Upper Critical Solution Temperature Polymer, Photothermal Agent, and Erythrocyte Membrane Coating: An Unexplored Recipe for Making Drug Carriers with Spatiotemporally Controlled Cargo Release

“On-demand” drug release within target site is critical for targeted drug delivery systems. We herein integrate the advantages of upper critical solution temperature (UCST) polymers, photothermal agent, and red blood cell (RBC) membrane coating into a single drug delivery nanosystem and, for the first time, achieve remotely controlled UCST polymer-based drug delivery system that undergoes “on-demand” drug release within specified zone. When in laser-off state, the resulting nanosystem demonstrates significantly diminished drug self-leakage, owing to shielding by the RBC membrane coating. Upon laser irradiation, this system undergoes responsive drug release, likely because of particle swelling due to its UCST polymer component’s hydrophobic-to-hydrophilic transition triggered by the rapid localized heating generated by its preloaded photothermal agent via photothermal effects. As a result, this drug delivery system exhibits spatiotemporally controlled cytotoxicity to cultured cells, efficiently eradicating irradiated cancerous cells without appreciably impacting nonirradiated ones, those ∼0.7 cm away from the irradiation zone. This work may open an avenue to thermosensitive drug delivery systems potentially “ideal” for intravenous administration and inspire future efforts on biomedical applications of UCST polymers

Acid-Responsive Therapeutic Polymer for Prolonging Nanoparticle Circulation Lifetime and Destroying Drug-Resistant Tumors

How to destroy drug-resistant tumor cells remains an ongoing challenge for cancer treatment. We herein report on a therapeutic nanoparticle, aHLP-PDA, which has an acid-activated hemolytic polymer (aHLP) grafted onto photothermal polydopamine (PDA) nanosphere via boronate ester bond, in efforts to ablate drug-resistant tumors. Upon exposure to oxidative stress and/or near-infrared laser irradiation, aHLP-PDA nanoparticle responsively releases aHLP, likely via responsive cleavage of boronate ester bond, and thus responsively exhibits acid-facilitated mammalian-membrane-disruptive activity. <i>In vitro</i> cell studies with drug-resistant and/or thermo-tolerant cancer cells show that the aHLP-PDA nanoparticle demonstrates preferential cytotoxicity at acidic pH over physiological pH. When administered intravenously, the aHLP-PDA nanoparticle exhibits significantly prolonged blood circulation lifetime and enhanced tumor uptake compared to bare PDA nanosphere, likely owing to aHLP’s stealth effects conferred by its zwitterionic nature at blood pH. As a result, the aHLP-PDA nanoparticle effectively ablates drug-resistant tumors, leading to 100% mouse survival even on the 32nd day after suspension of photothermal treatment, as demonstrated with the mouse model. This work suggests that a combination of nanotechnology with lessons learned in bacterial antibiotic resistance may offer a feasible and effective strategy for treating drug-resistant cancers often found in relapsing patients

Contributions of Abiotic and Biotic Processes to the Aerobic Removal of Phenolic Endocrine-Disrupting Chemicals in a Simulated Estuarine Aquatic Environment

The contributions of abiotic and biotic processes in an estuarine aquatic environment to the removal of four phenolic endocrine-disrupting chemicals (EDCs) were evaluated through simulated batch reactors containing water-only or water-sediment collected from an estuary in South China. More than 90% of the free forms of all four spiked EDCs were removed from these reactors at the end of 28 days under aerobic conditions, with the half-life of 17α-ethynylestradiol (EE₂) longer than those of propylparaben (PP), nonylphenol (NP) and 17β-estradiol (E₂). The interaction with dissolved oxygen contributed to NP removal and was enhanced by aeration. The PP and E₂ removal was positively influenced by adsorption on suspended particles initially, whereas abiotic transformation by estuarine-dissolved matter contributed to their complete removal. Biotic processes, including degradation by active aquatic microorganisms, had significant effects on the removal of EE₂. Sedimentary inorganic and organic matter posed a positive effect only when EE₂ biodegradation was inhibited. Estrone (E₁), the oxidizing product of E₂, was detected, proving that E₂ was removed by the naturally occurring oxidizers in the estuarine water matrixes. These results revealed that the estuarine aquatic environment was effective in removing free EDCs, and the contributions of abiotic and biotic processes to their removal were compound specific

Acid-Activated Antimicrobial Random Copolymers: A Mechanism-Guided Design of Antimicrobial Peptide Mimics

How to reduce the off-target adverse effects during antimicrobial administration remains an ongoing challenge. We show a mechanism-guided design of acid-activated antimicrobial peptide mimics (aSMAMPs) that have antibacterial activity triggered by acidic pH, a factor associated with many infected conditions. The cationicity of membrane-active antimicrobials is known to facilitate activity. By reinforcing a membrane-active antimicrobial random copolymer with an extra pH-responsive monomer, we obtain aSMAMP that is net neutral at physiological pH but net cationic at acidic pH. Plate killing assays indicate that Escherichia coli cells at pH 5.0 rather than those at pH 7.4 are susceptible to such aSMAMPs, whereas the opposite is true when challenged with conventional metabolic antibiotics. Comparison between the aSMAMPs and one homologue that is cationic at both pH conditions suggests that the acid-triggered antibacterial activity of aSMAMPs may be attributed to their pH-tunable net cationicity. At normal blood pH, these aSMAMPs demonstrate greatly diminished hemolytic toxicity against human erythrocytes. Taken together, such aSMAMPs show that switching on-or-off the cationic motif of a membrane-active antimicrobial via pH offers a feasible approach toward “smart” antimicrobials with activity triggered by acidic pH associated with many infected conditions, which may have implications in reducing the off-target adverse effects on both microbiota and host cells during antimicrobial administration

