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Background & objectives: For improved male contraception, a new polymeric drug molecule - Reversible Inhibition of Sperm under Guidance (RISUG) has been synthesized and has been found to be effective, safe and reversible in various animal species. Phase-I and phase-II clinical trials have confirmed its safety and contraceptive efficacy. The present study was undertaken as a multicentric-limited phase-III clinical trial to test the efficacy and safety of RISUG in human volunteers. Methods: One hundred and thirty nine young males each having at least two children and living with wife were given 120 μl of RISUG as bilateral vas intraluminal injection. After the single-dose administration, the individuals were followed in respect of general health and semen parameters. Their wives were also followed particularly to determine onset of pregnancy. Results: During the six month follow up, the health of male volunteers and their wives was normal with no significant adverse effects. Temporary scrotal enlargement and mild scrotal and inguinal region pain were manifested in most individuals and resolved within one month without any routine activity impairment. In six individuals, there was injection procedure failure and azoospermia was not achieved. The other 133 individuals had either severe oligozoospermia or azoospermia at the first semen examination one month following RISUG injection; 82.7 per cent individuals had continued azoospermia in the month following first semen examination onwards and the rest 17.3 per cent manifested azoospermia within three to six months. Interpretation & conclusions: RISUG intravasal injection appears to be a safe clinical procedure with no significant adverse effects and has high sustained contraceptive efficacy. The localized intervention and continued contraceptive action on single-dose administration were significant features of the RISUG technology.

Hyperkalemia is a potentially life-threatening condition that patients with heart failure or chronic kidney disease, especially those taking renin-angiotensin-aldosterone system inhibitors, are at high risk of developing. Sodium polystyrene sulfonate (SPS), a current treatment, binds potassium within the gastrointestinal tract to reduce potassium absorption. However, poor palatability limits its long-term use. RDX7675, a novel potassium binder in development for the treatment of hyperkalemia, is a calcium salt of a reengineered polystyrene sulfonate-based resin designed to have enhanced palatability. Here, the physical properties and palatability of RDX7675 and SPS are compared. RDX7675 and SPS particle sizes were measured using wet dispersion laser diffraction. Palatability was assessed in a randomized, crossover, healthy volunteer study with two visits. At visit 1 (open label), volunteers evaluated high-viscosity, intermediate-viscosity, and water-reconstituted formulations of RDX7675 (all vanilla flavor), and an equivalent reconstituted SPS (Resonium A ). At visit 2 (single-blind), volunteers evaluated RDX7675 as a high-viscosity formulation in vanilla, citrus, and mint flavors, and as intermediate-viscosity, low-viscosity, and reconstituted formulations in citrus flavor. Volunteers used a \"sip and spit\" technique to rate overall acceptability and seven individual characteristics from 1 (\"dislike everything\") to 9 (\"like extremely\"). RDX7675 particles were smaller than SPS particles, with a narrower size range (RDX7675, 80%, 14-52 µm; SPS, 11.3-124.2 µm), and had a smooth, spherical shape, in contrast to the shard-like SPS particles. Reconstituted RDX7675 was considered superior to SPS for five of the seven palatability characteristics and for overall acceptability (median, visit 1: reconstituted RDX7675, 5.0; SPS, 4.0). High-viscosity vanilla was the most highly rated RDX7675 formulation (median overall acceptability, visit 2: 7.0). The smaller, more uniformly shaped, spherical particles of RDX7675 resulted in improved palatability over SPS when reconstituted in water. The overall results are promising for future patient acceptability of RDX7675 treatment.

Evidence exists that humans are exposed to plastic microparticles via diet. Data on intestinal particle uptake and health-related effects resulting from microplastic exposure are scarce. Aim of the study was to analyze the uptake and effects of microplastic particles in human in vitro systems and in rodents in vivo. The gastrointestinal uptake of microplastics was studied in vitro using the human intestinal epithelial cell line Caco-2 and thereof-derived co-cultures mimicking intestinal M-cells and goblet cells. Different sizes of spherical fluorescent polystyrene (PS) particles (1, 4 and 10 µm) were used to study particle uptake and transport. A 28-days in vivo feeding study was conducted to analyze transport at the intestinal epithelium and oxidative stress response as a potential consequence of microplastic exposure. Male reporter gene mice were treated three times per week by oral gavage with a mixture of 1 µm (4.55 × 107 particles), 4 µm (4.55 × 107 particles) and 10 µm (1.49 × 106 particles) microplastics at a volume of 10 mL/kg/bw. Effects of particles on macrophage polarization were investigated using the human cell line THP-1 to detect a possible impact on intestinal immune cells. Altogether, the results of the study demonstrate the cellular uptake of a minor fraction of particles. In vivo data show the absence of histologically detectable lesions and inflammatory responses. The particles did not interfere with the differentiation and activation of the human macrophage model. The present results suggest that oral exposure to PS microplastic particles under the chosen experimental conditions does not pose relevant acute health risks to mammals.

