Preparation and effects of functionalized liposomes targeting breast cancer tumors using chemotherapy, phototherapy, and immunotherapy.

Breast cancer therapy has significantly advanced by targeting the programmed cell death-ligand 1/programmed cell death-1 (PD-L1/PD-1) pathway. BMS-202 (a smallmolecule PD-L1 inhibitor) induces PD-L1 dimerization to block PD-1/PD-L1 interactions, allowing the T-cell-mediated immune response to kill tumor cells. However, immunotherapy alone has limited effects. Clinically approved photodynamic therapy (PDT) activates immunity and selectively targets malignant cells. However, PDT aggravates hypoxia, which may compromise its therapeutic efficacy and promote tumor metastasis. We designed a tumor-specific delivery nanoplatform of liposomes that encapsulate the hypoxia-sensitive antitumor drug tirapazamine (TPZ) and the small-molecule immunosuppressant BMS. New indocyanine green (IR820)-loaded polyethylenimine-folic acid (PEI-FA) was complexed with TPZ and BMS-loaded liposomes via electrostatic interactions to form lipid nanocomposites. This nanoplatform can be triggered by near-infrared irradiation to induce PDT, resulting in a hypoxic tumor environment and activation of the prodrug TPZ to achieve efficient chemotherapy. The in vitro and in vivo studies demonstrated excellent combined PDT, chemotherapy, and immunotherapy effects on the regression of distant tumors and lung metastases, providing a reference method for the preparation of targeted agents for treating breast cancer.

Peg-interferon alpha add-on Tenofovir disoproxil fumarate achieved more HBsAg loss in HBeAg-positive chronic hepatitis B naïve patients.

Several studies have showed that combining peg-interferon alpha (Peg-IFNα) with nucleotide analogues has complementary effects in chronic hepatitis B (CHB), but the optimal regimen and potential mechanisms remain unclear. This was a prospective, longitudinal and multicentre clinical trial (NCT03013556). HBeAg-positive CHB naïve patients were randomly assigned to three groups: tenofovir disoproxil fumarate (TDF) monotherapy for 96 weeks, TDF alone for 48 weeks and sequentially Peg-IFNα added for 48 weeks, TDF de novo combination with Peg-IFNα for 48 weeks then TDF alone for 48 weeks. The primary endpoint was HBeAg seroconversion at week 96 and HBsAg loss as the secondary endpoint. Furthermore, the levels of 12 cytokines in serum were assessed at different time points. A total of 133 patients were included in the analysis. The rates of HBeAg seroconversion at 96 weeks were not significant different among the three groups (p = 0.157). Interestingly, patients in the Peg-IFNα add-on group showed markedly lower HBsAg level compared with the other two groups at week 96. In addition, only three patients in the Peg-IFNα add-on group achieved HBsAg loss. For the following 24 weeks from week 96, no HBsAg reappearance in the three patients and no new patients with HBsAg loss were observed in the three groups. Serum cytokine analysis showed that the baseline level of interferon-inducible protein-10 (IP-10) was strongly higher in HBeAg conversion patients and HBsAg loss patients. Compared with de novo combination and TDF alone, the addition of Peg-IFNα in TDF-treated group might be an effective strategy for HBsAg loss in HBeAg-positive CHB naïve patients.

Dendronized Arm Snowflake Polymer as a Highly Branched Scaffold for Cellular Imaging and Delivery.

