Skeletal muscle involvement in systemic amyloidosis is often overlooked.

AIM: Systemic amyloidosis is a condition in which misfolded amyloid fibrils are deposited within tissues. Amyloid myopathy is a rare manifestation of systemic amyloidosis. However, whether skeletal muscle involvement is underestimated and whether such deposition guarantees clinical and pathological myopathic features remain to be investigated. METHODS: We retrospectively reviewed patients with systemic amyloidosis, in whom skeletal muscle biopsies were performed at our centre between January 2018 and June 2023. In total, 28 patients with suspected systemic amyloidosis were included. Among these, 21 presented with cardiomyopathy but lacked myopathic symptoms. The clinical and pathological data of these patients were further analysed. The amyloid type was confirmed by immunohistochemistry. RESULTS: Twenty-eight patients with suspected systemic amyloidosis underwent muscle biopsy. Amyloid deposition in the skeletal muscle was confirmed in 24 patients, including 22 with light-chain amyloidosis (AL) and two with transthyretin amyloidosis (ATTR). Among the 24 patients, seven presented with muscle weakness and decreased muscle strength (Group 1, symptomatic myopathy), whereas the remaining 17 exhibited normal muscle strength (Group 2, asymptomatic myopathy). Group 1 included four patients with AL-λ, one with AL-κ and two with ATTR. Group 2 included 15 patients with AL-λ and two patients with AL-κ. In Group 1, six patients exhibited neuropathy, whereas only one patient in Group 2 presented with subclinical neuropathy on nerve conduction studies. Amyloid deposition in the interstitium was the most obvious change, observed in all 24 patients. Neuropathic changes, including denervation atrophy and muscle fibre grouping, were also common. Except for type 2 fibre atrophy, the other myopathic changes were mild and nonspecific. No sarcolemmal disruption was observed. Immunohistochemical analysis revealed marked positivity for MAC and MHC1 expression in the regions with amyloid deposits. Clinicopathological analysis revealed no significant differences in the extent of muscular amyloid deposition between the two groups. Nevertheless, patients in Group 1 displayed more pronounced neurogenic atrophy on skeletal muscle biopsies. CONCLUSIONS: Our study indicates that amyloid deposition in skeletal muscle is commonly observed but rarely causes symptomatic myopathy in systemic amyloidosis.

Supersaturation and Precipitation Applicated in Drug Delivery Systems: Development Strategies and Evaluation Approaches.

Supersaturation is a promising strategy to improve gastrointestinal absorption of poorly water-soluble drugs. Supersaturation is a metastable state and therefore dissolved drugs often quickly precipitate again. Precipitation inhibitors can prolong the metastable state. Supersaturating drug delivery systems (SDDS) are commonly formulated with precipitation inhibitors, hence the supersaturation is effectively prolonged for absorption, leading to improved bioavailability. This review summarizes the theory of and systemic insight into supersaturation, with the emphasis on biopharmaceutical aspects. Supersaturation research has developed from the generation of supersaturation (pH-shift, prodrug and SDDS) and the inhibition of precipitation (the mechanism of precipitation, the character of precipitation inhibitors and screening precipitation inhibitors). Then, the evaluation approaches to SDDS are discussed, including in vitro, in vivo and in silico studies and in vitro-in vivo correlations. In vitro aspects involve biorelevant medium, biomimetic apparatus and characterization instruments; in vivo aspects involve oral absorption, intestinal perfusion and intestinal content aspiration and in silico aspects involve molecular dynamics simulation and pharmacokinetic simulation. More physiological data of in vitro studies should be taken into account to simulate the in vivo environment. The supersaturation theory should be further completed, especially with regard to physiological conditions.

Sodium hyaluronates applied in the face affects the diversity of skin microbiota in healthy people.

