Multi-directionally evaluating the formation mechanism of 1,4-dihydropyridine drug nanosuspensions through experimental validation and computer-aided drug design

The poor aqueous solubility of 1,4-dihydropyridine drugs needs to be solved urgently to improve bioavailability. Nanotechnology can improve drug solubility and dissolution by reducing particle size, but usually, a specific polymer or surfactant is required for stabilization. In this study, Poloxamer-407(P-407) was screened as the optimal stabilize through energy simulation, molecular docking, and particle size. the morphological study, X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, Raman, in vitro dissolution test, and molecular simulation of interactions were utilized to explore the formation mechanisms of four 1,4-dihydropyridine drugs/P-407 nanosuspensions. The result shows that the optimized nanosuspensions had the particle size in the nano-size range and maintained the original crystal state. The in vitro dissolution rate of the nanosuspension was 3-4 times higher than the corresponding API and could reduce the restriction of drug dissolution in different pH environments. Raman spectroscopy, FTIR, and molecular docking simulations provided strong supporting evidence for the formation mechanism of 1,4-dihydropyridine drugs/P-407 nanosuspensions at the molecular level, which confirmed that the stable intermolecular hydrogen bond adsorption and hydrophobic interaction were formed between the drug and P-407. This research will provide practical concepts and technologies, which are helpful to develop nanosuspensions for the same class of drugs.</p

Normalizing Tumor Blood Vessels to Improve Chemotherapy and Inhibit Breast Cancer Metastasis by Multifunctional Nanoparticles

The abnormal tumor blood vessels with high leakage can promote tumor cells to infiltrate into the systemic circulation and increase the risk of tumor metastasis. In addition, chemotherapy may destroy tumor blood vessels and further aggravate metastasis. Normalizing tumor blood vessels can reduce vascular leakage and increase vascular integrity. The simultaneous administration of vascular normalization drugs and chemotherapy drugs may resist the blood vessels’ destruction of chemotherapy. Here, multifunctional nanoparticles (CCM@LMSN/DOX&St), which combined chemotherapy with tumor blood vessel normalization, were prepared for the treatment of breast cancer. The results showed that CCM@LMSN/DOX&St-loaded sunitinib (St) promoted the expression of junction proteins Claudin-4 and VE-cadherin of endothelial cells, reversed the destruction of DOX to the endothelial cell layer, protected the integrity of the endothelial cell layer, and inhibited the migration of 4T1 tumor cells across the endothelial cell layer. In vivo experiments showed that CCM@LMSN/DOX&St effectively inhibited tumor growth in situ; what is exciting was that it also inhibited distal metastasis of breast cancer. CCM@LMSN/DOX&St encapsulated with St can normalize tumor blood vessels, reverse the damage of DOX to tumor blood vessels, increase the integrity of blood vessels, and prevent tumor cell invasion into blood vessels, which can inhibit breast cancer spontaneous metastasis and reduce chemotherapy-induced metastasis. This drug delivery platform effectively inhibited the progression of tumors and provided a promising solution for effective tumor treatment

Advanced MnO_<i>x</i>/TiO₂ Catalyst with Preferentially Exposed Anatase {001} Facet for Low-Temperature SCR of NO

MnO_<i>x</i>/TiO₂ (anatase) nanosheets (NS) with a preferentially exposed {001} facet was found to be a better catalyst for selective catalytic reduction (SCR) of NO than conventionally employed MnO_<i>x</i>/TiO₂ nanoparticles (NP) with the {101} facet preferentially exposed, affording both high NO conversion and high N₂ selectivity at 80–280 °C. Further investigations indicated that Mn³⁺ as the major species on TiO₂ (NS) was incorporated into octahedral vacancies with a lower polymerization degree, resulting in high catalytic activity for SCR and low activity for NH₃ oxidation, thus restraining the undesirable N₂O generation. In comparison, on the surface of TiO₂ (NP), Mn⁴⁺ as the major species was incorporated into tetrahedral vacancies in a highly polymerized state, leading to lower NO conversion and lower N₂ selectivity. The results indicate that it is possible to enhance the low-temperature SCR activity of the catalysts by tailoring the preferentially exposed facet of TiO₂

GSH-Responsive Polymeric Micelles for Remodeling the Tumor Microenvironment to Improve Chemotherapy and Inhibit Metastasis in Breast Cancer