Incorporation of branched structures is a major pathway to build macromolecules with desired three-dimensional (3D) structures, which are of high importance in the rational design of functional polymeric scaffolds. Dendrimers and hyperbranched polymers have been extensively studied for this purpose, but proper gain-of-function for these structures usually requires large enough molecular weights and a highly branched interior so that a spherical 3D core-shell architecture can be obtained, yet it is generally challenging to achieve precise control over the structure, high molecular weight, and high degree of branching (DoB) simultaneously. In this article, we present a set of snowflake-shaped star polymers with functional cores and dendronized arms, which ensure a high DoB and an overall globular conformation, thus facilitating the introduction of functional moieties onto the easily achieved scaffold without the need for high-generation dendrons. Using a polyglycerol dendron (PGD) as a proof of concept, we propose that this dendronized arm snowflake polymer (DASP) structure can serve as a better performing alternative to high-generation PGDs. DASPs with molecular weights of 750, 1220, 2120, and 3740 kDa were prepared with >85% yields in all cases, and we show that these DASPs have high encapsulating efficiency of Nile Red due to their high DoB and high biocompatibility due to their hydroxyl-rich nature after ketal removal, as well as high cell permeability that is molecular-weight-dependent. Introduced fluorophores such as fluorescein and difluoroboron 1,3-diphenylaminophenyl ß-diketonate with suitable excitation wavelengths may turn the DASPs into stable, endosome-staining fluorophores with ultra-large Stokes shifts, narrowed emission bands, and suitability for long-term cellular tracing. Moreover, the scaffold can encapsulate antibiotic molecules and deliver them into phagolysosomes for efficient elimination of intracellular Staphylococcus aureus, which is insensitive toward many antibiotics but is a key target for the clinical success of methicillin-resistant Staphylococcus aureus infection treatment. Elimination of Staphylococcus aureus could be improved to >99.9% for chloramphenicol at 32 µg/mL with 450 µg/mL DASP.

Novel brain-targeted nanomicelles for anti-glioma therapy mediated by the ApoE-enriched protein corona in vivo.

BACKGROUND: The interactions between nanoparticles (NPs) and plasma proteins form a protein corona around NPs after entering the biological environment, which provides new biological properties to NPs and mediates their interactions with cells and biological barriers. Given the inevitable interactions, we regard nanoparticle‒protein interactions as a tool for designing protein corona-mediated drug delivery systems. Herein, we demonstrate the successful application of protein corona-mediated brain-targeted nanomicelles in the treatment of glioma, loading them with paclitaxel (PTX), and decorating them with amyloid ß-protein (Aß)-CN peptide (PTX/Aß-CN-PMs). Aß-CN peptide, like the Aß1-42 peptide, specifically binds to the lipid-binding domain of apolipoprotein E (ApoE) in vivo to form the ApoE-enriched protein corona surrounding Aß-CN-PMs (ApoE/PTX/Aß-CN-PMs). The receptor-binding domain of the ApoE then combines with low-density lipoprotein receptor (LDLr) and LDLr-related protein 1 receptor (LRP1r) expressed in the blood-brain barrier and glioma, effectively mediating brain-targeted delivery. METHODS: PTX/Aß-CN-PMs were prepared using a film hydration method with sonication, which was simple and feasible. The specific formation of the ApoE-enriched protein corona around nanoparticles was characterized by Western blotting analysis and LC-MS/MS. The in vitro physicochemical properties and in vivo anti-glioma effects of PTX/Aß-CN-PMs were also well studied. RESULTS: The average size and zeta potential of PTX/Aß-CN-PMs and ApoE/PTX/Aß-CN-PMs were 103.1 nm, 172.3 nm, 7.23 mV, and 0.715 mV, respectively. PTX was efficiently loaded into PTX/Aß-CN-PMs, and the PTX release from rhApoE/PTX/Aß-CN-PMs exhibited a sustained-release pattern in vitro. The formation of the ApoE-enriched protein corona significantly improved the cellular uptake of Aß-CN-PMs on C6 cells and human umbilical vein endothelial cells (HUVECs) and enhanced permeability to the blood-brain tumor barrier in vitro. Meanwhile, PTX/Aß-CN-PMs with ApoE-enriched protein corona had a greater ability to inhibit cell proliferation and induce cell apoptosis than taxol. Importantly, PTX/Aß-CN-PMs exhibited better anti-glioma effects and tissue distribution profile with rapid accumulation in glioma tissues in vivo and prolonged median survival of glioma-bearing mice compared to those associated with PMs without the ApoE protein corona. CONCLUSIONS: The designed PTX/Aß-CN-PMs exhibited significantly enhanced anti-glioma efficacy. Importantly, this study provided a strategy for the rational design of a protein corona-based brain-targeted drug delivery system. More crucially, we utilized the unfavorable side of the protein corona and converted it into an advantage to achieve brain-targeted drug delivery.

Application of HPMC HME polymer as hot melt extrusion carrier in carbamazepine solid dispersion.