OBJECTIVE: A healthy and stable microbiome has many beneficial effects on the host, while an unbalanced or disordered microbiome can lead to various skin diseases. Hyaluronic acid is widely used in the cosmetics and pharmaceutical industries; however, specific reports on its effect on the skin microflora of healthy people have not been published. This study aimed to determine the effect of sodium hyaluronate on the facial microflora of healthy individuals. METHODS: Face of 20 healthy female volunteers between 18 and 24 years was smeared with sodium hyaluronate solution once per day. Cotton swabs were used to retrieve samples on days 0, 14, and 28, and high-throughput sequencing of 16 S rRNA was used to determine the changes in bacterial community composition. RESULTS: Facial application of HA can reduce the abundance of pathogenic bacteria, such as Cutibacterium and S. aureus, and increase the colonization of beneficial bacteria. CONCLUSION: This is the first intuitive report to demonstrate the effect of hyaluronic acid on facial microflora in healthy people. Accordingly, sodium hyaluronate was found to have a positive effect on facial skin health.

A Triptycene-Based 2D MOF with Vertically Extended Structure for Improving the Electrocatalytic Performance of CO2 to Methane.

Two-dimensional conductive metal-organic frameworks (2D-c-MOFs) have attracted extensive attention owing to their unique structures and physical-chemical properties. However, the planarly extended structure of 2D-c-MOFs usually limited the accessibility of the active sites. Herein, we designed a triptycene-based 2D vertically conductive MOF (2D-vc-MOF) by coordinating 2,3,6,7,14,15-hexahydroxyltriptycene (HHTC) with Cu2+ . The vertically extended 2D-vc-MOF(Cu) possesses a weak interlayer interaction, which leads to a facile exfoliation to the nanosheet. Compared with the classical 2D-c-MOFs with planarly extended 2D structures, 2D-vc-MOF(Cu) exhibits a 100 % increased catalytic activity in terms of turnover number and a two-fold increased selectivity. Density functional theory (DFT) calculations further revealed that higher activity originated from the lower energy barriers of the vertically extended 2D structures during the CO2 reduction reaction process.

Oxybutynin nanosuspension gel for enhanced transdermal treatment for overactive bladder syndrome.

Oxybutynin (OXY) is the most common drug to treat overactive bladder (OAB) syndrome. Transdermal administration is a more ideal route replacing oral administration to resolve problems of low bioavailability and severe side effects. However, commercial transdermal products of OXY frequently cause skin irritation and low permeation efficiency arising discontinued medication. Here, oxybutynin nanosuspension (OXY-NS) and its gel preparation (OXY-NG) were constructed to resolve these issues. In vitro permeation test and in vivo pharmacokinetics study confirmed that OXY-NG significantly enhanced the transdermal permeation of OXY, about 4-fold and 3-fold higher than oxybutynin coarse suspension (OXY-CG), respectively, and in vitro retention test certified that OXY-NG increased OXY concentration especially in viable epidermis (VE) and Dermis (about 3 times that of OXY-CG), consequently improving the bioavailability. Skin irritation assay demonstrated that OXY-NG would not trigger skin adverse effects. In addition, selectively blocking hair follicles test evidenced that hair follicles pathway played an important role in OXY-NS transdermal delivery. In general, by virtue of excellent drug loading, low toxicity and ease of scale-up, OXY-NG is a promising strategy to ameliorate skin permeation of insoluble OXY for better transdermal treatment for OAB, hence increasing its bioavailability, reducing adverse effects, and achieving good patient compliance.

mPEG-Cholic acid/TPGS mixed micelles for combined delivery of paclitaxel and bufalin to treat hepatocellular carcinoma.

In this study, amphiphilic block copolymer mPEG-cholic acid was synthesized in conjunction with TPGS as stabilizer to prepare multifunctional micelles. The formed polymeric micelles (PCTm) were used for the delivery of paclitaxel (PTX) and bufalin (BF). PEG group could enhance solubility and extend circulation time, while cholic acid groups achieved the liver targeted function. Combinations of these approaches could realize a synergistic therapeutic effect in the treatment of advanced hepatocellular carcinoma. CLSM in vitro results demonstrated that drug capsulation into PCTm could enhance cellular uptake. FCM results confirmed the uptake amount of C6/PCTm was 7.5-fold higher than that of free C6 after incubation for 2 h. Competitive inhibition test proved the Na+-taurocholate co-transporting polypeptide (NTCP) involved in the uptake mechanism of PCTm. Meanwhile, in vivo imaging assays demonstrated that the fluorescence intensity of Cy5.5/PCTm was higher than that of free Cy5.5 on liver and tumor with extended circulation time to 48 h. In addition, in vivo studies confirmed that the combined therapy exhibited the strongest tumor inhibition rate of 82.29% with lower systemic toxicity. Hence, these results indicated that PCTm could provide a promising strategy for targeting hepatocellular carcinoma and achieve the goal of synergism and attenuation.