Nanoplastics (NPs) pose health concerns worldwide. However, robust quantitative data on their absorption, distribution, and excretion in mammals remain scarce. Here, we provide a comprehensive assessment of polystyrene (PS) NP biodistribution and elimination in rats using 14 C-radiolabeling, the most accurate and quantitative method available. Pregnant rats were exposed to 14 C-labeled 20 nm or 100 nm PS NPs (PS 20 or PS 100 ) via oral gavage, intratracheal aerosolization, or intravenous injection, and tissue distribution and excretion were determined by radioactivity measurements. We found that PS NPs were exclusively excreted through faeces, irrespective of the exposure routes, without urinary elimination. Both PS 20 and PS 100 crossed multiple biological barriers, yet only PS 20 reached the brain. Maternal transfer of PS 20 occurred through both placenta and milk, while PS 100 transferred solely via milk. A physiologically based toxicokinetic model further simulated accumulation kinetics across tissues. This study establishes the most comprehensive and reliable quantitative profile of PS NP biodistribution in mammals to date, revealing distinct size-dependent translocation patterns that provide a robust foundation for evaluating their health impacts. Previous studies on biodistribution of microplastics showed discrepancies. This study provides quantitative data to date on how nanoplastics distribute and eliminate from the body using carbon-14-radiolabelled particles in rats.

Immunotherapy is emerging as one of the most effective methods for treating many cancers. However, immunotherapy can still introduce significant off-target toxicity, and methods are sought to enable targeted immunotherapy at tumor sites. Here, we show that relatively large (>100-nm) anionic nanoparticles administered intraperitoneally (i.p.) selectively accumulate in tumor-associated macrophages (TAMs). In a mouse model of metastatic ovarian cancer, fluorescently labeled silica, poly(lactic-co-glycolic acid), and polystyrene nanoparticles administered i.p. were all found to selectively accumulate in TAMs. Quantifying silica particle uptake indicated that >80% of the injected dose was in TAMs. Particles that were smaller than 100 nm or cationic or administered intravenously (i.v.) showed no TAM targeting. Moreover, this phenomenon is likely to occur in humans because when freshly excised human surgical samples were treated with the fluorescent silica nanoparticles no interaction with healthy tissue was seen but selective uptake by TAMs was seen in 13 different patient samples. Ovarian cancer is a deadly disease that afflicts ∼22,000 women per year in the United States, and the presence of immunosuppressive TAMs at tumors is correlated with decreased survival. The ability to selectively target TAMs opens the door to targeted immunotherapy for ovarian cancer.

Nanoparticles represent an attractive option for systemic delivery of therapeutic compounds to the heart following myocardial infarction. However, it is well known that physicochemical properties of nanoparticles such as size, shape and surface modifications can vastly alter the distribution and uptake of injected nanoparticles. Therefore, we aimed to provide an examination of the rapid size-dependent uptake of fluorescent PEG-modified polystyrene nanoparticles administered immediately following cardiac ischaemia-reperfusion injury in mice. By assessing the biodistribution of nanoparticles with core diameters between 20 nm and 2 μm 30 minutes after their administration, we conclude that 20–200 nm diameter nanoparticles are optimal for passive targeting of the injured left ventricle.

Background Microplastics have been repeatedly detected in the human body, yet uncertainties surround their bioavailability and fate due to experimental challenges and limitations, especially regarding their nano-sized counterparts. Knowing that toxicokinetics information is essential for accurate risk assessment and management, this research aimed to (1) evaluate different sample preparation and quantification methods for nanoplastics particles in mammalian tissue, and (2) investigate the lung retention, bioavailability and fate of these particles. Methods In this study, rats inhaled aerosols with up to 50 mg/m 3 of Nile Red-labeled polystyrene (PS-NR) or unlabeled polyamide particles (PA-6) particles for 28 days. The tissues were analyzed for the presence of polymer particles. PS-NR were quantified in formalin-fixed tissue by confocal fluorescence laser microscopy with semi-automatic imaging analysis, and PA-6 particles were quantified in dried tissues by pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS). Results PA-6 deposition was detected and quantified in lung and lymph nodes. Deposition of PS-NR was quantified in lungs and lung-draining lymph nodes, but no particles were detected in the liver, spleen, and kidneys. The lung burdens and translocation to the draining lymph nodes were similar for both particles, and particles were still detectable after the end of the exposure periods (five weeks for PS-NR and 13 weeks for PA-6). Conclusions This work highlights limitations and applicability of the various methods for sample preparation, detecting and quantifying polymer particles in mammalian tissues. In addition, it provides reliable data on the internal dose of inhaled polymer particles. Graphical Abstract