AIM: This work is to investigate the application characteristics of a new hot melt extrusion (HME) polymer (HME-grade hydroxypropyl methylcellulose, namely HPMC HME 15LV) in solid dispersion by HME. METHODS: Carbamazepine (CBZ) was chosen as the model drug. And two types of solid dispersion system was prepared by HME, that is, single carrier system which was composed of PVP VA64(VA64) or Soluplus (SOL), and binary carrier which was composed of HPMC HME 15LV and SOL. Phase analysis of the extrudates were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The dissolution, moisture absorption and thermal stability CBZ solid dispersion (CBZ-SD) were also investigated. In addition, the mechanism that affects the capsule dissolution was evaluated by the viscosity test and infiltration capability test. RESULTS: CBZ-SD was prepared by HME. DSC and PXRD results indicated that CBZ was amorphous in all solid dispersions. Unlike CBZ-SD powder with high dissolution, CBZ-SD capsules showed the variable gelatinization phenomenon during dissolution and different dissolution behaviors, which can be interpreted by the viscosity test and infiltration capacity test. Furthermore, compared with single carrier system, CBZ-SD made by binary carrier exhibited lower moisture absorption and better thermal stability, which is benefit to the long-term stability of CBZ-SD. CONCLUSION: HPMC HME 15LV, as a new HME carrier, has certain advantages in producing well CBZ-SD preparation. Its low viscosity can prevent the gelatinization phenomenon during capsule dissolution, as well as suitable Tg and low hygroscopicity were also benefit to the stability of CBZ-SD.

Amino Acid-Linked Low Molecular Weight Polyethylenimine for Improved Gene Delivery and Biocompatibility.

The construction of efficient and low toxic non-viral gene delivery vectors is of great significance for gene therapy. Herein, two novel polycations were constructed via Michael addition from low molecular weight polyethylenimine (PEI) 600 Da and amino acid-containing linkages. Lysine and histidine were introduced for the purpose of improved DNA binding and pH buffering capacity, respectively. The ester bonds afforded the polymer biodegradability, which was confirmed by the gel permeation chromatography (GPC) measurement. The polymers could well condense DNA into nanoparticles and protect DNA from degradation by nuclease. Compared with PEI 25 kDa, these polymers showed higher transfection efficiency, lower toxicity, and better serum tolerance. Study of this mechanism revealed that the polyplexes enter the cells mainly through caveolae-mediated endocytosis pathway; this, together with their biodegradability, facilitates the internalization of polyplexes and the release of DNA. The results reveal that the amino acid-linked low molecular weight PEI polymers could serve as promising candidates for non-viral gene delivery.

An AIE-Based Probe for Rapid and Ultrasensitive Imaging of Plasma Membranes in Biosystems.

The abnormality of the plasma membrane (PM) is an important biomarker for cell status and many diseases. Hence, visualizing the PM, especially in complex systems, is an emerging field in the life sciences, especially in low-resource settings. Herein, we developed a water-soluble PM-specific probe utilizing electrostatic and hydrophobic interaction strategies with aggregation-induced emission as the signal output. The probe could image the PM with many advanced features (wash-free, ultrafast staining process, excellent PM specificity, and good biocompatibility), which were demonstrated by the PM imaging of neurons. The probe allowed for the first time the imaging of erythrocytes in the complex brain environment through a fluorescence-based method. Moreover, the PM of the epidermal and partial view of the eyeball structure of live zebrafish are also revealed.

Fast on-Site Visual Detection of Active Ricin Using a Combination of Highly Efficient Dual-Recognition Affinity Magnetic Enrichment and a Specific Gold Nanoparticle Probe.

Ricin, a highly toxic protein, is a controlled substance by both the Chemical Weapons Convention (CWC) and the Biological Weapons Convention (BWC). Therefore, fast precaution of potential ricin toxin plays an important role in national security and public safety. Herein, a simple, sensitive, and accurate visual detection of active ricin in complex samples is presented by combining magnetic affinity enrichment with a specific gold nanoparticle (AuNP) probe. In the first step, a dual-recognition magnetic absorbent was fabricated by simultaneously incorporating two different affinity ligands (concanavalin A and galactosamine) on low-foul polymer brushes grafted magnetic beads, which showed remarkable multivalent synergy binding capacity for ricin even under complex interfering environments. Subsequently, a homoadenine-constituted oligodeoxynucleotide named poly(21dA) was conjugated to AuNPs (the poly(21dA)-AuNPs), which served as a specific depurination substrate of active ricin. Coralyne can trigger the intact poly(21dA)-AuNPs aggregate by forming a non-Watson-Crick homoadenine/coralyne complex, but the poly(21dA)-AuNPs after reacting with active ricin failed to form this complex due to the loss of adenines. Based on these facts, active ricin can be detected as low as 12.5 ng mL-1 with the naked eyes. This detection strategy could be well-applied in various ricin-spiked complex matrices. The features such as ready operation, facile readout, and easy accessibility make the assay a better choice for fast on-site active ricin detection.

