Construction and in vitro/in vivo evaluation of menantine hydrochloride oral liquid sustained-release drug delivery system.

OBJECTIVE: The purpose of the present study was to formulate a menantine hydrochloride (MH) sustained-release suspension. METHODS: Menantine hydrochloride drug resin complex (MH-DRC) was prepared with strong acid cation exchange resin as carrier using water bath method. The MH-DRC was characterized using scanning electron microscopy, X-ray diffraction and infrared spectroscopy. The MH-coated microcapsule (MH-CM) with optimized formulation was further dispersed in a suitable medium to obtain a sustained-release suspension. The rats were given both the MH sustained-release suspension and the commercial MH sustained-release capsule by intragastric administration. The plasma concentration-time curves and related pharmacokinetic parameters were also investigated using a non-atrioventricular model. RESULTS: MH and ion-exchange resin were ionically bonded. AmberliteIRP®69 had a higher affinity for MH at the initial concentration of 5 mg·mL-1 and a reaction temperature of 25.0 ± 0.5 °C. In vitro drug release profile showed that both the drug resin complex and the coated microcapsules had a certain level of sustained-release effect. The t1/2 of MH sustained-release suspension was extended from 68.44 h to 72.79 h with the peak blood concentration being decreased to 3.56 µg·mL-1 and the Tmax extended to 12 h compared with the commercial MH sustained-release capsule. The concentration-time curve of the self-made MH sustained-release suspension was flattened and the average relative bioavailability (Fr) was 116.65% compared with the commercial MH sustained-release capsules. CONCLUSIONS: The findings showed that the MH sustained-release suspension was successfully formulated with acceptable pharmacokinetic indices for effective treatment of Alzheimer's disease.

Effect of hydroxyethyl starch on drug stability and release of semaglutide in PLGA microspheres.

The degradation of peptide drugs limits the application of peptide drug microspheres. Structural changes of peptides at the water-oil interface and the destruction of their spatial structure in the complex microenvironment during polymer degradation can affect drug release and in vivo biological activity. This study demonstrates that adding hydroxyethyl starch (HES) to the internal aqueous phase (W1) significantly enhances the stability of semaglutide and optimizes its release behavior in PLGA microspheres. The results showed that this improvement was due to a spontaneous exothermic reaction (ΔH = -132.20 kJ mol-1) facilitated by hydrogen bonds. Incorporating HES into the internal aqueous phase using the water-in-oil-in-water (W1/O/W2) emulsion method yielded PLGA microspheres with a high encapsulation rate of 94.38 %. Moreover, microspheres with HES demonstrated well-controlled drug release over 44 days, unlike the slower and incomplete release in microspheres without HES. The optimized h-MG2 formulation achieved a more complete drug release (83.23 %) and prevented 30.65 % of drug loss compared to the HES-free microspheres within the same period. Additionally, the optimized semaglutide microspheres provided nearly three weeks of glycemic control with adequate safety. In conclusion, adding HES to the internal aqueous phase improved the in-situ drug stability and release behavior of semaglutide-loaded PLGA microspheres, effectively increasing the peptide drug payload in PLGA microspheres.

Improving the prediction performance of leaf water content by coupling multi-source data with machine learning in rice (Oryza sativa L.).

