Temperature-Triggered Fusion of Vesicles Composed of Right-Handed and Left-Handed Amphiphilic Helical Peptides

Vesicles prepared from a mixture of (Sar)25-b-(l-Leu-Aib)6 (SLL) and (Sar)25-b-(d-Leu-Aib)6 (SDL) fused with themselves upon heating to 90 °C. The vesicles also fused with (Sar)28-b-(l-Leu-Aib)8 vesicles upon heating to 90 °C. The temperature-triggered fusion was due to the phase transition of the mixed membrane of SLL and SDL at 90 °C and should be driven by the bending energy stored in the stereocomplex membrane upon taking a vesicular structure

Size Control of Core–Shell-type Polymeric Micelle with a Nanometer Precision

Amphiphilic polydepsipeptides having a hydrophobic poly­(l-lactic acid) block and varying numbers of a hydrophilic poly­(sarcosine) block ranging from 1 to 3, AB-, A₂B-, and A₃B-type, were prepared and studied on their molecular assemblies. The morphologies were found to be polymeric micelles for the AB- and the A₃B-type polydepsipeptides, but worm-like micelles for the A₂B-type polydepsipeptide. The hydrodynamic diameter of the A₃B-type polydepsipeptide (22 nm) became smaller than the AB-type polydepsipeptide (34 nm). The polymeric micelle sizes composed of the AB-type polydepsipeptide were adjustable up to ca. 100 nm with incorporation of poly­(l-lactic acid) into the hydrophobic core. On the other hand, with varying mixing ratio of the AB-type and A₃B-type polydepsipeptides, the hydrodynamic diameters were tunable to become smaller sizes with a precise control in the range from 22 to 34 nm. The polydispersity indices of the polymeric micelles were less than 0.1, indicating that we can obtain the homogeneous polymeric micelles with diameters in the range from 20 to 100 nm under a precise control

Factors Influencing <i>in Vivo</i> Disposition of Polymeric Micelles on Multiple Administrations

Lactosome is a polymeric micelle composed of amphiphilic polydepsipeptide, poly­(sarcosine)₆₄-<i>block</i>-poly­(l-lactic acid)₃₀ (AB-type), which accumulates in solid tumors through the enhanced permeability and retention (EPR) effect. However, lactosome on multiple administrations changed its pharmacokinetics from accumulation in tumors to liver due to the production of antilactosome IgM, which was triggered by the first administration. This phenomenon is called the accelerated blood clearance (ABC). In order to reduce the production of antilactosome IgM, a novel nanoparticle composed of (poly­(sarcosine)₂₃)₃-<i>block</i>-poly­(l-lactic acid)₃₀ (A₃B-type) was prepared. The A₃B-type lactosome at the second administration showed an <i>in vivo</i> disposition similar to that at the first administration due to suppression of antibody production. This study involving the AB- and A₃B-type lactosomes, with variation of conditions, revealed that the high local density of poly­(sarcosine) chains of the A₃B-type lactosome should relate to the prevention of a polymeric micelle from interacting B-cell receptors

Morphology Control between Twisted Ribbon, Helical Ribbon, and Nanotube Self-Assemblies with His-Containing Helical Peptides in Response to pH Change

pH-Responsive molecular assemblies with a variation in morphology ranging from a twisted ribbon, a helical ribbon, to a nanotube were prepared from a novel A₃B-type amphiphilic peptide having three hydrophilic poly­(sarcosine) (A block) chains, a hydrophobic helical dodecapeptide (B block), and two histidine (His) residues between the A₃ and B blocks. The A₃B-type peptide adopted morphologies of the twisted ribbon at pH 3.0, the helical ribbon at pH 5.0, and the nanotube at pH 7.4, depending upon the protonation states of the two His residues. On the other hand, another A₃B-type peptide having one His residue between the A₃ and B blocks showed a morphology change only between the helical ribbon and the relatively planar sheets with pH variation in this range. The morphology change is thus induced by one- or two-charge generation at the linking site of the hydrophilic and hydrophobic blocks of the component amphiphiles but in different ways

Self-Assemblies of Triskelion A₂B-Type Amphiphilic Polypeptide Showing pH-Responsive Morphology Transformation

A pH-responsive rolled-sheet morphology was prepared from a triskelion A₂B-type amphiphilic polypeptide having a histidine residue as a pH-responsive unit. The dimensions of the rolled sheet were 85 nm diameter and 210 nm length with a sheet turn number of 2.0 at pH 7.4. Upon decreasing the pH from 7.4 to 5.0, the layer spacing of the rolled sheets was widened from ca. 9 to ca. 19 nm due to electrostatic repulsion caused by histidine protonation. This morphology change occurred reversibly with a pH change between 7.4 and 5.0. The molecular packing in the rolled sheets was shown to be loosened at pH 5.0 on the basis of electron diffraction measurements. The tightness of the rolled sheets was thus controlled reversibly by a pH change due to a single protonation in the amphiphilic polypeptide