Bio-reducible polycations from ring-opening polymerization as potential gene delivery vehicles.

Synthetic polycations show great potential for the construction of ideal non-viral gene delivery systems. Several cationic polymers were synthesized by the epoxide ring-opening polymerization between diepoxide and various polyamines. Disulfide bonds were introduced to afford the polymers bio-reducibility, while the oxygen-rich structure might enhance the serum tolerance and biocompatibility. The polycations have much lower molecular weights than PEI 25 kDa, but still could well bind and condense DNA into nano-sized particles. DNA could be released from the polyplexes by addition of reductive DTT. Compared to PEI, the polycations have less cytotoxicity possibly due to their lower molecular weights and oxygen-rich structure. More significantly, these materials exhibit excellent serum tolerance than PEI, and up to 6 times higher transfection efficiency than PEI could be obtained in the presence of serum. The transfection mediated by was seldom affected even at a high concentration of serum. Much lower protein adsorption of polycations than PEI was proved by bovine serum albumin adsorption experiments. Flow cytometry also demonstrates their good serum resistance ability.

Stretchable Electrochemical Sensor for Real-Time Monitoring of Cells and Tissues.

Stretchable electrochemical sensors are conceivably a powerful technique that provides important chemical information to unravel elastic and curvilinear living body. However, no breakthrough was made in stretchable electrochemical device for biological detection. Herein, we synthesized Au nanotubes (NTs) with large aspect ratio to construct an effective stretchable electrochemical sensor. Interlacing network of Au NTs endows the sensor with desirable stability against mechanical deformation, and Au nanostructure provides excellent electrochemical performance and biocompatibility. This allows for the first time, real-time electrochemical monitoring of mechanically sensitive cells on the sensor both in their stretching-free and stretching states as well as sensing of the inner lining of blood vessels. The results demonstrate the great potential of this sensor in electrochemical detection of living body, opening a new window for stretchable electrochemical sensor in biological exploration.

Cyclen-based cationic lipids containing a pH-sensitive moiety as gene delivery vectors.

A series of novel cationic lipids based on 1,4,7,10-tetrazacyclododecane (cyclen) with the imidazole group as the pH-sensitive moiety and various aliphatic long chains were designed and synthesized. Cationic liposomes were prepared by mixing the lipids and the helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in an appropriate molar ratio. The liposomes showed good stability and could condense plasmid DNA into nanosized particles (∼100 to ∼250 nm) with a positive zeta-potential (+10-25 mV). CCK-8-based cell viability assays showed a relatively lower cytotoxicity of the lipoplexes compared to commercially available lipofectamine 2000. Both enhanced green fluorescent protein and luciferase assays were carried out to investigate the in vitro transfection efficiency (TE) of the lipoplexes. Results showed that both the structures of the hydrophobic chain and the linking bond significantly affected the TE, and the linoleyl-containing lipoplex gave the best TE, which is comparable to lipofectamine 2000. The imidazole group was demonstrated to play an important role in the transfection, and the imidazole-absent analog gave dramatically lower TE. Furthermore, it was also found that Ca(2+) could largely enhance the TE of these lipids, and the optimized TE was about 5 times higher than lipofectamine 2000. Flow cytometry demonstrates that the enhancement of TE by Ca(2+) was caused by the improvement of cellular uptake. These results suggest that the cyclen-imidazole containing lipids might be promising non-viral gene delivery vectors.

Synthesis and gene transfection activity of cyclen-based cationic lipids with asymmetric acyl-cholesteryl hydrophobic tails.