BACKGROUND: Leaf water content (LWC) significantly affects rice growth and development. Real-time monitoring of rice leaf water status is essential to obtain high yield and water use efficiency of rice plants with precise irrigation regimes in rice fields. Hyperspectral remote sensing technology is widely used in monitoring crop water status because of its rapid, nondestructive, and real-time characteristics. Recently, multi-source data have been attempted to integrate into a monitored model of crop water status based on spectral indices. However, there are fewer studies using spectral index model coupled with multi-source data for monitoring LWC in rice plants. Therefore, 2-year field experiments were conducted with three irrigation regimes using four rice cultivars in this study. The multi-source data, including canopy ecological factors and physiological parameters, were incorporated into the vegetation index to accurately predict LWC in rice plants. RESULTS: The results presented that the model accuracy of rice LWC estimation after combining data from multiple sources improved by 6-44% compared to the accuracy of a single spectral index normalized difference index (ND). Additionally, the optimal prediction accuracy of rice LWC was produced using a machine algorithm of gradient boosted decision tree (GBDT) based on the combination of ND(1287,1673) and crop water stress index (CWSI) (R2 = 0.86, RMSE = 0.01). CONCLUSIONS: The machine learning estimation model constructed based on multi-source data fully utilizes the spectral information and considers the environmental changes in the crop canopy after introducing multi-source data parameters, thus improving the performance of spectral technology for monitoring rice LWC. The findings may be helpful to the water status diagnosis and accurate irrigation management of rice plants.

An adaptive drug-releasing contact lens for personalized treatment of ocular infections and injuries.

This research introduces an innovative solution to address the challenges of bacterial keratitis and alkali burns. Current treatments for bacterial keratitis and alkali burns rely on the frequent use of antibiotics and anti-inflammatory eye drops. However, these approaches suffer from poor bioavailability and fluctuating concentrations, leading to limited efficacy and potential drug resistance. Our approach presents an adaptive drug-releasing contact lens responsive to reactive oxygen species (ROS) at ocular inflammation sites, synchronously releasing Levofloxacin and Diclofenac. During storage, minimal drug release occurred, but over 7 days of wear, the lens maintained a continuous, customizable drug release rate based on disease severity. This contact lens had strong antibacterial activity and biofilm prevention, effectively treating bacterial keratitis. When combined with autologous serum, this hydrophilic, flexible lens aids corneal epithelial regeneration, reducing irritation and promoting healing. In summary, this ROS-responsive drug-releasing contact lens combines antibacterial and anti-inflammatory effects, offering a promising solution for bacterial keratitis and alkali burns.

Synthesis of the DEF-Ring Spirocyclic Core of Cyclopamine.

A stereoselective synthesis of the DEF-ring spirocyclic core of cyclopamine was accomplished using commercially available materials. The key steps in the synthesis were (i) the enantioselective vinylogous Mannich reaction, followed by lactamization to generate the piperidine F ring, and (ii) intramolecular oxidative dearomative spiroetherification to construct the DEF-ring spirocyclic core of cyclopamine. We found that the stereochemistry of the spirocyclization was controlled by the configuration of the methyl group (C-20) in the substrate.

Novel solid self-emulsifying drug delivery system to enhance oral bioavailability of cabazitaxel.

In this study, a novel cabazitaxel solid self-emulsifying drug delivery system (CTX S-SEDDS) was developed by solvent evaporation and liquid-solid compression technology, which overcame the limitations of the traditional SEDDS and improved the oral bioavailability. From the results of solubility, pseudo-ternary phase diagram, and single-factor analysis, Tween 80 (surfactant), Tricaprylin (oil), and Glyceryl monooleate (oil) with the ratio of 30:55:15 showed optimized particle size (140.87 nm), short emulsification and high cabazitaxel (CTX) loading capacity (50 mg·g-1). Based on the liquid-solid compression mathematical model, Syloid XDP3050 was determined as carrier material and Syloid 244FP as coating material. The prepared CTX S-SEDDS showed excellent flowability, tabletability, and reconstitution property. In vivo pharmacokinetics in rats demonstrated the absolute bioavailability of CTX S-SEDDS (17.27 %) was significantly enhanced compared with CTX solution (1.69 %), which was close to that of CTX-SEDSS (20.48 %). Lymphatic absorption was verified by in vitro imaging to be an important absorption route for self-emulsifying preparations. These results suggested that CTX S-SEDDS could enhance oral bioavailability of poorly water-soluble drug cabazitaxel while avoiding SEDDS limitations and harnessing the dual advantages of solid and liquid preparations.

Intramuscular injection of palmitic acid-conjugated Exendin-4 loaded multivesicular liposomes for long-acting and improving in-situ stability.

