Observation of plaid-like spin splitting in a noncoplanar antiferromagnet.

Spatial, momentum and energy separation of electronic spins in condensed-matter systems guides the development of new devices in which spin-polarized current is generated and manipulated1-3. Recent attention on a set of previously overlooked symmetry operations in magnetic materials4 leads to the emergence of a new type of spin splitting, enabling giant and momentum-dependent spin polarization of energy bands on selected antiferromagnets5-10. Despite the ever-growing theoretical predictions, the direct spectroscopic proof of such spin splitting is still lacking. Here we provide solid spectroscopic and computational evidence for the existence of such materials. In the noncoplanar antiferromagnet manganese ditelluride (MnTe2), the in-plane components of spin are found to be antisymmetric about the high-symmetry planes of the Brillouin zone, comprising a plaid-like spin texture in the antiferromagnetic (AFM) ground state. Such an unconventional spin pattern, further found to diminish at the high-temperature paramagnetic state, originates from the intrinsic AFM order instead of spin-orbit coupling (SOC). Our finding demonstrates a new type of quadratic spin texture induced by time-reversal breaking, placing AFM spintronics on a firm basis and paving the way for studying exotic quantum phenomena in related materials.

Integrated manganese (III)-doped nanosystem for optimizing photothermal ablation: Amplifying hyperthermia-induced STING pathway and enhancing antitumor immunity.

Despite the great promise initially demonstrated by photothermal ablation (PTA) therapy, its inability to completely ablate large tumors is problematic, because this has been found to result in residual tumors at ablation margins and bring a relative high rate of subsequent recurrences and metastases. To address this issue, we herein report a smart photothermal nanosystem (PBM) based on FDA-approved Prussian blue (PB) nanoparticles, doped with Mn (III) to suppress the tumor debris left by incomplete ablation. Notably, our study demonstrated that PTA-induced hyperthermia plays a crucial role in initiating the cGAS-STING pathway by generating damaged cytosolic DNA. This PBM nanosystem, which consumes glutathione and continuously releases Mn(II), further amplifies the PTA-induced cGAS-STING pathway in CT26 colon and 4T1 breast tumor models. Moreover, treatment with PBM following PTA boosted the robust immune response in situ and extended to the whole body with a remarkable suppression effect on both local residual and distant tumors. This work, which improves the antitumor efficacy of nonablated areas utilizing hyperthermia-enhanced immune therapy, may therefore provide a promising adjuvant antitumor strategy for the issue of incomplete ablation. STATEMENT OF SIGNIFICANCE: This work discovered, for the first time, that photothermal ablation-induced hyperthermia plays a crucial role in initiating the cGAS-STING pathway. Taking advantage of this finding, we developed a smart photothermal material (PBM) tailored for incomplete tumor ablation. This integrated Mn(III)-doped nanosystem (PBM) demonstrated superior therapeutic benefits due to the thermal ablation process and immune enhancement. As the photothermal ablation-induced cGAS-STING pathway was triggered, the released Mn(III) consumes GSH while continuously transferred to Mn(II), which further amplified STING activation and facilitated a more robust antitumor immunity, thereby remarkably inhibiting both local residual and distant tumors in virtue of the biological changes under thermal ablation.

Development of a Novel MR Colonography via Iron-Based Solid Lipid Nanoparticles.

PURPOSE: To develop an iron-based solid lipid nanoparticle (SLN) absorbable by the intestinal wall and assess the differential diagnostic value of intestinal lesions in magnetic resonance imaging (MRI). METHODS: SLNs were prepared with the simultaneous loading of trivalent Fe ions (Fe3+), levodopa methyl ester (DM), and fluorescein isothiocyanate (FITC). We evaluated the particle size, loading rate, encapsulation efficiency, and cytotoxicity of SLNs. The T1 contrast effects of the FeDM-FITC-SLNs and gadolinium-based contrast agent (GBCA) were compared in different mouse models: acute ulcerative colitis (AUC), chronic ulcerative colitis (CUC), colon adenocarcinoma (COAD), and normal control. MRI was performed in the same mouse with intravenous injection of GBCA on day 1 and enema of FeDM-FITC-SLNs on day 2. The signal-to-noise ratios (SNRs) were compared using one-way analysis of variance. Tissues were then collected for histology. RESULTS: The average particle size of FeDM-FITC-SLN was 220 nm. The mean FeDM loading rate was 94.3%, and the encapsulation efficiency was 60.3%. The relaxivity was 4.02 mM-1·s-1. After enema with FeDM-FITC-SLNs, MRI showed the following contrast enhancement duration: AUC = COAD > normal > CUC. Confocal fluorescence microscopy confirmed that FeDM-FITC-SLNs were mainly distributed in the intestinal mucosa and tumor capsule. CONCLUSION: Iron-based SLNs are promising alternatives for contrast enhancement at T1-weighted MRI and will help in the differential diagnosis of intestinal bowel diseases (IBDs).