A series of novel 1,4,7,10-tetraazacyclododecane (cyclen)-based cationic lipids with asymmetric double hydrophobic tails (cholesteryl and long aliphatic chains) were designed and synthesized. Lysine was chosen as a linking moiety in the molecular backbone. The liposomes formed from 8 and dioleoylphosphatidylethanolamine (DOPE) could bind and condense plasmid DNA into nanoparticles under a low N/P ratio. These nano-scaled lipoplexes have low cytotoxicity, and might efficiently transfect A549 cells. In vitro transfection results revealed that all cationic lipids showed a comparable or better transfection efficiency (TE) than commercially available Lipofectamine 2000. The length and saturation degree of the aliphatic chain would affect their gene transfection performance, and the linoleic acid-containing 8e could give the best TE.

Effect of novel fiber ingredients on ileal and total tract digestibility of energy and nutrients in semi-purified diets fed to growing pigs.

BACKGROUND: Consumption of different dietary fibers may influence the digestibility of carbohydrates and other nutrients. Therefore the objectives of this experiment were to determine the effect of novel fiber ingredients on the apparent ileal digestibility (AID) and apparent total tract digestibility (ATTD) of gross energy (GE), dry matter (DM), crude protein (CP) and total dietary fiber (TDF) in pigs and to calculate the standardized digestibility of analyzed TDF in four novel fiber ingredients. RESULTS: The AID of DM and GE in diets containing novel fiber ingredients was less (P < 0.05) than in a maltodextrin diet. Addition of cellulose or pullulan, but not resistant starch (RS) 60, RS 75 or soluble corn fiber 70, reduced (P < 0.05) the AID of CP. The average ileal and total tract endogenous losses of analyzed TDF were calculated at 25.25 and 42.87 g kg⁻¹ DM intake, respectively. CONCLUSION: Addition of novel fiber ingredients to a maltodextrin-based diet had different effects on the AID of DM, CP, GE and TDF. Measurements of the standardized digestibility of analyzed TDF may be a better indicator of TDF fermentability than measurements of AID and ATTD of TDF, because some endogenous metabolites may be analyzed as TDF.

Treatment of oilfield fracturing wastewater by a sequential combination of flocculation, Fenton oxidation and SBR process.

In this study, a combined process was developed that included flocculation, Fenton oxidation and sequencing batch reactor (SBR) to treat oilfield fracturing wastewater (FW). Flocculation and Fenton oxidation were applied to reduce chemical oxygen demand (COD) organic load and to enhance biodegradability, respectively. For flocculation, the optimum conditions were: polymeric aluminium chloride dosage, 40 mg/L; polyacrylamide dosage, 4 mg/L; dilution ratio, 1:2 and stirring time, 30 min. For Fenton oxidation, a total reaction time of 60 min, a H2O2dosage of 2 m mol/L, with a [H2O2]/[FeSO4] ratio of 2 were selected to achieve optimum oxidation. Under these optimum flocculation and Fenton oxidation conditions, the COD removal efficiency was found to be 76.6%. Following pretreatment with flocculation and Fenton oxidation, the FW was further remediated using a SBR. Results show that COD was reduced to 92 mg/L, and the overall water quality of the final effluent could meet the class I national wastewater discharge standard of petrochemical industry of China.

[Short-term curative effect of ribavirin combination therapy with pegylated interferon alfa-2a vs. interferon alfa-2a in patients with chronic hepatitis C].