BACKGROUND: Exendin-4 (Ex4) is a promising drug for diabetes mellitus with a half-life of 2.4 h in human bodies. Besides, the Ex4 formulations currently employed in the clinic or under development have problems pertaining to stability. In this study, palmitic acid-modified Ex4 (Pal-Ex4) was prepared and purified to extend the half-life of Ex4. In addition, Pal-Ex4-MVLs were further designed and optimized as a long-acting delivery system for intramuscular injection. METHODS: Pal-Ex4 was encapsulated within multivesicular liposomes (MVLs) via a two-step double emulsification process. The formulated products were then assessed for their vesicle size, encapsulation efficiency, and in vitro and in vivo. RESULTS: Pal-Ex4-MVLs with a notable encapsulation efficiency of 99.18% were successfully prepared. Pal-Ex4-MVLs, administered via a single intramuscular injection in Sprague-Dawley rats, sustained stable plasma concentrations for 168 h, presenting extended half-life (77.28 ± 12.919 h) and enhanced relative bioavailability (664.18%). MVLs protected Ex4 through providing stable retention and slow release. This approach considerably improved the in-situ stability of the drug for intramuscular administration. CONCLUSIONS: The combination of palmitic acid modification process with MVLs provides dual protection for Ex4 and can be a promising strategy for other hydrophilic protein/polypeptide-loaded sustained-release delivery systems with high drug bioactivity.

Activate the endogenous Cu2+ switch for Zn(DDC)2 liposomes conversion: Providing a safer and less toxic alternative in cancer therapy.

The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC)2 to overcome the limitations, like the poor water solubility. However, Cu (DDC)2 liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn2+ to form zinc diethyldithiocarbamate (Zn (DDC)2). Furthermore, this study prepared stable and homogeneous Zn (DDC)2 liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC)2 was converted to Cu (DDC)2 with the help of endogenous Cu2+-switch enriched in the TME, which has a higher stability constant compared with Zn (DDC)2. In other words, the Cu2+-switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC)2 to the more cytotoxic Cu (DDC)2 for effective tumor therapy so that the Zn (DDC)2 liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC)2 liposomes in cancer therapy.

Asymmetric Synthesis of Cyclopamine, a Hedgehog (Hh) Signaling Pathway Inhibitor.

Cyclopamine is a teratogenic steroidal alkaloid, which inhibits the Hedgehog (Hh) signaling pathway by targeting the Smoothened (Smo) receptor. Suppression of Hh signaling with synthetic small molecules has been pursued as a therapeutic approach for the treatment of cancer. We report herein the asymmetric synthesis of cyclopamine based on a two-stage relay strategy. Stage-I: total synthesis of veratramine through a convergent approach, wherein a crucial photoinduced excited-state Nazarov reaction was applied to construct the basic [6-6-5-6] skeleton of C-nor-D-homo-steroid. Stage-II: conversion of veratramine to cyclopamine was achieved through a sequence of chemo-selective redox manipulations.

Design of carboxymethylcellulose-conjugated polymeric prodrug micelles for enhanced in vivo performance of docetaxel.

Docetaxel (DTX) has become one of the most important cytotoxic drugs to treat cancer; nevertheless, its poor hydrophilicity and non-specific distribution of DTX lead to detrimental side effects. In this article, we devised carboxymethylcellulose (CMC)-conjugated polymeric prodrug micelles (mPEG-CMC-DTX PMs) for DTX delivery. The ester-bonded polymeric prodrug, mPEG-CMC-DTX, was synthesized and exhibited the capacity for self-assembling into polymeric micelles. The CMC is profusely substituted and acetylated to promote the coupling rate of DTX. Covalent binding of DTX and CMC through an ester bond can be hydrolyzed to dissociate the bond under the action of esterase in the tumor. The mPEG-CMC-DTX PMs displayed promoted drug loading (>50 %, wt), commendable stability, and sustained release behavior in vitro. The gradual release of the prodrug amplified the selectivity of cytotoxicity between normal cells and tumor cells, mitigating the systemic toxicity of mPEG-CMC-DTX PMs and enabling dose intensification. Notably, mPEG-CMC-DTX PMs demonstrated a superior antitumor efficacy and low systemic toxicity due to the elevated tolerance dosage (even at 40 mg/kg DTX). In summation, mPEG-CMC-DTX PMs harmonized the antitumor efficacy and toxicity of DTX. In essence, innovative perspectives for the rational design of CMC-conjugated polymeric prodrug micelles for the delivery of potently toxic drugs were proffered.