The tumor microenvironment (TME) of breast cancer is hypoxic, which can promote tumor progression, including invasion and metastasis, and limit the efficacy of anti-tumor treatment. Nitric oxide (NO) can dilate blood vessels, effectively alleviate hypoxia, and regulate the TME, which has the potential to improve the anti-tumor therapeutic efficacy. Here, chitosan (CO) and octadecylamine (ODA) were linked by the disulfide bond, and the LinTT1 peptide was linked onto CO–SS–ODA for targeting tumor cells and endothelial cells in tumors. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) was connected to CO. Doxorubicin (DOX) was encapsulated, and GSH hierarchically responsive polymer micelles (TSCO–SS–ODA/DOX) were constructed for the treatment of breast cancer. The micelles had differently responsive drug release in different GSH concentrations. In endothelial cells, the micelles rapidly responded to release NO. In tumor cells, the disulfide bond rapidly broke and released DOX to effectively kill tumor cells. The disulfide bond was not sensitive to GSH concentration in endothelial cells, which had less release of DOX. The killing effect of the micelles to endothelial cells was much lower than that to tumor cells. The cell selective drug release of the drug delivery systems enabled safe and effective treatment of drugs. TSCO–SS–ODA/DOX, which had the excellent ability to target tumors, can alleviate tumor hypoxia, decrease the infiltration of M2 macrophages in tumors, increase the infiltration of M1 macrophages in tumors, and remodel the TME. Notably, TSCO–SS–ODA/DOX can significantly inhibit the growth of the primary tumor and effectively inhibit tumor metastasis. The drug delivery system provided a potential solution for effectively treating breast cancer

Autoantigenic Peptide and Immunomodulator Codelivery System for Rheumatoid Arthritis Treatment by Reestablishing Immune Tolerance

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by abnormal activation of CD4+ T cells and an imbalance of T helper 17 (Th17) and regulatory T (Treg) cells. Tolerogenic therapy via administration of self-antigens is a promising strategy for RA treatment, but delivery of autoantigens alone may exacerbate disease conditions. Current studies indicated that codelivery of autoantigens with immunomodulators can lead to a more tolerogenic immune response. Here, we constructed an autoantigen type II collagen peptide (CII250–270)- and immunomodulator leflunomide (LEF)-coloaded phosphatidylserine liposome vaccine (CII250–270-LEF-PSL) for RA treatment via induction of tolerant dendritic cells (tolDC) for further activation of Treg cells. The in vivo results showed that CII250–270-LEF-PSL can effectively induce tolDC, regulate the balance of Th1/Th2 and Th17/Treg, and reduce the secretion of pro-inflammatory cytokines (IFN-γ, IL-1β, and IL-17A) and IgG antibodies to inhibit synovial inflammation and bone erosion. Furthermore, our study also suggested that LEF regulated Th1 cell differentiation by inhibiting the activation of the JAK1/STAT1 signaling pathway, further alleviating RA. Overall, this work proved that the combination of autoantigenic peptides and immunomodulators was a promising modality for RA treatment by reestablishing antigen-specific immune tolerance, which also inspired additional insights into the development of combination therapies for the tolerability of RA

Targeting High Expressed α₅β₁ Integrin in Liver Metastatic Lesions To Resist Metastasis of Colorectal Cancer by RPM Peptide-Modified Chitosan-Stearic Micelles

Liver metastasis is a leading death cause in colorectal cancer. The pathological differences between orthotopic tumors and metastatic lesions increased the therapeutic difficulty of metastasis. Herein, the α₅β₁ integrin receptor expression on metastatic cells was first measured, the result showed that metastatic cells expressed the α₅β₁ integrin higher than that of the original cells from orthotopic tumors. Afterward, RPM peptide-modified chitosan-stearic (RPM-CSOSA) was designed based on α₅β₁ integrin expression. The cytotoxicity and resistance to migration and the invasion ability of the targeting drug delivery system loading doxorubicin (DOX) and curcumin (CUR) were evaluated in vitro. The metastatic inhibition of the targeting drug delivery system was also investigated in HT29 liver metastatic models. The modified RPM peptide could increase the cellular internalization of CSOSA micelles in metastatic tumor cells and endothelial cells mediated by α₅β₁ integrin. The synergistic effects of RPM-CSOSA/DOX and RPM-CSOSA/CUR could obviously inhibit migratory and invasive abilities of HT29 cells and endothelial cells. Moreover, the RPM-CSOSA/DOX&RPM-CSOSA/CUR could obviously decrease the number of metastatic sites by 86.96%, while CSOSA/DOX&CSOSA/CUR decreased liver metastasis by 66.58% compared with that in the saline group. In conclusion, the RPM peptide-modified drug delivery system may provide insights into targeting the metastatic cells overexpressing the α₅β₁ integrin, and it has the potential to inhibit liver metastasis of colorectal cancer

NIR-Triggered Thermosensitive Nanoreactors for Dual-Guard Mechanism-Mediated Precise and Controllable Cancer Chemo-Phototherapy