OBJECTIVE: To perform a retrospective cohort study in order to determine the differences in short-term curative effect of ribavirin in combination with interferon alfa (IFNa)-2a vs. pegylated (Peg)-IFNa-2a in patients with chronic hepatitis C (CHC). METHODS: One-hundred-and-eighty-eight treatment of the CHC patients who were administered combination therapy of ribavirin with IFNa from 2010 to 2012. One-hundred-and-thirty-three of the patients received the therapy with IFNa-2a and the remaining 55 received Peg-IFNa-2a. Hepatitis C virus (HCV) load and levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured at treatment weeks 4, 12, 24, and 48. Adverse reactions were recorded. Differences between the groups were assessed by statistical analysis. RESULTS: The patients in the Peg-IFNa-2a group and the IFNa-2a group showed no significant difference in sex distribution, age, smoking habits, or drinking habits at baseline (all P more than 0.05). Both antiviral therapies significantly reduced the HCV load and levels of ALT and AST (baseline levels vs. all treatment weeks examined, P less than 0.05); however, the reduction in the HCV load at week 4 was significantly more robust with the Peg-IFNa-2a therapy (2.96 ± 0.66) log10 IU/ ml vs. (3.47 ± 1.42)1og10 IU/ml; F =4.14, P=0.04). The Peg-IFNa-2a group also showed a significant higher rate of rapid virological response (RVR) than the IFNa-2a group (72.72% vs .57.14%; x²=4.37, P=0.04), but there were no statistically significant differences found between the two groups for early virological response rate (EVR), endpoint antiviral treatment virologic response rate (ETR), biochemical response rate, or rate of adverse reactions (all P more than 0.05). CONCLUSION: Ribavirin in combination with Peg-IFNa-2a produces a better RVR than in combination with IFNa-2a .Yet, the EVR, ETR, biochemical response rate, and rate of adverse reactions is similar for the two forms of IFNa-2a. Further studies are required to determine the potential superiority of Peg-IFNa-2a for a long-term curative effect.

Advances in Nanomedicine and Biomaterials for Endometrial Regeneration: A Comprehensive Review.

The endometrium is an extremely important component of the uterus and is crucial for individual health and human reproduction. However, traditional methods still struggle to ideally repair the structure and function of damaged endometrium and restore fertility. Therefore, seeking and developing innovative technologies and materials has the potential to repair and regenerate damaged or diseased endometrium. The emergence and functionalization of various nanomedicine and biomaterials, as well as the proposal and development of regenerative medicine and tissue engineering techniques, have brought great hope for solving these problems. In this review, we will summarize various nanomedicine, biomaterials, and innovative technologies that contribute to endometrial regeneration, including nanoscale exosomes, nanomaterials, stem cell-based materials, naturally sourced biomaterials, chemically synthesized biomaterials, approaches and methods for functionalizing biomaterials, as well as the application of revolutionary new technologies such as organoids, organ-on-chips, artificial intelligence, etc. The diverse design and modification of new biomaterials endow them with new functionalities, such as microstructure or nanostructure, mechanical properties, biological functions, and cellular microenvironment regulation. It will provide new options for the regeneration of endometrium, bring new hope for the reconstruction and recovery of patients' reproductive abilities.

PEG-modified nano liposomes co-deliver Apigenin and RAGE-siRNA to protect myocardial ischemia injury.

Ischemic heart disease (IHD) is a cardiac disorder in which myocardial damage occurs as a result of myocardial ischemia and hypoxia. Evidence suggests that oxidative stress and inflammatory responses are critical in the development of myocardial ischemia. Therefore, the combination of antioxidant and anti-inflammatory applications is an effective strategy to combat ischemic heart disease. In this paper, polyethylene glycol (PEG)-modified cationic liposomes were used as carriers to deliver apigenin (Apn) with small interfering RNA (siRNA) targeting the receptor for glycosylation end products (RAGE) (siRAGE) into cardiomyocytes to prevent myocardial ischemic injury through antioxidant and anti-inflammatory effects. Our results showed that we successfully prepared cationic PEG liposomes loaded with Apn and siRAGE (P-CLP-A/R) with normal appearance and morphology, particle size and Zeta potential, and good encapsulation rate, drug loading and in vitro release degree. In vitro, P-CLP-A/R was able to prevent oxidative stress injury in H9C2 cells, downregulate the expression of RAGE, reduce the secretion of cellular inflammatory factors and inhibit apoptosis through the RAGE/NF-κB pathway; In vivo, P-CLP-A/R was able to prevent arrhythmia and myocardial pathological injury, and reduce apoptosis and the area of necrotic myocardium in rats. In conclusion, P-CLP-A/R has a protective effect on myocardial ischemic injury and is expected to be a potential drug for the prevention of ischemic heart disease in the future.

A self-targeting MOFs nanoplatform for treating metastatic triple-negative breast cancer through tumor microenvironment remodeling and chemotherapy potentiation.