Intratumoral injection of norcantharidin liposome emulsion hybrid delivery system amplifies the cancer-fighting effects of oral sorafenib against hepatocellular carcinoma.

Interventional therapies are increasingly used in clinical trials for hepatocellular carcinoma (HCC). Sorafenib is the front-line remedy for HCC, however, chemoresistance occurs immutably and affects the effectiveness of treatment. In a previous study, a norcantharidin liposome emulsion hybrid (NLEH) delivery system for HCC was developed. This study aims to examine the therapeutic effects of the combination of intratumoral injection of NLEH and sorafenib in treating HCC. Sorafenib combined with NLEH activated the apoptosis pathway by synergistically upregulating caspase-9, promoting cytotoxicity, apoptosis (64.57%), and G2/M cell cycle arrest (48.96%). Norcantharidin could alleviate sorafenib resistance by counteracting sorafenib-induced phosphorylation of Akt. Additionally, intratumoral injection of NLEH exhibited a sustained accumulation in the tumor within 24 h and didn't distribute to other major organs. Intratumoral injection of NLEH in combination with oral sorafenib displayed the most potent tumor growth inhibitory effect (77.91%) in vivo. H&E staining results and the indicators of the renal and liver function tests demonstrated the safety of this combination therapy. Overall, these results showed that intratumoral injection of NLEH in combination with oral sorafenib treatment represented a rational potential therapeutic option for HCC.

Research on the preparation process of the cytarabine/daunorubicin dual-encapsulation liposome and its physicochemical properties and performances in vitro/vivo.

As the only Food and Drug Administration (FDA)-approved dual-encapsulation liposome injection for treating Acute myeloid leukemia (AML), CPX-351 outperforms the standard chemotherapy treatment "DA 7 + 3″ in terms of clinical effectiveness. Although research on dual-loaded liposomes has increased in recent years, little attention has been paid to their preparation, which can affect their quality, efficacy, and safety. This study explored various preparation processes to create the cytarabine/daunorubicin co-loaded liposome (the Cyt/Daun liposome) and eventually settled on two methods: the sequential loading approach, thin film hydration-extrusion-copper ion gradient, and the simultaneous encapsulation technique, copper ion gradient-concentration gradient. Different preparation methods resulted in different particle sizes and encapsulation efficiencies; the two aforementioned preparation processes generated dual-loaded liposomes with comparable physicochemical properties. The sequential encapsulation technique was selected for the subsequent research owing to its higher encapsulation efficiency prior to purification; the prepared Cyt/Daun liposomes had small and uniform particle size (108.6 ± 1.02 nm, Polydispersity index (PDI) 0.139 ± 0.01), negative charge (-(60.2 ± 1.15) mV), high drug encapsulation efficiency (Cyt 88.2 ± 0.24 %, Duan 94.2 ± 0.45 %) and good plasma stability. To improve its storage stability, the Cyt/Daun liposome was lyophilized (-40 °C for 4 h, maintained for 130 min, and dried for 1200 min) using sucrose-raffinose (mass ratio 7:3; glycolipid ratio 4:1, w/w) as a lyoprotectant. The lyophilized liposomes were purple cakes, redissolved rapidly with insignificant alterations in particle size and encapsulation efficiency, and possessed well storage stability. The pharmacokinetic and tissue distribution studies demonstrated that the Cyt/Daun liposome could achieve long circulation and maintain synergic proportions of drugs within 24 h, increasing the accumulation of drugs at tumor sites. Furthermore, the in vitro/in vivo pharmacodynamic studies confirmed its good anti-tumor activity and safety.

