein with multiple polymer chains to create a corona to solve these problems. The resulting uricase-POEGMA is well-defined, has high bioactivity, and outperforms its PEG counterparts in its pharmacokinetics (PK). Furthermore, the conjugate does not induce anti-POEGMA antibodies and is not recognized by anti-PEG antibodies. These findings suggest that POEGMA conjugation may provide a solution to the immunogenicity and antigenicity limitations of PEG while improving upon its PK benefits. These results transcend uricase and can be applied to other PEGylated therapeutics and the broader class of biologics with suboptimal PK.

Genetically Encoded Stealth Nanoparticles of a Zwitterionic Polypeptide-Paclitaxel Conjugate Have a Wider Therapeutic Window than Abraxane in Multiple Tumor Models.

Small-molecule therapeutics demonstrate suboptimal pharmacokinetics and bioavailability due to their hydrophobicity and size. One way to overcome these limitations-and improve their efficacy-is to use "stealth" macromolecular carriers that evade uptake by the reticuloendothelial system. Although unstructured polypeptides are of increasing interest as macromolecular drug carriers, current recombinant polypeptides in the clinical pipeline typically lack stealth properties. We address this challenge by developing new unstructured polypeptides, called zwitterionic polypeptides (ZIPPs), that exhibit "stealth" behavior in vivo. We show that conjugating paclitaxel to a ZIPP imparts amphiphilicity to the polypeptide chain that is sufficient to drive its self-assembly into micelles. This in turn increases the half-life of paclitaxel by 17-fold compared to free paclitaxel, and by 1.6-fold compared to the nonstealth control, i.e., ELP-paclitaxel. Treatment of mice bearing highly aggressive prostate or colon cancer with a single dose of ZIPP-paclitaxel nanoparticles leads to near-complete eradication of the tumor, and these nanoparticles have a wider therapeutic window than Abraxane, an FDA-approved taxane nanoformulation.

Eukaryotic translation elongation factor 2 (eEF2) catalyzes reverse translocation of the eukaryotic ribosome.

During protein synthesis, a ribosome moves along the mRNA template and, using aminoacyl-tRNAs, decodes the template nucleotide triplets to assemble a protein amino acid sequence. This movement is accompanied by shifting of mRNA-tRNA complexes within the ribosome in a process called translocation. In living cells, this process proceeds in a unidirectional manner, bringing the ribosome to the 3' end of mRNA, and is catalyzed by the GTPase translation elongation factor 2 (EF-G in prokaryotes and eEF2 in eukaryotes). Interestingly, the possibility of spontaneous backward translocation has been shown in vitro for bacterial ribosomes, suggesting a potential reversibility of this reaction. However, this possibility has not yet been tested for eukaryotic ribosomes. Here, using a reconstituted mammalian translation system, we show that the eukaryotic elongation factor eEF2 catalyzes ribosomal reverse translocation at one mRNA triplet. We found that this process requires a cognate tRNA in the ribosomal E-site and cannot occur spontaneously without eEF2. The efficiency of this reaction depended on the concentrations of eEF2 and cognate tRNAs and increased in the presence of nonhydrolyzable GTP analogues. Of note, ADP-ribosylation of eEF2 domain IV blocked reverse translocation, suggesting a crucial role of interactions of this domain with the ribosome for the catalysis of the reaction. In summary, our findings indicate that eEF2 is able to induce ribosomal translocation in forward and backward directions, highlighting the universal mechanism of tRNA-mRNA movements within the ribosome.

All-fiber coherent combining of Er-doped amplifiers through refractive index control in Yb-doped fibers.

We propose a simple all-fiber solution for coherent beam combining of Er-doped fiber amplifiers. This method, which we believe to be a new method, employs the effect of refractive index changes in Yb-doped fibers induced at approximately 1.55 microm by optical pumping at approximately 980 nm, which is performed for an active phase control in the fiber configuration. An algorithm based on population inversion in a two-level system supports the straightforward implementation of the effect into a feedback loop. Combining two 500 mW Er-doped amplifiers in a single-mode fiber is successfully demonstrated with control by approximately 120 mW laser diode. The method is shown to operate against the acoustic phase noise within the range of approximately pi rad and with a rate of approximately 2.6 pi rad/ms that potentially serves combining of at least 50 amplifiers similar to those used in practical work.