Thermosensitive nanoparticles can be activated by externally applying heat, either through laser irradiation or magnetic fields, to trigger the release of drug payloads. This controlled release mechanism ensures that drugs are specifically released at the tumor site, maximizing their effectiveness while minimizing systemic toxicity and adverse effects. However, its efficacy is limited by the low concentration of drugs at action sites, which is caused by no specific target to tumor sties. Herein, hyaluronic acid (HA), a gooey, slippery substance with CD44-targeting ability, was conjugated with a thermosensitive polymer poly(acrylamide-co-acrylonitrile) to produce tumor-targeting and thermosensitive polymeric nanocarrier (HA-P) with an upper critical solution temperature (UCST) at 45 °C, which further coloaded chemo-drug doxorubicin (DOX) and photosensitizer Indocyanine green (ICG) to prepare thermosensitive nanoreactors HA-P/DOX&ICG. With photosensitizer ICG acting as the “temperature control element”, HA-P/DOX&ICG nanoparticles can respond to temperature changes when receiving near-infrared irradiation and realize subsequent structure depolymerization for burst drug release when the ambient temperature was above 45 °C, achieving programmable and on-demand drug release for effective antitumor therapy. Tumor inhibition rate increased from 61.8 to 95.9% after laser irradiation. Furthermore, the prepared HA-P/DOX&ICG nanoparticles possess imaging properties, with ICG acting as a probe, enabling real-time monitoring of drug distribution and therapeutic response, facilitating precise treatment evaluation. These results provide enlightenment for the design of active tumor targeting and NIR-triggered programmable and on-demand drug release of thermosensitive nanoreactors for tumor therapy

Video_9_Intradermal Injection of Oxytocin Aggravates Chloroquine-Induced Itch Responses via Activating the Vasopressin-1a Receptor/Nitric Oxide Pathway in Mice.mp4

Oxytocin (OT), a hormone synthesized within the paraventricular nucleus and supraoptic nucleus of the hypothalamus, when given intracerebroventricularly, induces strong scratching behaviors. However, it is not clear whether intradermal injection (ID) of OT elicits itch sensation. Herein, we found that OT (0.02 mg/ml) did not elicit an itch-scratching response in mice but aggravated chloroquine (CQ, 3 mmol/L)-elicited scratching behavior. Similar to OT, arginine vasopressin (AVP, 0.02 mg/ml), which is structurally related to OT, also enhanced CQ-induced scratching behavior but did not directly induce scratching behavior in mice. Mechanistically, OT-mediated enhancement of CQ-induced scratching behavior was significantly suppressed by conivaptan (0.05 mg/ml), a vasopressin-1a receptor (V1AR) antagonist and 1,400 W (3 mg/kg), inhibitor of inducible nitric oxide synthase (iNOS), but not OT receptor (OTR) antagonist L-368,899 (0.05 mg/ml). Notably, conivaptan also directly decreased CQ-induced scratching. In conclusion, OT plays a role in CQ-induced scratching behavior via V1AR binding events. V1AR antagonists could be used as possible treatments for CQ-induced itch.</p

A54 Peptide Modified and Redox-Responsive Glucolipid Conjugate Micelles for Intracellular Delivery of Doxorubicin in Hepatocarcinoma Therapy

Redox-responsive nanomaterials applied in drug delivery systems (DDS) have attracted an increasing attention in pharmaceutical research as a carrier for antitumor therapy. However, there would be unwanted drug release from a redox-responsive DDS with no selection at nontarget sites, leading to undesirable toxicities in normal tissues and cells. Here, an A54 peptide modified and PEGylated reduction cleavable glucolipid conjugate (A54-PEG-CSO-ss-SA, abbreviated to APCssA) was designed for intracellular delivery of doxorubicin (DOX). The synthesized APCssA could be assembled via micellization self-assembly in aqueous water above the critical micelle concentration (54.9 μg/mL) and exhibited a high drug encapsulation efficiency (77.92%). The APCssA micelles showed an enhanced redox sensitivity in that the disulfide bond could be degraded quickly and the drug would be released from micelles in 10 mM levels of glutathione (GSH). The cellular uptake studies highlighted the affinity of APCssA micelles toward the hepatoma cells (BEL-7402) compared to that toward HepG2 cells. In contrast with the nonresponsive conjugate, the drug was released from APCssA micelles more quickly in 10 mM level of GSH concentration (tumor cells). Moreover, the DOX-loaded APCssA micelles displayed an increased cytotoxicity which was 1.6- to 2.0-fold that of unmodified and nonresponsive micelles. In vivo, the APCssA micelles had stronger distribution to liver and hepatoma tissue and prolonged the circulation and retention time, while the drug release only occurred in the tumor tissue. The APCssA/DOX showed the tumor inhibition rate equal to that of commercial doxorubicin hydrochloric without negative consequence. This study suggested that the APCssA/DOX showed promising potential to treat the tumor for its special tumor targeting, selective intracellular drug release, enhanced antitumor activity, and reduced toxicity on normal tissues