Preparation and Characterization of Honokiol Nanosuspensions and Preliminary Evaluation of Anti-Inflammatory Effect.

The study mainly aimed to improve the solubility of honokiol (HK) by preparing honokiol nanosuspensions (HNS). In this study, HNS were obtained using Kolliphor®P407 (P407) as a stabilizer through melting method combined with high pressure homogenization (HPH). The crystalline state of HNS was confirmed through differential scanning calorimetry (DSC) and X-ray Diffraction (XRD). In vitro, the dissolution rate of HNS was significantly improved than that of pure HK. In vivo, higher anti-inflammatory activity was achieved after free HK had been made into HNS. There was no significant difference between the degree of edema (DE) of HNS group and that of aspirin group. Consequently, melting method combined with HPH was a potent technique to prepare HNS. Furthermore, nanosuspension was a valid formulation that could be utilized to enhance the anti-inflammatory effect of HK.

Impacts of Polymeric Additives on Nucleation and Crystal Growth of Indomethacin from Supersaturated Solutions.

Three polymers, polyvinylpyrrolidone (PVP K30), hydroxypropyl methyl cellulose (HPMC E5), and Kollidone VA64 (PVP-VA64), have been assessed for their impact on the nucleation and crystal growth of indomethacin (IND) from supersaturation solutions. PVP was the most effective inhibitor on IND nucleation among three polymers, but the effect of three polymers on inhibiting nucleation is quite limited when the degree of supersaturation S is higher than about 9. Analysis of the nucleation data by classical nucleation theory model generally afforded good data fitting with the model and showed that addition of polymers may affect the crystal/solution interfacial free energy γ and also the pre-exponential kinetic factor. PVP-VA showed better inhibitory effects on crystal growth of IND when the polymer concentration is high (0.1%, w/w) as reflected by the crystal growth inhibition factor R, and PVP exhibited relatively stronger effects on inhibiting crystal growth at low polymer concentrations (0.005%, w/w). The crystal growth inhibitory effect of polymers should be attributable to the retardation of the surface integration of the drug, and such effect should also be polymer and drug dependent. The enhancement of supersaturation level of IND should be attributable to both nucleation and crystal growth inhibition by polymers. The nucleation and crystal growth rate of α-polymorph IND is higher than that of γ-polymorph, and α-polymorph is the predominant form appeared in supersaturated solutions. A rational selection of the appropriate polymer for specific drug is critical for developing supersaturated drug delivery formulations.

Tyroservatide-TPGS-paclitaxel liposomes: Tyroservatide as a targeting ligand for improving breast cancer treatment.

Tyroservatide (YSV) is a tripeptide that has been approved for clinical testing, as a new anticancer drug. In the current study, YSV-stearic acid (YSV-SA) was inserted into the surface of d-alpha-tocopheryl polyethylene glycol 1000 succinate monoester (TPGS)-modified paclitaxel (PTX) liposomes (TP-Lip) to form YSV-conjugated TP-Lip (TYP-Lip). Both in vivo imaging and in vitro cell uptake analysis indicated that these modifications could increase tumor-targeting and cell uptake of the liposomes. Optimal antitumor effects were achieved via tail vein injections of TYP-Lip in MB-231 tumor-bearing nude mice. Overall, the formed TYP-Lip not only achieved a synergistic anticancer effect through YSV and PTX, but also improved tumor-targeting and exhibited further antitumor capabilities. These results indicated that combining biological (YSV) and chemotherapeutic (PTX) agents is an efficient combinatorial delivery strategy for enhanced tumor targeting and synergistic antitumor effects.