Dual-responsive PEG-lipid polyester nanoparticles for siRNA and vaccine delivery elicit anti-cancer immune responses by modulating tumor microenvironment.

Cancer vaccine-based immunotherapy has great potential; however, the vaccines have been hindered by the immunosuppressive tumor microenvironment (TME). In this study, dual-responsive PEG-lipid polyester nanoparticles (PEG BR647-NPs) for tumor-targeted delivery were proposed. PEG BR647-NPs containing the model tumor-associated antigen (TAA) OVA and the signal transduction and activator of transcription 3 (STAT3) siRNA were delivered to the tumor. The PEG BR647-NPs were internalized by tumor-associated dendritic cells (TADCs), where the TAA and siRNA were released into the cytoplasm via the endo/lysosome escape effect. The released OVA was presented by the major histocompatibility complex class I to activate T cells, and the released STAT3 siRNA acted to relieve TADC dysfunction, promote TADC maturation, improve antigen-presenting ability, and enhance anticancer T cell immunity. Meanwhile, the PEG BR647-NPs were ingested by tumor cells, killing them by the pro-apoptosis effect of STAT3 siRNA. Moreover, PEG BR647-NPs could reduce the proportion of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumors and abrogate immunosuppression. The integration of relieved TADC dysfunction, promoted TADC maturation, enhanced antigen cross-presentation, abrogated immunosuppression, and improved pro-apoptosis effect boosted the vaccination for tumor immunotherapy. Thus, PEG BR647-NPs efficiently delivered the vaccine and STAT3 siRNA to the tumor and modulated immunosuppressive TME, thus providing better antitumor effects.

The interplay between PEGylated nanoparticles and blood immune system.

During the last two decades, an increasing number of reports have pointed out that the immunogenicity of polyethylene glycol (PEG) may trigger accelerated blood clearance (ABC) and hypersensitivity reaction (HSR) to PEGylated nanoparticles, which could make PEG modification counterproductive. These phenomena would be detrimental to the efficacy of the load and even life-threatening to patients. Consequently, further elucidation of the interplay between PEGylated nanoparticles and the blood immune system will be beneficial to developing and applying related formulations. Many groups have worked to unveil the relevance of structural factors, dosing schedule, and other factors to the ABC phenomenon and hypersensitivity reaction. Interestingly, the results of some reports seem to be difficult to interpret or contradict with other reports. In this review, we summarize the physiological mechanisms of PEG-specific immune response. Moreover, we speculate on the potential relationship between the induction phase and the effectuation phase to explain the divergent results in published reports. In addition, the role of nanoparticle-associated factors is discussed based on the classification of the action phase. This review may help researchers to develop PEGylated nanoparticles to avoid unfavorable immune responses based on the underlying mechanism.

Human Serum Albumin Nanoparticles as a Carrier of 20(S)-Protopanaxadiol via Intramuscular Injection to Alleviate Cyclophosphamide-Induced Myelosuppression.

Myelosuppression is a prevalent and potentially life-threatening side effect during chemotherapy. As the main active component of ginseng, 20(S)-protopanaxadiol (PPD) is capable of relieving myelosuppression by restoring hematopoiesis and immunity. In this study, PPD was encapsulated in human albumin nanoparticles (PPD-HSA NPs) by nanoparticle albumin-bound (Nab) technology for intramuscular injection to optimize its pharmacokinetic properties and promote recovery of myelosuppression. The prepared PPD-HSA NPs had a particle size of about 280 nm with a narrow size distribution. PPD dispersed as an amorphous state within the PPD-HSA NPs, and the NPs exhibited in vitro sustained release behavior. PPD-HSA NPs showed a favorable pharmacokinetic profile with high absolute bioavailability, probably due to the fact that NPs entered into the blood circulation via lymphatic circulation and were eliminated slowly. In vivo distribution experiments demonstrated that PPD-HSA NPs were mainly distributed in the liver and spleen, but a strong fluorescence signal was also found in the inguinal lymph node, indicating drug absorption via a lymph route. The myelosuppressive model was established using cyclophosphamide as the inducer. Pharmacodynamic studies confirmed that PPD-HSA NPs were effective in promoting the level of white blood cells. Moreover, the neutrophil and lymphocyte counts were significantly higher in the PPD-HSA NPs group compared with the control group. This preliminary investigation revealed that PPD-HSA NPs via intramuscular administration may be an effective intervention strategy to alleviate myelosuppression.