Progress and perspective of microneedle system for anti-cancer drug delivery.

Transdermal drug delivery exhibited encouraging prospects, especially through superficial drug administration routes. However, only a few limited lipophilic drug molecules could cross the skin barrier, those are with low molecular weight and rational Log P value. Microneedles (MNs) can overcome these limitations to deliver numerous drugs into the dermal layer by piercing the outermost skin layer of the body. In the case of superficial cancer treatments, topical drug administration faces severely low transfer efficiency, and systemic treatments are always associated with side effects and premature drug degradation. MN-based systems have achieved excellent technical capabilities and been tested for pre-clinical chemotherapy, photothermal therapy, photodynamic therapy, and immunotherapy. In this review, we will focus on the features, progress, and opportunities of MNs in the anticancer drug delivery system. Then, we will discuss the strategies and advantages in these works and summarize challenges, perspectives, and translational potential for future applications.

Integration of Polymerization and Biomineralization as a Strategy to Facilely Synthesize Nanotheranostic Agents.

Integration of biological macromolecules with inorganic materials via biomineralization has demonstrated great potential for development of nanotheranostic agents. To produce multifunctionality, integration of multiple components in the biomineralized theranostic agents is required; however, how to efficiently and reproducibly implement this is challenging. In this report, a universal biomineralization strategy is developed by incorporation of oxidization polymerization into albumin-templated biomineralization for facile synthesis of nanotheranostic agents. A series of biomineralized polymers and manganese dioxide hybrid nanoparticles (PMHNs) can be synthesized via the polymerization of various monomers, including dopamine (DA), epigallocatechin (EGC), pyrrole (PY), and diaminopyridine (DP), along with the reduction of KMnO4 and formation of manganese dioxide nanoparticles in albumin templates. These biomineralized PMHNs demonstrate ultrahigh MRI (longitudinal relaxivity up to 38 mM-1 s-1) and ultrasonic (US) imaging contrasting capabilities and have excellent photothermal therapy efficacy with complete ablation of orthotopic tumors. Moreover, these biomineralized hybrid nanoparticles can be effectively excreted through the kidneys, avoiding potential systemic toxicity. Thus, integration of polymerization into biomineralization presents a strategy for the fabrication of hybrid nanomaterials, allowing the production of multifunctional and biocompatible nanotheranostic agents via a facile one-pot method.

Solid lipid nanoparticles as carriers for oral delivery of hydroxysafflor yellow A.

Hydroxysafflor yellow A (HSYA) is the main bioactive flavonoid extracted from the flower of Carthamus tinctorius L., which is widely used in traditional Chinese medicine for the treatment of myocardial ischemia and cerebral ischemia. HSYA has high water solubility but poor intestinal membrane permeability, resulting in low oral bioavailability. Currently, only HSYA sodium chloride injection has been approved for clinical use and oral formulations are urgently needed. In this study, HSYA solid lipid nanoparticles (SLNs) with the structure of w/o/w were prepared by a warm microemulsion process using approved drug excipients for oral delivery to increase the oral absorption of HSYA. The optimized HSYA SLNs are spherical with an average size of 214nm and the encapsulation efficiency is 55%. HSYA SLNs exhibited little cytotoxicity in Caco-2 and Hela cells, but increased the oral absorption of HSYA about 3.97-fold in rats, compared to HSYA water solution. In addition, cycloheximide pretreatment significantly decreased the oral absorption of HSYA delivered by SLNs. Importantly, the pharmacodynamics evaluation demonstrated that SLNs further decreased the infarct areas in rats. In conclude, SLNs could be a promising delivery system to enhance the oral absorption and pharmacological activities of HSYA.

Pharmacokinetics, tissue distribution and anti-tumour efficacy of paclitaxel delivered by polyvinylpyrrolidone solid dispersion.