Study of a novel disintegrable oleanolic acid-polyvinylpolypyrrolidone solid dispersion.

Novel solid dispersions of oleanolic acid-polyvinylpolypyrrolidone (OLA-PVPP SDs) were designed and prepared to improve the apparent solubility of drug, as well as to improve the stability, fluidity and compressibility of SDs. Disintegrable OLA-PVPP SDs were then evaluated both in vitro and in vivo. DSC, XRD, IR and SEM analysis proved the formation of OLA-PVPP SD and its amorphous state. The results of fluidity study, moisture absorption test and stability test showed that OLA-PVPP SD with good fluidity and qualified stability was successfully obtained. Meanwhile excellent dissolution rate was achieved for in vitro studies; dissolution test showed that ∼50-75% of OLA was dissolved from SDs within the first 10 min, which is about 10-15 times of free OLA. In vivo study indicated that the formation of solid dispersion could largely improve the absorption of OLA, resulting in a much shorter Tmax (p < .05) and higher Cmax (p < .01) than those of free drug. The AUC0→∞ of OLA-PVPP SDs (1:6) were 155.4 ± 37.24 h·ng/mL compared to the 103.11 ± 26.69 h·ng/mL and 94.92 ± 13.05 h·ng/mL of OLA-PVPP physical mixture (1:6) and free OLA, respectively. These proved PVPP could be a promising carrier of solid dispersions and was industrially feasible alternative carrier in the manufacture of solid dispersions.

Improved solubility and oral bioavailability of apigenin via Soluplus/Pluronic F127 binary mixed micelles system.

The aim of this study was to develop a novel mix micelles system composing of two biocompatible copolymers of Soluplus® and Pluronic F127 to improve the solubility, oral bioavailability of insoluble drug apigenin (AP) as model drug. The AP-loaded mixed micelles (AP-M) were prepared by ethanol thin-film hydration method. The formed optimal formulation of AP-M were provided with small size (178.5 nm) and spherical shape at ratio of 4:1 (Soluplus®:Pluronic F127), as well as increasing solubility of to 5.61 mg/mL in water which was about 3442-fold compared to that of free AP. The entrapment efficiency and drug loading of AP-M were 95.72 and 5.32%, respectively, and a sustained release of AP-M was obtained as in vitro release study indicated. Transcellular transport study showed that the cell uptake of AP was increased in Caco-2 cell transport models. The oral bioavailability of AP-M was 4.03-fold of free AP in SD rats, indicating the mixed micelles of Soluplus® and Pluronic F127 is an industrially feasible drug delivery system to promote insoluble drug oral absorption in the gastrointestinal tract.

[Preparation and in vitro dissolution of magnolol solid dispersion].

In this study, solid dispersion system of magnolol in croscarmellose sodium was prepared by using the solvent evaporation method, in order to increase the drug dissolution. And its dissolution behavior, stability and physical characteristics were studied. The solid dispersion was prepared with magnolol and croscarmellose sodium, with the proportion of 1∶5, the in vitro dissolution of magnolol solid dispersion was up to 80.66% at 120 min, which was 6.9 times of magnolol. The results of DSC (differential scanning calorimetry), IR (infra-red) spectrum and SEM (scanning electron microscopy) showed that magnolol existed in solid dispersion in an amorphous form. After an accelerated stability test for six months, the drug dissolution and content in magnolol solid dispersion showed no significant change. So the solid dispersion prepared with croscarmellose sodium as the carrier can remarkably improve the stability and dissolution of magnolol.

Amorphous solid dispersion with increased gastric solubility in tandem with oral disintegrating tablets: a successful approach to improve the bioavailability of atorvastatin.

