Showing papers by "Zhiyuan Zhong published in 2023"

Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid‐Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia

Abstract: Acute myeloid leukemia (AML) is the most refractory hematologic malignancy characterized by acute onset, rapid progression, and high recurrence rate. Here, codelivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors using phenylboronic acid‐functionalized polypeptide nanovehicles to achieve synergetic and potent treatment of AML is adopted. Leveraging the dynamic boronic ester bonds, BN coordination, and π–π stacking, the nanovehicles reveal remarkably efficient and robust drug coencapsulation. ABT199 can induce a series of pro‐apoptotic reactions by promoting the dissociation of the pro‐apoptotic protein Bim from BCL2, while the released Bim is often captured by MCL1 protein overexpressed in AML. TW37 has a strong inhibitory ability to MCL1, thereby can restrain the depletion of Bim protein. Dual inhibitor‐loaded nanoparticles (NPAT) reveal excellent stability, acid/enzyme/H2O2‐triggered drug release, and significant cytotoxicity toward MOLM‐13‐Luc and MV‐411 AML cells with low half maximal inhibitory concentrations of 1.15 and 7.45 ng mL−1, respectively. In mice bearing MOLM‐13‐Luc or MV‐411 AML cancer, NPAT reveal significant inhibition of tumor cell infiltration in bone marrow and main organs, potent suppression of tumor growth, and remarkably elevated mouse survival. With facile construction, varying drug combination, superior safety, synergetic efficacy, the phenylboronic acid‐functionalized smart nanodrugs hold remarkable potential for AML treatment.

Nanoparticle-Mediated STING Activation for Cancer Immunotherapy.

Abstract: As the first line of host defense against pathogenic infections, innate immunity plays a key role in antitumor immunotherapy. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) (cGAS-STING) pathway attracts numerous attentions because of the secretion of various proinflammatory cytokines and chemokines. Many STING agonists have been identified and applied into preclinical or clinical trials for cancer immunotherapy. However, the fast excretion, low bioavailability, non-specificity and adverse effects of the small molecule STING agonists limit their therapeutic efficacy and in vivo application. Nano-delivery systems with appropriate size, charge and surface modification are capable of addressing these dilemmas. In this review, we discuss the mechanism of cGAS-STING pathway and summarize the STING agonists, focusing on nanoparticle-mediated STING therapy and combined therapy for cancers. Finally, the future direction and challenges of nano-STING therapy are expounded, emphasizing the pivotal scientific problems and technical bottlenecks and hoping to provide general guidance for its clinical application. This article is protected by copyright. All rights reserved.

Exogenous Antigen Upregulation Empowers Antibody Targeted Nanochemotherapy of Leukaemia.

Abstract: Acute myeloid leukaemia (AML) is afflicted by high mortality rate and few treatment options. The lack of specific surface antigens severely hampers the development of targeted therapeutics and cell therapy. Here, we show that exogenous all-trans retinoic acid (ATRA) mediates selective and transient CD38 upregulation on leukaemia cells by up to 20 folds, which enables high-efficiency targeted nanochemotherapy of leukaemia with daratumumab antibody-directed polymersomal vincristine sulfate (DPV). Strikingly, treatment of two CD38-low expressing AML orthotopic models with ATRA and DPV portfolio strategy effectively eliminates circulating leukaemia cells and leukaemia invasion into bone marrow and organs, leading to exceptional survival benefits with 20-40% mice becoming leukaemia-free. The combination of exogenous CD38 upregulation and antibody-directed nanotherapeutics provides a unique and powerful targeted therapy for leukaemia. This article is protected by copyright. All rights reserved.

CD38-selective immuno-nano-DM1 conjugates for depleting multiple myeloma.

Abstract: Multiple myeloma (MM) is a neoplasm of aberrant plasma cells and ranks second among hematologic malignancies. Despite a substantial improvement in clinical outcomes with advances in therapeutic modalities over the past two decades, MM remains incurable, necessitating the development of new and potent therapies. Herein, we engineered a daratumumab-polymersome-DM1 conjugate (DPDC) based highly potent and CD38-selective immuno-nano-DM1 toxin for depleting MM cells in vivo. DPDC with controllable daratumumab density and disulfide-linked DM1 is of small size (51-56 nm), with high stability and reduction-triggered DM1 release. D6.2PDC potently inhibited the proliferation of CD38-overexpressed LP-1 and MM.1S MM cells with IC50 values of 2.7 and 1.2 ng DM1 equiv. per mL, about 4-fold stronger than non-targeted PDC. Moreover, D6.2PDC effectively and safely depleted LP-1-Luc MM cells in an orthotopic mouse model at a low DM1 dosage of 0.2 mg kg-1, thus alleviating osteolytic bone lesion and extending the median survival by 2.8-3.5-fold compared to all controls. This CD38-selective DPDC provides a safe and potent treatment strategy for MM.

Water Recycling in the Deep Earth: Insights From Integrated μ‐XRF, THz‐TDS Spectroscopy, TG, and DCS of High‐Pressure Granulite

Abstract: Subduction‐related dehydration and exhumation‐related rehydration play an important role in water recycling on Earth. Water can be transported to the deep mantle through crustal subduction, whereas the behavior of water in the subducted crust during exhumation remains enigmatic. Here, we use an integrated micro X‐ray fluorescence spectrometry, transmission terahertz time‐domain, thermogravimetry, and differential scanning calorimetry approach for the first time on high‐pressure mafic granulite and amphibolite to investigate the water species and contents, as well as exhumation rehydration reactions. Our study demonstrates that garnet, hornblende, and ilmenite contain considerable amounts, and plagioclase contains minor amounts of water as molecular and structural species, whereas quartz contains only a minor amount of structural water. Water released from garnet and external fluids from the grain boundary will either migrate into hornblende, plagioclase, ilmenite, and quartz, or stored in the mantle wedge, or further subducted into the deep mantle. We suggest that water recycling between the Earth's surface and deep mantle is an unequilibrium process, and the lower crust and mantle may store a significant amount of water in deep Earth and can function as a container to feed and maintain the water recycling balance.

Mannose-mediated nanodelivery of methotrexate to macrophages augments rheumatoid arthritis therapy.

Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease that gravely jeopardizes the quality of life of numerous people. Methotrexate (MTX) is a disease-modifying anti-rheumatic drug commonly used in clinics; however, it suffers from slow onset, moderate efficacy, and adverse reactions such as renal dysfunction, myelosuppression, and bone erosion after long-term treatment. Here, we explored macrophage targeted delivery of MTX using mannose-installed chimaeric polymersomes (Man-PMTX) as an advanced treatment for RA. Man-PMTX exhibited high (∼18 wt%) and robust loading of MTX, uniform size of 51-55 nm, minimal hemolytic activity, and glutathione-actuated drug release property. Man-PMTX showed better uptake by activated macrophages than PMTX, and more repolarization of bone marrow-derived macrophages (BMDMs) to anti-inflammatory M2 type macrophages and less secretion of TNF-α and IL-1β compared with free MTX and PMTX. In vivo studies revealed that Man-PMTX showed significantly higher accumulation in inflammatory joints than in healthy joints and effectively treated RA by relieving inflammation, repolarizing macrophages from M1 type to M2 type, and mitigating proinflammatory cytokines. Accordingly, Man-PMTX effectively protected the synovium and bone from damage. Mannose-mediated nanodelivery of methotrexate to macrophages appears to be an attractive strategy to augment rheumatoid arthritis therapy.