Triple-negative breast cancer (TNBC) is the most aggressive and fatal subtype of breast cancer with disappointing treatment and high mortality. Tumor microenvironment (TME) plays an important role in the invasion and metastasis of TNBC through multiple complex processes. Most anti-metastatic therapies only focus on cancer cells themselves or interfering with single factors of the metastasis process, which is often related to poor outcomes. Thus, effective TNBC treatment relies on regulating multiple key metastasis-related aspects of the TME. Herein, a self-targeting Metal-Organic Frameworks (MOFs) nanoplatform (named as MTX-PEG@TPL@ZIF-8) was designed to improve treatment of TNBC through tumor microenvironment remodeling and chemotherapy potentiation. The self-targeting MOF nanoplatform is consist of ZIF-8 nanoparticles loaded triptolide (TPL) and followed by the coating with methotrexate-polyethylene glycol conjugates (MTX-PEG). Due to MTX's affinity for the overexpressed folate receptor on tumor cell surfaces, MTX-PEG@TPL@ZIF-8 enables effective accumulation and deep penetration in the tumor area by an MTX-mediated self-targeting strategy. This MOF nanoplatform could promptly release the medication after penetrating the tumor cell, due to pH-triggered degradation. Its anti-metastasis mechanism is to inhibit tumor invasion and metastasis by down-regulating the expression of Vimentin, MMP-2 and MMP-9 and increasing the expression of E-cadherin, upregulation of cleaved caspase-3 and cleaved caspase-9 protein expression promote the apoptosis of tumor cells, thereby reducing their migration. It also downregulated the expression of VEGF and CD31 protein to inhibit the generation of neovascularization. Overall, these findings suggest the self-targeting MOF nanoplatform offers new insights into the treatment of metastatic TNBC by TME remodeling and potentiating chemotherapy.

[Prohibited substances in cosmetics: prospect of the toxicity of acrylamide].

Prohibited substances in cosmetics refer to substances which must not be among the raw material ingredients of cosmetic products. These substances are absorbed mostly through skin, as well as via lung and gastrointestinal tract. Polyacrylamide is ubiquitously used in industry and its decomposition residue acrylamide (ACR) easily finds its way into cosmetic products. ACR can either be oxidized to epoxide glycidamide or conjugated with glutathione, hemoglobin or DNA; ultimately it is excreted in urine. ACR causes neurotoxicity, reproductive toxicity and tumors in rodents. Occupational exposure to ACR causes neurotoxicity in humans; however, epidemiological evidence have not unambiguously answered the question of whether ACR exposure can increase cancer risk for humans.

Sequential Delivery of Quercetin and Paclitaxel for the Fibrotic Tumor Microenvironment Remodeling and Chemotherapy Potentiation via a Dual-Targeting Hybrid Micelle-in-Liposome System.

Cancer-associated fibroblasts (CAFs), an important type of stromal cells in the tumor microenvironment (TME), are responsible for creating physical barriers to drug delivery and penetration in tumor tissues. Thus, effectively downregulating CAFs to destroy the physical barrier may allow enhanced penetration and accumulation of therapeutic drugs, thereby improving therapeutic outcomes. Herein, a matrix metalloproteinase (MMP)-triggered dual-targeting hybrid micelle-in-liposome system (RPM@NLQ) was constructed to sequentially deliver quercetin (Que) and paclitaxel (PTX) for fibrotic TME remodeling and chemotherapy potentiation. Specifically, antifibrotic Que and small-sized RGD-modified micelles containing PTX (RPM) were co-encapsulated into MMP-sensitive liposomes, and the liposomes were further adorned with the NGR peptide (NL) as the targeting moiety. The resulting RPM@NLQ first specifically accumulated at the tumor site under the guidance of the NGR peptide after intravenous administration and then released Que and RPM in response to the extensive expression of MMP in the TME. Subsequently, Que was retained in the stroma to remarkably downregulate fibrosis and decrease the stromal barrier by downregulating Wnt16 expression in CAFs, which further resulted in a significant increase of RPM for deeper tumor. Thus, RPM could precisely target and kill breast cancer cells locally. Consequently, prolonged blood circulation, selective cascade targeting of tumor tissue and tumor cells, enhanced penetration, and excellent antitumor efficacy have been demonstrated in vitro and in vivo. In conclusion, as-designed sequential delivery systems for fibrotic TME remodeling and chemotherapy potentiation may provide a promising adjuvant therapeutic strategy for breast and other CAF-rich tumors.