CONTEXT: Serious efforts have been made to overcome the bioavailability problems of ever increasing number of poorly soluble drugs, including atorvastatin (ATO); however, enhancing its gastric solubility has not received much attention. OBJECTIVES: To improve the bioavailability of ATO by increasing its gastric solubility in a stable oral disintegration tablet (ODT) formulation. MATERIALS AND METHODS: Amorphous solid dispersion (ASD) of ATO with Eudragit® EPO was used as API in ODT formulation. Characterization using Differential scanning calorimetry, Powder X-ray diffraction, Fourier transform infrared drug-polymer interaction simulated by molecular modeling, solubility, dissolution and stability studies together with in vivo evaluation. RESULTS AND DISCUSSION: In ASD there was uniform distribution of drug in the polymer and it retained the amorphous nature without any chemical interactions except the possibility of hydrogen bond formation, with substantially higher gastric solubility. The dissolution profile of the ODT containing ASD was significantly improved >90% within 15 min compared with 25% of plain ATO formulation. In vivo results showed an overall enhancement in the apparent bioavailability (83% and 434% more than Lipitor® and plain amorphous ATO tablets, respectively). Combining the ASD with ODT presents a reliable solution to overcome the low solubility and bioavailability problems of ATO in a simple, robust and cost effective formulation.

N-octyl-N-arginine-chitosan (OACS) micelles for gambogic acid oral delivery: preparation, characterization and its study on in situ intestinal perfusion.

CONTEXT: Gambogic acid (GA) can inhibit the growth of various cancer cells. However, the low bioavailability caused by insolubility, limits its clinical application. L-arginine is always used with GA to form a complex to obtain the higher solubility. Moreover, guanidyl group from arginine, which can facilitate the cellular uptake, was identified. OBJECTIVE: In this study, L-arginine and chitosan (CS) were used for the first time to prepare N-octyl-N-arginine CS (OACS), a novel amphiphilic carrier for GA with solubility- and absorption-enhancing functions; the characterization of the GA loaded OACS micelles (GA-OACS) and its absorption-enhancing effect were also investigated. MATERIALS AND METHODS: GA-OACS were prepared by the dialysis method. The formed micelles were characterized and evaluated by atomic force microscope (AFM), dynamic light scattering, differential scanning calorimeter (DSC), solubility test, in vitro release and in situ intestinal perfusion. RESULTS: The GA-OACS micelles were successfully prepared attaining a 35.3% drug loading and 82.2% entrapment efficiency. GA-OACS had a homogeneous particle size of 160.3 nm; +21.8 mv zeta potential with smooth continuous surface was observed by using AFM. DSC diagram suggested that GA was encapsulated in the micelles. Meanwhile, GA encapsulated in micelles exhibited a desirable slow release in vitro experiment. The solubility of GA in OACS micelles was increased up to 3.16 ± 0.13 mg/mL, 2320 times than that of free GA. The single pass perfusion showed that the absorption of GA-OACS micelles was enhanced 3.6-fold, 2.1-fold and 2.2-fold for jejunum, ileum and colon, respectively. DISCUSSION AND CONCLUSION: OACS provided excellent ability of drug loading, increasing solubility and enhanced absorption for GA, which indicated that OACS micelles as an oral drug delivery carrier may have potential research and application values.

Aqueous solubility and degradation kinetics of the phytochemical anticancer thymoquinone; probing the effects of solvents, pH and light.

Thymoquinone (TQ) is a potent anticancer phytochemical with confirmed in vitro efficacy. Its clinical use has not yet established, and very few reports have documented its formulation. There also are no reports about the aqueous solubility and stability of this valuable drug, despite their direct correlation with the in vivo efficacy. In the current research, we have established and validated a stability-indicating HPLC method for the detection of TQ and its degradation products under different conditions. We then investigated the solubility and stability profiles of TQ in aqueous solutions. The stability study was aimed to determine the effect of pH, solvent type and light on the degradation process of TQ, along with the investigation of the kinetics of this degradation. The solubility of TQ varied in different aqueous solvents, and might be compromised due to stability issues. However, these findings confirm that the aqueous solubility is not the major obstacle for the drug formulations mainly due to the considerable water solubility (>500 µg/mL) that may be enough to exert pharmacologic effects if administered via parenteral route. Stability study results showed a very low stability profile of TQ in all the aqueous solutions with rapid degradation that varied with solvent type. The study of the degradation kinetics showed a significant effect of pH on the degradation process. The process followed first order kinetics at more acidic and alkaline pH values, and second order kinetics at pH 5-7.4, regardless of the solvent type. The results also expressed that light has a greater impact on the stability of TQ as a shorter period of exposure led to severe degradation, independent of the solution pH and solvent type. Our results also addressed some discrepancies in previously published researches regarding the formulation and quantification of TQ with suggested solutions. Overall, the current study concludes that TQ is unstable in aqueous solutions, particularly at an alkaline pH, in addition to presenting severe light sensitivity. This data indicates the inappropriateness of aqueous solutions as pharmaceutical vehicles for TQ preparations. To the best of our knowledge, this is the first study describing TQ aqueous solubility and stability that may lead to the development of a stable and effective TQ formulation.