Enzymatic Polymerization to Novel Polysaccharides Having a Glucose-<i>N</i>-acetylglucosamine Repeating Unit, a Cellulose−Chitin Hybrid Polysaccharide

A cellulose−chitin hybrid polysaccharide having alternatingly β(1→4)-linked d-glucose (Glc) and N-acetyl-d-glucosamine (GlcNAc) was synthesized via two modes of enzymatic polymerization. First, a sugar oxazoline monomer of Glcβ(1→4)GlcNAc (1) was designed as a transition-state analogue substrate (TSAS) monomer for chitinase catalysis. Monomer 1 was recognized by chitinase from Bacillus sp., giving rise to a cellulose−chitin hybrid polysaccharide (2) via ring-opening polyaddition with perfect regioselectivity and stereochemistry. Molecular weight (Mn) of 2 reached 4030, which corresponds to 22 saccharide units. Second, a sugar fluoride monomer of GlcNAcβ(1→4)Glc (3) was synthesized for the catalysis of cellulase from Trichoderma viride. The enzyme catalyzed polycondensation of 3, providing a cellulose−chitin hybrid polysaccharide (4) in regio- and stereoselective manner. Mn of 4 reached 2840, which corresponds to 16 saccharide units. X-ray diffraction measurements revealed that these hybrid polysaccharides did not form any characteristic crystalline structures. Furthermore, these unnatural hybrids of 2 and 4 were successfully digested by lysozyme from human neutrophils

Kaplan-Meier curves of progression-free survival (PFS) (a) and cause-specific survival (CSS) (b) in patients with HNC.

<p>Two groups with the accumulation of large (> 8.1, dotted lines) and small (≤ 8.1, solid lines) volumes of ¹⁸F-FDG were determined by metabolic-tumor-volume (MTV), one of the volume-based metabolic parameters. The two groups showed significant differences in PFS (<i>p</i> = 0.03) and CSS (<i>p</i> = 0.03). Three-year PFS and CSS rates were 70% and 73% for patients with a smaller metabolic volume (MTV ≤ 8.1), and 30% and 37% for those with a larger metabolic volume (MTV > 8.1), respectively.</p

Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for treating non-small-cell lung cancer (NSCLC) with EGFR mutations. Genetic testing is required to detect the mutation for selecting patients who can use osimertinib. Here, we report an attempt to develop nuclear imaging probes that detect the EGFR mutations. We designed and synthesized I-osimertinib and Br-osimertinib with a radioactive or nonradioactive halogen atom at an indole ring in osimertinib and evaluated them. In vitro assays suggested that both I-osimertinib and Br-osimertinib exhibit a specifically high activity toward NSCLC with EGFR L858R/T790M mutations. In biodistribution experiments, the accumulation of both [125I]­I-osimertinib and [77Br]­Br-osimertinib in tumors with mutations was significantly higher than that in blood and muscle. However, these osimertinib derivatives showed a significantly higher accumulation in lungs than in tumors. Therefore, for detecting the mutations in lung cancer, further structural modifications of the probes are required

Cu(II)-ATSM and fluorinated nitroimidazole (FR-NO₂) retention mechanisms in cancer cells.

<p>During the course of tracer retention in cancer cells, key factors are shown in red for both Cu(II)-ATSM and fluorinated nitroimidazole (FR-NO₂). Cu(II)-ATSM is a neutral lipophilic molecule that easily penetrates cell membranes. In cancer cells over-reduced due to mitochondrial dysfunction and hypoxia, Cu(II)-ATSM may be converted to [Cu(I)-ATSM]^- with electrons (e^-) supplied from abnormally reduced mitochondria in a number of forms including NADH and NADPH, and retained in cells because of its negative charge. Cu(I) is subsequently dissociated by reactive chemical species (RS) generated in the reduced condition and is irreversibly trapped as Cu(I)-RS in cells. FR-NO₂ pass through cell membranes by slow diffusion and may be converted to a reduced form, FR-NO₂^-, by xanthine oxidoreductase. Under hypoxic conditions (low pO₂), FR-NO₂^- may be reduced further by intracellular reductases in a low oxygen concentration-dependent manner to R-NH₂, which binds covalently to macromolecules in cancer cells.</p

PET images of ⁶²Cu-ATSM (a) and ¹⁸F-FDG (b) of a 64-year-old man with right parotid cancer.

<p>Tumor contours were delineated to include voxels presenting SUV values greater than 70% SUV_ATSM of 6.9 for ⁶²Cu-ATSM PET and 40% SUV_FDG of 8.8 for ¹⁸F-FDG PET. Volume-based parameters were calculated as follows; RTV = 5.9, MTV = 6.3, TLR = 32.0, and TLG = 30.0. He developed iliac bone metastasis 15 months after being treated (CRT + SO). The volume-based redox parameters, RTV and TLR, which were greater than each cut-off value (RTV: 2.9 and TLR: 14.0, respectively), correctly predicted his outcome. On the other hand, volume-based metabolic indices were smaller than each cut-off value.</p