Integration of MyD88 inhibitor into mesoporous cerium oxide nanozymes-based targeted delivery platform for enhancing treatment of ulcerative colitis.

Excessive reactive oxygen species (ROS) and stressed inflammatory response are major characteristics of ulcerative colitis, which cause disease progression and aggravation. Herein, a novel mesoporous cerium oxide nanozymes (MCN) was designed and then loaded with Myeloid differentiation factor-88 (MyD88) inhibitor for synergistic treatment of colitis by scavenging ROS and regulating inflammation. This innovative MCN with average particle size of 200.7 nm, specific surface area of 119.78 m2/g and mesopores of 4.47 nm not only exhibited excellent SOD-like and CAT-like activities to scavenge ROS but also could act as a carrier to load MyD88 inhibitor, TJ-M2010-5, (abbreviated as TJ-5) into their mesopores, achieving the effect of 'two birds with one stone'. Besides, the modification of dextran sulfate sodium (TJ-5/MCN/DSS) increased the internalization of nanozymes into activated macrophages and enhanced in vitro anti-inflammatory ability. To enhance colon targeting, we coated TJ-5/MCN/DSS with the enteric material Eudragit S100, preventing premature release or absorption of the drug in the gastrointestinal tract after oral administration. The results demonstrated that TJ-5/MCN/DSS/Eudragit not only achieved delayed drug release and improved colon targeting but also exhibited optimal therapeutic efficacy in colitis mice. Mechanistically, the MCN-mediated ROS scavenging and TJ-5-mediated MyD88 blockade synergistically inhibited the NF-κB signaling pathway, thereby reducing the inflammatory response. Importantly, TJ-5/MCN/DSS/Eudragit did not induce systemic toxicity. In conclusion, our work not only presents a novel carrier capable of scavenging ROS but also provides proof of concept for the synergistic treatment of colitis using this carrier in combination with MyD88 inhibitors. This study proposes a safe and efficient strategy for targeting ROS-associated inflammation.

pH-Activatable copper-axitinib coordinated multifunctional nanoparticles for synergistic chemo-chemodynamic therapy against aggressive cancers.

Chemodynamic therapy (CDT) is an emerging oncological treatment that eliminates tumor cells by generating lethal hydroxyl radicals (˙OH) through Fenton or Fenton-like reactions within tumors. However, the effectiveness of CDT is limited by the overexpression of glutathione (GSH) and low reaction efficiency in the tumor microenvironment (TME). To address these challenges and enhance tumor treatment, we developed a novel pH-activatable metal ion-drug coordinated nanoparticle (Cu-AXB NPs) system, incorporating a CDT agent (Cu2+) and a chemotherapeutic agent (axitinib, AXB). The obtained Cu-AXB NPs exhibited exceptional characteristics, including ultrahigh drug loading capacity (87.55%) and an average size of 180 nm. These nanoparticles also demonstrated excellent plasma stability and pH-responsive drug release, enabling prolonged circulation in the bloodstream and targeted therapy at weakly acidic tumor sites. Upon release, AXB acted as a chemotherapeutic agent, effectively eliminating tumor cells, while Cu2+ ions were reduced to Cu+ by GSH, further generating toxic ˙OH with hydrogen peroxide (H2O2) for CDT through a Fenton-like reaction. Additionally, the Cu-AXB NPs efficiently disrupted the copper metabolic balance and increased the intracellular Cu content, further amplifying the therapeutic impact of CDT. In vitro studies assessing cytotoxicity and apoptosis confirmed the superior tumor cell-killing efficacy of the Cu-AXB NPs. This enhanced efficacy can be attributed to the synergistic effect of CDT and chemotherapy. Moreover, the Cu-AXB NPs exhibited excellent tumor targeting capabilities, resulting in significant tumor inhibition (77.53% inhibition) while maintaining favorable biocompatibility in tumor-bearing mice. In conclusion, this study presents a promising and safe strategy for cancer therapy by combining CDT with chemotherapy, offering a potential breakthrough in the field of oncology.