Photoelectrochemical Performance of Multiple Semiconductors (CdS/CdSe/ZnS) Cosensitized TiO₂ Photoelectrodes

The morphology of TiO₂ nanotubes with nanowires directly formed on top (designed as TiO₂ NTWs) would be a promising nanostructure in fabricating photoelectrochemical solar cells for its advantages in charge separation, electronic transport, and light harvesting. In this study, a TiO₂ NTWs array film was prepared by a simple anodization method. The formation of CdS, CdSe, and ZnS quantum dots (QDs) sensitized TiO₂ NTWs photoelectrode was carried out by successive ionic layer adsorption. The as-prepared materials were characterized by scanning electron microscopy, high-resolution transmission electron microscopy, and X-ray diffraction. Our results indicate that the nanocrystals have effectively covered both inner and outer surfaces of TiO₂ NTWs array. The interfacial structure of QDs/TiO₂ was also investigated for the first time in our experiment, and the growth interface when annealed to 300 °C was verified. Under AM 1.5G illumination, we found the photoelectrodes have an optimum short-circuit photocurrent density of 4.30 mA/cm² and corresponding energy conversation efficiency of 2.408%, which is 28 times higher than that of a bare TiO₂ NTWs array. The excellent photoelectrochemical properties of our photoanodes suggest that the TiO₂ NTWs array films (2.6–2.8 μm) cosensitized by CdS, CdSe, and ZnS nanoclusters have potential applications in solar cells

Cooperative Nanoparticle System for Photothermal Tumor Treatment without Skin Damage

How to ablate tumors without using skin-harmful high laser irradiance remains an ongoing challenge for photothermal therapy. Here, we achieve this with a cooperative nanosystem consisting of gold nanocage (AuNC) “activator” and a cationic mammalian-membrane-disruptive peptide, cTL, as photothermal antenna and anticancer agent, respectively. Specifically, this nanosystem is prepared by grafting cTL onto AuNC via a Au–S bond, followed by attachment of thiolated polyethylene glycol (PEG) for stealth effects. Upon NIR irradiation at skin-permissible dosage, the resulting cTL/PEG-AuNC nanoparticle effectively ablates both irradiated and nonirradiated cancer cells, likely owing to cTL being responsively unleashed by intracellular thiols exposed to cTL/PEG-AuNC via membrane damage initiated by AuNC’s photothermal effects and deteriorated by the as-released cTL. When administered systematically in a mouse model, cTL/PEG-AuNC populates tumors through their porous vessels and effectively destroys them without damaging skin

Surface Disinfection Enabled by a Layer-by-Layer Thin Film of Polyelectrolyte-Stabilized Reduced Graphene Oxide upon Solar Near-Infrared Irradiation

We report an antibacterial surface that kills airborne bacteria on contact upon minutes of solar near-infrared (NIR) irradiation. This antibacterial surface employs reduced graphene oxide (rGO), a well-known near-infrared photothermal conversion agent, as the photosensitizer and is prepared by assembling oppositely charged polyelectrolyte-stabilized rGO sheets (PEL-rGO) on a quartz substrate with the layer-by-layer (LBL) technique. Upon solar irradiation, the resulting PEL-rGO LBL multilayer efficiently generates rapid localized heating and, within minutes, kills >90% airborne bacteria, including antibiotic-tolerant persisters, on contact, likely by permeabilizing their cellular membranes. The observed activity is retained even when the PEL-rGO LBL multilayer is placed underneath a piece of 3 mm thick pork tissue, indicating that solar light in the near-infrared region plays dominant roles in the observed activity. This work may pave the way toward NIR-light-activated antibacterial surfaces, and our PEL-rGO LBL multilayer may be a novel surface coating material for conveniently disinfecting biomedical implants and common objects touched by people in daily life in the looming postantibiotic era with only minutes of solar exposure

MOESM1 of In vitro chemokine (C-C motif) receptor 6-dependent non-inflammatory chemotaxis during spermatogenesis

Additional file 1: Figure S1. Expression of CCR6 in normal adult human testis. Representative western blot results showing the expression of CCR6 in normal adult human testis (n = 5). β-Tubulin was used as loading control

<i>DAX-1</i> mutations and SNPs identified in the secretory azoospermia patients and controls.

<p><i>DAX-1</i> mutations and SNPs identified in the secretory azoospermia patients and controls.</p

Six missense mutations in <i>DAX-1</i> identified in patients with secretory azoospermia.

<p>(A) Chromatogram traces from Sanger sequencing, showing the validated missense mutations. (B) Evolutionary conservation of amino acids affected by the missense mutations. Multiple protein alignments were performed with MegAlign (Demonstration System DNASTAR, Inc.). The identification numbers of the DAX-1 protein were as follows: human (NP_000466.2), chimpanzee (XP_520991.2), rhesus (XP_002806222.1), pig (NP_999552.1), rat (NP_445769.1), mouse (NP_031456.1), chicken (NP_989924.1), and Medaka fish (NP_001104259.1). The mutant alleles are boxed, and the star (*) indicates the conserved residue.</p