Cerebrospinal fluid (CSF) is produced in the cerebral ventricles and circulates within the subarachnoid space (SAS) of the brain and spinal cord, where it exchanges with interstitial fluid of the parenchyma. The access of CSF to the entire central nervous system (CNS) makes it an attractive medium for drug delivery. However, few intrathecal (IT) therapies have reached the clinic due, in part, to limited distribution and rapid clearance. Given the success of nanoparticle (NP) carriers in prolonging circulation and improving delivery of systemically administered agents, we sought to evaluate the distribution of IT injected NPs within the CNS. We administered fluorescent, 100 nm PEGylated-NPs into the cisterna magna of healthy mice and studied their distribution along the brain and spinal cord. Our data demonstrate that NPs are capable of distributing rapidly through the SAS along the entire neuraxis with reproducible, anatomically defined patterns of delivery. NPs were well retained within the leptomeninges for over 3 weeks, showing preference for ventral surfaces and minimal penetration into the CNS parenchyma. Clearance of NPs occurred across the cribriform plate into the nasal mucosa, with a small fraction of NPs localizing with nerve roots exiting the spinal column. Larger 10 µm particles were also capable of moving through the SAS but did not achieve as widespread distribution. These studies demonstrate the ability of NPs to achieve widespread delivery along the neuraxis and highlight IT administration as a potentially significant route of administration for delivery of nanomedicine to the subarachnoid space.

Objectives: Microplastics have been detected in the atmosphere, raising concerns about their impact on the lungs. There have been reports on the effects of surface functional groups in evaluating the physicochemical properties of microplastics, but no reports have evaluated their chronic effects. We performed intratracheal instillation in rats to evaluate the acute and chronic effects on the lungs of microplastics with different surface functional groups.Methods: Unmodified, NH2-modified, and COOH-modified polystyrene particles with a particle size of 1 μm were intratracheally instilled into the lungs of rats. Rats were dissected at 3 days, 1 week, 1 month, 3 months, and 6 months after exposure to analyze inflammatory cells and lung injury factors in bronchoalveolar lavage fluid (BALF) and to observe histopathological findings in the lungs.Results: A significant increase in the number of inflammatory cells in BALF was observed up to 1 week after exposure to the NH2-based modified polystyrene compared with the negative control group. A significant increase was observed 3 days after exposure, and histopathological findings in the lungs also showed an influx of inflammatory cells into the alveolar space in the acute phase, but not in the chronic phase. In in vitro studies using RAW cell lines, NH2-based modified polystyrene also induced the highest oxidative stress compared with unmodified and COOH-based modified polystyrene.Conclusions: These results suggest that these polystyrenes do not have high pulmonary toxicity, although there are differences in toxicity due to differences in surface functional groups only in the acute phase.

The use of engineered nanoparticles in food and pharmaceuticals is expected to increase, but the impact of chronic oral exposure to nanoparticles on human health remains unknown. Here, we show that chronic and acute oral exposure to polystyrene nanoparticles can influence iron uptake and iron transport in an in vitro model of the intestinal epithelium and an in vivo chicken intestinal loop model. Intestinal cells that are exposed to high doses of nanoparticles showed increased iron transport due to nanoparticle disruption of the cell membrane. Chickens acutely exposed to carboxylated particles (50 nm in diameter) had a lower iron absorption than unexposed or chronically exposed birds. Chronic exposure caused remodelling of the intestinal villi, which increased the surface area available for iron absorption. The agreement between the in vitro and in vivo results suggests that our in vitro intestinal epithelium model is potentially useful for toxicology studies. Chickens acutely exposed to polystyrene nanoparticles are less efficient at absorbing iron across the epithelial cells of their intestines than chickens chronically exposed and those that are not exposed at all.