Sulfated hyaluronic acid gel for the treatment of rheumatoid arthritis in rats.

Rheumatoid arthritis (RA) is a chronic autoimmune disease. NSAIDS, cyclophosphamide and glucocorticoid were commonly used to treat RA in clinical application, which long-term administration of these drugs caused serious adverse reactions. Therefore, sulfated hyaluronic acid (sHA) gel (SG) was prepared to firstly treat the RA and avoid the problem of toxic side effect caused by long-term application. In vitro evaluation showed that sHA inhibited the level of reactive oxygen species and TNF-α, IL-1ß, and IL-6, and decreased the ratio of macrophage M1/M2 type, which exerted better anti-inflammatory capacity. In vivo studies showed that the injection of SG into the joint cavity of collagen-induced rheumatoid arthritis (CIA) rats could effectively treat joint swelling and reduce the level of inflammatory factors in the serum. Immunofluorescence showed that SG exerted its anti-inflammatory activity by decreasing the ratio of M1/M2 type macrophages in synovial tissue. Cartilage tissue sections showed that SG reduced bone erosion and elevated chondrocyte expression. These results confirmed that sHA is expected to be developed as a drug to treat or relieve RA, which could effectively regulate the level of macrophages in rat RA, alleviate the physiological state of inflammatory over-excitation, and improve its anti-inflammatory and antioxidant capacity.

Potential effects of sodium hyaluronate on constipation-predominant irritable bowel syndrome.

Treatment strategies for constipation-predominant irritable bowel syndrome (IBS-C) continue to improve. However, effective drugs are still lacking. Herein, we explored whether sodium hyaluronate (SH) could be used to treat IBS-C. The effects of SH with different molecular weights were compared in a rat model of IBS-C. Low-molecular-weight SH (LMW-SH, 5 âˆ¼ 10 kDa), medium-molecular-weight SH (MMW-SH, 200 âˆ¼ 400 kDa), and high-molecular-weight SH (HMW-SH, 1300 âˆ¼ 1500 kDa) were screened for efficacy in IBS-C using the following indicators: body weight, number of fecal pellets, fecal moisture, visceral hypersensitivity, and gastrointestinal transit rate. H-HMW-SH was the most effective in improving IBS-C symptoms. The ELISA kits indicated that H-HMW-SH reduced the levels of pro-inflammatory cytokines IL-1ß, IL-18, and TNF-α in IBS-C rats. In addition, both western blot and immunofluorescence analyses showed that H-HMW-SH increased the protein expressions of claudin-1, occludin and zonula occludens-1. Furthermore, H-HMW-SH restored the balance of intestinal flora in different intestinal contents (duodenum, jejunum, ileum, and colon) and feces of rats with IBS-C. Overall, our study illustrates the therapeutic potential of H-HMW-SH in the treatment of IBS-C.

Glutamate affects self-assembly, protein corona, and anti-4 T1 tumor effects of melittin/vitamin E-succinic acid-(glutamate)n nanoparticles.