FRET-based analysis on the structural stability of polymeric micelles: Another key attribute beyond PEG coverage and particle size affecting the blood clearance.

Various attributes of micelles, such as PEG density and particle size, are considered to be related to blood clearance. The structural stability of micelles is another key attribute that will affect the in vivo fate. This study employed fluorescence resonance energy transfer (FRET) analysis to guide the preparation of polymeric micelles with different structural stability. Micelles prepared using copolymers with longer hydrophobic blocks showed higher structural stability; emulsification was a better method than nanoprecipitation to prepare stable micelles. The fast chain exchange kinetics and the high-water content of micellar cores explained the low structural stability of those micelles. Moreover, this study highlighted the importance of structural stability that affected blood clearance in concert with PEG length and particle size. One-third of the small and stable micelles were detected in the blood 24 h after injection. While unstable micelles would be cleared from the circulation within 4 h. Notably, there would be a threshold of structural stability. Micelles with structural stability below this threshold were quickly cleared even if they possessed a longer PEG length and a smaller size. In contrast, higher structural stability allowed polymeric micelles to maintain higher integrity in vivo and enhance tumor accumulation and anti-tumor efficacy. In conclusion, this study systematically analyzed the importance of the structural stability of micelles on the in vivo fate.

Environmental explanation of prostate cancer progression based on the comprehensive analysis of perfluorinated compounds.

Perfluorinated compounds (PFCs) are man-made chemicals used in the manufacture of many products with water and dirt repellent properties. Many diseases have been proved to be related to the exposure of PFCs, including breast fibroadenoma, hepatocellular carcinoma, breast cancer and leydig cell adenoma. However, whether the PFCs promote the progression of prostate cancer remains unclear. In this work, through comprehensive bioinformatics analysis, we discovered the correlation between the prostate cancer and five PFCs using Comparative Toxicogenomics Database (CTD), Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. In addition, further analysis showed that several PFCs-related genes demonstrated strong prognostic value for prostate cancer patients. The survival analysis and receiver operating characteristic (ROC) curves revealed that PFCs-related genes based prognostic model held great predictive value for the prognosis of prostate cancer, which could potentially serve as an independent risk factor in the future. In vitro experiments verified the promotive role of perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) in the growth of prostate cancer cells. This study provided novel insights into understanding the role of PFCs in prostate cancer and brought attention to the environmental association with cancer risks and progression.

Asymmetric Total Synthesis of Cephalotaxus Diterpenoids: Cephinoid P, Cephafortoid A, 14-epi-Cephafortoid A and Fortalpinoids M-N, P.

The asymmetric total syntheses of cephalotaxus C19 diterpenoids, bearing a unique cycloheptene A ring with a chiral methyl group at C-12, were disclosed based on a universal strategy. Six members, including cephinoid P, cephafortoid A, 14-epi-cephafortoid A and fortalpinoids M-N, P, were accomplished for the first time. The concise approach relies on two crucial steps: (1) a Nicholas/Hosomi-Sakurai cascade reaction was developed to efficiently generate the cycloheptene ring bearing a chiral methyl group; (2) an intramolecular Pauson-Khand reaction was followed to facilitate the construction of the complete skeleton of target molecules. Our studies provide a new strategy for the synthetic analysis of cephalotaxus diterpenoids and structurally related polycyclic natural products.