OBJECTIVES: Paclitaxel is a potent anti-cancer drug that has exhibited clinical activity against several tumours. Unfortunately, serious side effects are associated with Taxol, the commercial formulation of paclitaxel, which contains Cremophor EL (CrEL). Currently, the main focus of developing paclitaxel formulations is on improving efficacy and reducing toxicity. A novel, Cremophor-free, paclitaxel solid dispersion (PSD) was prepared in our laboratory previously. The primary aim of this study was to evaluate the pharmacokinetics, tissue distribution, acute toxicity and anti-tumour efficacy of the PSD compared with Taxol. METHODS: SD rats were used to examine the pharmacokinetics and tissue distribution of PSD. The acute toxicity of PSD was evaluated in ICR mouse. The anti-tumor activity of PSD was assessed in an in vivo anti-tumor nude mice model inoculated with human SKOV-3 cancer cells. KEY FINDINGS: The two formulations presented different pharmacokinetic behaviour. The plasma AUC of paclitaxel in the PSD was 5.84-fold lower than that of Taxol, and the mean residence time, total body clearance and apparent volume of distribution of paclitaxel in the PSD were increased by 1.73, 4.67 and 8.57 fold, respectively. However, the two formulations showed similar tissue distribution properties. CrEL, the vehicle in Taxol, decreased the clearance of paclitaxel from plasma. The LD50 (median lethal dose) was 34.8 mg/kg for Taxol, whereas no death was observed at 160 mg/kg for the PSD. The anti-tumour activity of PSD was similar to that of Taxol at a dose of 15 mg/kg. Most importantly, the improved tolerance of PSD enabled a higher administrable dose of paclitaxel, which resulted in improved efficacy compared with Taxol administered at its maximum tolerated dose. CONCLUSIONS: These results suggest that the PSD, a CrEL-free formulation, is a promising approach to increase the safety and efficacy of paclitaxel.

Halogen-enriched fragment libraries as leads for drug rescue of mutant p53.

The destabilizing p53 cancer mutation Y220C creates a druggable surface crevice. We developed a strategy exploiting halogen bonding for lead discovery to stabilize the mutant with small molecules. We designed halogen-enriched fragment libraries (HEFLibs) as starting points to complement classical approaches. From screening of HEFLibs and subsequent structure-guided design, we developed substituted 2-(aminomethyl)-4-ethynyl-6-iodophenols as p53-Y220C stabilizers. Crystal structures of their complexes highlight two key features: (i) a central scaffold with a robust binding mode anchored by halogen bonding of an iodine with a main-chain carbonyl and (ii) an acetylene linker, enabling the targeting of an additional subsite in the crevice. The best binders showed induction of apoptosis in a human cancer cell line with homozygous Y220C mutation. Our structural and biophysical data suggest a more widespread applicability of HEFLibs in drug discovery.

CDKI-71, a novel CDK9 inhibitor, is preferentially cytotoxic to cancer cells compared to flavopiridol.

Cancer cells appear to depend heavily on antiapoptotic proteins for survival and so targeted inhibition of these proteins has therapeutic potential. One innovative strategy is to inhibit the cyclin-dependent kinases (CDKs) responsible for the regulation of RNA polymerase II (RNAPII). In our study, we investigated the detailed cellular mechanism of a novel small-molecule CDK inhibitor (CDKI-71) in cancer cell lines, primary leukemia cells, normal B - & T- cells, and embryonic lung fibroblasts and compared the cellular and molecular responses to the clinical CDK inhibitor, flavopiridol. Like flavopiridol, CDKI-71 displayed potent cytotoxicity and caspase-dependent apoptosis induction that were closely associated with the inhibition of RNAPII phosphorylation at serine-2. This was caused by effective targeting of cyclinT-CDK9 and resulted in the downstream inhibition of Mcl-1. No correlation between apoptosis and inhibition of cell-cycle CDKs 1 and 2 was observed. CDKI-71 showed a 10-fold increase in potency in tumor cell lines when compared to MRC-5 human fibroblast cells. Significantly, CDKI-71 also demonstrated potent anti-chronic lymphocytic leukemia activity with minimal toxicity in normal B- and T-cells. In contrast, flavopiridol showed little selectivity between cancer and normal cells. Here, we provide the first cell-based evidence that flavopiridol induces DNA double-strand breaks: a fact which may explain why flavopiridol has such a narrow therapeutic window in preclinical and clinical settings. Taken together, our data provide a rationale for the development of selective CDK inhibitors as therapeutic agents and CDKI-71 represents a promising lead in this context.