Combating multidrug resistance of breast cancer with ginsenoside Rh2-irrigated nano-in-thermogel.

The emergence of multidrug resistance (MDR) is the leading cause of mortality in patients with breast cancer. Overexpressed P-glycoprotein (P-gp) that can pump out chemotherapeutics from multidrug-resistant cancer cells is the main cause of chemotherapy failure. P-gp inhibitors are hence increasingly used to sensitize chemotherapy to breast cancer with MDR by reducing the efflux of drugs. However, representative P-gp inhibitors usually have severe side effects and the effect of their release behavior on chemotherapy are neglected in current studies. We constructed a nano-in-thermogel delivery system with the sequential release of ginsenoside Rh2 (GRh2) and a chemotherapeutic drug in the tumor microenvironment as a drug compounding "reservoir" to combat MDR in breast cancer. Briefly, paclitaxel (PTX) and GRh2 were encapsulated in solid lipid nanoparticles (SLNs) and dispersed in a poloxamer-based thermogel (SLNs-Gel). GRh2 was used as an innovative and safe P-gp inhibitor to lower P-gp expression and cellular adenosine triphosphate context, thereby sensitizing PTX-resistant breast cancer cells (MCF-7/PTX) to PTX. Pharmacodynamic and in vivo safety studies confirmed that intratumoral injection of SLNs-Gel significantly suppressed the proliferation of PTX-resistant breast cancer and alleviated the PTX-induced hematotoxicity. The GRh2-irrigated nano-in-thermogel delivery system shows great potential in combating multidrug-resistant cancer.

Site-Specifically Launched Microneedles for the Combined Treatment of Psoriasis-Diabetic Comorbidity.

Psoriasis and diabetes are both common comorbidities for each other, where inflammation and insulin resistance act in a vicious cycle, driving the progression of disease through the activation of the NF-κB signaling pathway. Therefore, disrupting the linkage between inflammation and insulin resistance by inhibiting the NF-κB pathway presents a promising therapeutic strategy for addressing psoriasis-diabetic comorbidity. Herein, an open-loop therapy was developed by integrating microneedle-mediated short- and long-range missiles to target psoriasis and diabetes, respectively. The short-range missile (curcumin nanoparticle) could be stationed in the psoriatic skin for topical and prolonged antipsoriasis therapy, while the long-range missile (metformin) is capable of penetrating transdermal barriers to induce a systemic hypoglycemic effect. More attractively, the short- and long-range missiles could join hands to inhibit the NF-κB signaling pathway and diminish inflammation, effectively disrupting the crosstalk between inflammation and insulin resistance. Pharmacodynamic studies showed that this microneedle-mediated combination, possessing dual anti-inflammatory and antihyperglycemic properties, proves to be highly efficacious in alleviating typical symptoms and inflammatory response in both nondiabetic and diabetic mice with imiquimod (IMQ)-induced psoriasis models. Hence, the microneedle-mediated open-loop therapy shows great potential in the management of psoriasis-diabetes comorbidity.

HOXC11 drives lung adenocarcinoma progression through transcriptional regulation of SPHK1.

Lung adenocarcinoma (LUAD) is a fatal threat to human health, while the mechanism remains unclear, and the therapy brings limited therapeutic effects. Transcription factor Homeobox C11 (HOXC11) was previously proved to be related to hind limbs and metanephric development during the embryonic phase, and its role in tumors has been gradually recognized. Our study found that HOXC11 overexpressed in LUAD and was associated with worse overall survival. Moreover, its expression in lung cancer was regulated by IκB kinase α (IKKα), a pivotal kinase in NF-κB signaling, which was related to the ubiquitination of HOXC11. We further proved that HOXC11 could enhance the ability of proliferation, migration, invasion, colony formation, and the progression of the cell cycle in LUAD cells. Meanwhile, it also accelerated the formation of subcutaneous and lung metastases tumors. In contrast, loss of HOXC11 in LUAD cells significantly inhibited these malignant phenotypes. At the same time, HOXC11 regulated the expression of sphingosine kinase 1 (SPHK1) by directly binding to its promoter region. Therefore, we conclude that HOXC11 impacts the development of LUAD and facilitates lung cancer progression by promoting the expression of SPHK1.

Hyaluronidase-powered microneedles for significantly enhanced transdermal delivery efficiency.

Microneedles (MNs) with enhanced delivery efficiency have revolutionized the transdermal drug delivery system for treating systemic illness. However, the bioavailability of MNs was still far from the clinical requirements by only overcoming the stratum corneum barrier. Herein, hyaluronidase (HAase)-powered MNs were developed as a top-down permeation-enhancement strategy to hijack the sequential transdermal barriers for improved bioavailability. HAase MNs with robust mechanical strength showed excellent skin penetration ability and significantly enhanced the transdermal delivery efficacy of macromolecular drugs as compared to that of HAase-absent MNs, resulting in considerable effect to subcutaneous injection in terms of biodistribution, bioavailability, and therapeutical efficacy. As evidenced from the distribution of trypan blue and fluorescence underlying skin, the positive effects exerted by HAase MNs could be ascribed to the depolymerization of HA that would loosen the subcutaneous space and destruct the extracellular matrix barrier to promote drug diffusion and permeation in larger area and greater depth. Notably, the transient interconversion of keratin from α-helix to ß-sheet that might assist the drug residues on the skin surface permeate across the stratum corneum during administration might be another reason not to be ignored. As a labor-saving strategy, HAase-powered MNs offers a promising and painless administration route for macromolecules.