Melittin (M) has attracted increasing attention for its significant antitumor effects and various immunomodulatory effects. However, various obstacles such as the short plasma half-life and adverse reactions restrict its application. This study aimed to systematically investigate the self-assembly mechanism, components of the protein corona, targeting behavior, and anti-4 T1 tumor effect of vitamin E-succinic acid-(glutamate)n /melittin nanoparticles with varying amounts of glutamic acid. Here, we present a new vitamin E-succinic acid-(glutamate)5 (E5), vitamin E-succinic acid-(glutamate)10 (E10) or vitamin E-succinic acid-(glutamate)15 (E15), and their co-assembly system with positively charged melittin in water. The molecular dynamics simulations demonstrated that the electrostatic energy and van der Waals force in the system decreased significantly with the increase in the amount of glutamic acid. The melittin and E15 system exhibited the optimal stability for nanoparticle self-assembly. When nanoparticles derived from different self-assembly systems were co-incubated with plasma from patients with breast cancer, the protein corona showed heterogeneity. In vivo imaging demonstrated that an increase in the number of glutamic acid residues enhanced circulation duration and tumor-targeting effects. Both in vitro and in vivo antitumor evaluation indicated a significant increase in the antitumor effect with the addition of glutamic acid. According to our research findings, the number of glutamic acid residues plays a crucial role in the targeted delivery of melittin for immunomodulation and inhibition of 4 T1 breast cancer. Due to the self-assembly capabilities of vitamin E-succinic acid-(glutamate)n in water, these nanoparticles carry significant potential for delivering cationic peptides such as melittin.

A Self-Amplifying ROS-Responsive Nanoplatform for Simultaneous Cuproptosis and Cancer Immunotherapy.

Cuproptosis is an emerging cell death pathway that depends on the intracellular Cu ions. Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and trigger cuproptosis. However, ES can be rapidly removed and metabolized during intravenous administration, leading to a short half-life and limited tumor accumulation, which hampers its clinical application. Here, the study develops a reactive oxygen species (ROS)-responsive polymer (PCP) based on cinnamaldehyde (CA) and polyethylene glycol (PEG) to encapsulate ES-Cu compound (EC), forming ECPCP. ECPCP significantly prolongs the systemic circulation of EC and enhances its tumor accumulation. After cellular internalization, the PCP coating stimulatingly dissociates exposing to the high-level ROS, and releases ES and Cu, thereby triggering cell death via cuproptosis. Meanwhile, Cu2+-stimulated Fenton-like reaction together with CA-stimulated ROS production simultaneously breaks the redox homeostasis, which compensates for the insufficient oxidative stress treated with ES alone, in turn inducing immunogenic cell death of tumor cells, achieving simultaneous cuproptosis and immunotherapy. Furthermore, the excessive ROS accelerates the stimuli-dissociation of ECPCP, forming a positive feedback therapy loop against tumor self-alleviation. Therefore, ECPCP as a nanoplatform for cuproptosis and immunotherapy improves the dual antitumor mechanism of ES and provides a potential optimization for ES clinical application.

Cell uptake of paclitaxel solid lipid nanoparticles modified by cell-penetrating peptides in A549 cells.

The aim of this study was to investigate the cytotoxicity of paclitaxel solid lipid nanoparticles (SLN) modified with stearic acid octaarginine (SA-R8-PTX-SLN) as well as the cellular uptake of coumarin-6-loaded SLN modified with SA-R8 (SA-R8-C6-SLN) in human lung cancer cells, A549. SLN were prepared using a film dispersion method; and then their particle size, zeta potential, morphology, bound efficiency of SAR8, drug loading efficiency, and in vitro release were characterized. SA-R8-PTX-SLN and SA-R8-C6-SLN were incubated with A549 cells to measure their cytotoxicity and cellular uptake, respectively. The results indicated that the cytotoxicity of SA-R8-PTX-SLN was enhanced significantly with the increasing amount of SA-R8 and the cellular uptakes of SLN increased with the incubated concentrations and the incubated time of SLN. In contrast, SA-R8-SLN could significantly enhance the cellular uptake of SLN and the cytotoxicity of PTX in A549 cells. These in vitro results suggest that SA-R8-SLN could be proposed as alternative drug delivery system.