Fully armed photodynamic therapy with spear and shear for topical deep hypertrophic scar treatment.

5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) has emerged as a promising therapy for hypertrophic scar (HS). However, the poor permeability of ALA across biological barriers and pro-survival autophagy of fibroblasts largely restricted the efficacy of PDT. Herein, PDT was well equipped with spear and shear to overcome the therapeutic resistance. Specifically, hyaluronidase (HAase) based dissolving microneedles (MN)with improved stiffness and permeability were developed as a spear to deliver ALA into deep lesions by combating the dual barriers of stratum corneum and dense extracellular matrix (ECM). Besides, metformin (Met) MN was applied as a shear to intervene the respiration and autophagic process for amplified PDT. HAase significantly enhanced the in vitro and in vivo transdermal delivery efficiency of ALA, while the combination of HAase and Met successfully amplified the anti-scarring efficacy of PDT by elevating cytotoxicity, promoting permeation, activating signal pathways, and interdicting the autophagy process simultaneously. The pharmacodynamics study revealed that the combination therapy achieved the lowest scar elevation index (SEI), downregulated expression of collagen I and TGF-ß1, and decreased LC3 II/I ratio, showing excellent therapeutic efficacy. Therefore, such a fully armed PDT integrating double-prolonged attack on the physiological and pathological barriers offers a promising topical treatment for deep HS.

AIE-active polyelectrolyte based photosensitizers: the effects of structure on antibiotic-resistant bacterial sensing and killing and pollutant decomposition.

A facile and effective multifunctional platform with high bacterial detection sensitivity, good antibacterial activity, and excellent dye decomposition efficiency holds great promise for wastewater treatment. To explore the design rationality and mechanism of material platforms with various integrated components into a single molecule for wastewater treatment applications, herein, four kinds of polyelectrolyte photosensitizers with aggregation-induced emission (AIE) fluorescent units are synthesized and systematically studied to investigate the structure-property relationship that influences the level of conjugation and the hydrophobicity-hydrophilicity balance. By improving the strength of the conjugation, the new AIE photosensitizers DBPVEs (including DBPVE-4 and DBPVE-6) generate a reactive oxygen species (ROS), and a decomposition efficiency of around 55% is obtained for dyes when they are exposed to DBPVEs under white light irradiation, which is higher than those of DBPEs (including DBPE-4 and DBPE-6). More importantly, owing to the longer and more flexible aliphatic chains of DBPVE-6 that facilitate efficient intercalation into cell membranes, the staining ability of DBPVE-6 for methicillin-resistant S. epidermidis (MRSE) is greatly enhanced as compared to that of DBPVE-4. It should be noted that the antibacterial experiment indicates that DBPVE-6 displays potent toxicity to MRSE with 99.9% killing efficiency under white light irradiation. This work provides essential theoretical and experimental guidance on the designing of new photosensitizers for wastewater treatment.

Using dynamic cell communication improves treatment strategies of breast cancer.

Several insights from the clinical treatment of breast cancer patients have revealed that only a portion of patients achieve the expected curative effect after traditional targeted therapy, that surgical treatment may promote the development of cancer metastasis, and that the optimal combination of neoadjuvant chemotherapy and traditional treatment is not clear. Therefore, a more precise classification of breast cancer and selection of treatment methods should be undertaken to improve the efficacy of clinical treatment. In the clinical treatment of breast cancer, cell communication molecules are often selected as therapeutic targets. However, various cell communications are not static. Their dynamic changes are related to communicating cells, communicating molecules, and various intertwined internal and external environmental factors. Understanding the dynamic microenvironment can help us improve therapeutic efficacy and provide new ways to more accurately determine the cancer status. Therefore, this review describes multiple types of cellular communication in the breast cancer microenvironment and incorporates internal and external environmental factors as variable signaling factors in cell communication. Using dynamic and developmental concepts, we summarize the functional changes in signaling molecules and cells to aid in the diagnosis and treatment of breast cancer.

Two Chemically Stable Cd(II) Polymers as Fluorescent Sensor and Photocatalyst for Aromatic Dyes.

Two new 2D Cd(II)-based coordination polymers (CPs), viz. [Cd2(H2L)2(2,2'-bipy)2] (1) and [Cd(L)0.5(phen)·0.5H2O] (2), have been constructed using ethylene glycol ether bridging tetracarboxylate ligand 5,5'(4,4'-phenylenebis(methyleneoxy)) diisophthalic acid (H4L). Both CPs behaved as profound fluorescent sensor for Fe3+ ion and nitro-aromatics (NACs), specifically 2,4,6-trinitrophenol (TNP). The stability at elevated temperature and photocatalytic behaviors of both 1 and 2 for photo-decomposition of aromatic dyes have also been explored. An attempt has been made to explore the plausible mechanism related with the decrease in fluorescence intensity of 1 and 2 in presence of NACs using theoretical calculations. Additionally, the probable mechanism of photo catalysis by 1 and 2 to photo-degrade aromatic dyes has been explained using density of states (DOS) calculations.