Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood-brain barrier and exhibits potent activity against glioblastoma

Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly controlled.Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment.Therefore,this study developed a novel and selective inhibitor of CSFIR and VEGFR,SYHA1813,possessing potent antitumor activity against GBM.SYHA1813 inhibited VEGFR and CSFIR kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo.SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models,including temozolomide(TMZ)insensitive tumors.Notably,SYHA1813 could penetrate the blood-brain barrier(BBB)and prolong the survival time of mice bearing intracranial GBM xenografts.Moreover,SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody.As a clinical proof of concept,SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial.The data of this study support the rationale for an ongoing phase I clinical study(ChiCTR2100045380).

Bioactive elements manipulate bone regeneration

While bone tissue is known for its inherent regenerative abilities,various pathological conditions and trauma can disrupt its meticulously regulated processes of bone formation and resorption.Bone tissue engineering aims to replicate the extracellular matrix of bone tissue as well as the sophisticated biochemical mechanisms crucial for effective regeneration.Traditionally,the field has relied on external agents like growth factors and pharmaceuticals to modulate these processes.Although efficacious in certain scenarios,this strategy is compromised by limitations such as safety issues and the transient nature of the compound release and half-life.Conversely,bioactive elements such as zinc(Zn),magnesium(Mg)and silicon(Si),have garnered increasing interest for their therapeutic benefits,superior stability,and reduced biotic risks.Moreover,these elements are often incorporated into biomaterials that function as multifaceted bioactive components,facilitating bone regeneration via release on-demand.By elucidating the mechanistic roles and therapeutic efficacy of the bioactive elements,this review aims to establish bioactive elements as a robust and clinically viable strategy for advanced bone regeneration.

One-pot synthesis of hydroxyapatite hybrid bioinks for digital light processing 3D printing in bone regeneration

Three-dimensional(3D)bioprinting has revolutionized tissue engineering by enabling precise fabrication with bioinks.Among these techniques,digital light processing(DLP)stands out due to its exceptional resolution,speed,and biocompatibility.However,the progress of DLP is hindered by the limited availability of suitable bioinks.Currently,some studies involve simple mixing of different materials,resulting in bioinks that lack uniformity and photopolymerization characteristics.To address this challenge,we present an innovative one-pot synthesis method for bioinks based on methacrylated gelatin/alginate with hydroxyapatite(HAP).This approach offers significant advantages in terms of efficiency and uniformity.The synthesized bioinks demonstrate excellent printability,stability,and notably enhanced mechanical properties,facilitating optimal in vitro compatibility.Additionally,the HAP-hybrid bioinks printed scaffolds demonstrated impressive bone repair capabilities in vivo compared with pure organic bioinks.In conclusion,the Gel/Alg/HAP bioinks presented herein offer an innovative solution for DLP bioprinting within the field of bone tissue engineering.Their multifaceted advantages help overcome the limitations of restricted bioink choices,pushing forward the boundaries of bioprinting technology and contributing to the progress of regenerative medicine and tissue engineering.

Boosting cartilage repair with silk fibroin-DNA hydrogel-based cartilage organoid precursor

Osteoarthritis(OA),a common degenerative disease,is characterized by high disability and imposes substantial economic impacts on individuals and society.Current clinical treatments remain inadequate for effectively managing OA.Organoids,miniature 3D tissue structures from directed differentiation of stem or progenitor cells,mimic native organ structures and functions.They are useful for drug testing and serve as active grafts for organ repair.However,organoid construction requires extracellular matrix-like 3D scaffolds for cellular growth.Hydrogel microspheres,with tunable physical and chemical properties,show promise in cartilage tissue engineering by replicating the natural microenvironment.Building on prior work on SF-DNA dual-network hydrogels for cartilage regeneration,we developed a novel RGD-SF-DNA hydrogel microsphere(RSD-MS)via a microfluidic system by integrating photopolymerization with self-assembly techniques and then modified with Pep-RGDfKA.The RSD-MSs exhibited uniform size,porous surface,and optimal swelling and degradation properties.In vitro studies demonstrated that RSD-MSs enhanced bone marrow mesenchymal stem cells(BMSCs)proliferation,adhesion,and chondrogenic differentiation.Transcriptomic analysis showed RSD-MSs induced chondrogenesis mainly through integrin-mediated adhesion pathways and glycosaminoglycan biosynthesis.Moreover,in vivo studies showed that seeding BMSCs onto RSD-MSs to create cartilage organoid precursors(COPs)significantly enhanced cartilage regeneration.In conclusion,RSD-MS was an ideal candidate for the construction and long-term cultivation of cartilage organoids,offering an innovative strategy and material choice for cartilage regeneration and tissue engineering.

MMP13-targeted siRNA-loaded micelles for diagnosis and treatment of posttraumatic osteoarthritis

Posttraumatic osteoarthritis(PTOA)patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective.Early PTOA is characterized by overexpressed matrix metalloprotease 13(MMP13).Herein,we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable,cyanine 5(Cy5)-containing PEG,black hole quencher-3(BHQ3),and cRGD ligands and loaded with siRNA silencing MMP13(siM13),namely ERMs@siM13.ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell,causing cRGD exposure.Accordingly,the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surfaceαvβ3 integrin,increasing intracellular siM13 delivery for on-demand MMP13 downregulation.Meanwhile,the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle,precisely reflecting the diseased cartilage state.In particular,the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity,enabling the physicians to adjust the therapeutic regimen.Finally,in the murine PTOA model,ERMs@siM13 could diagnose the early-stage PTOA,perform timely interventions,and monitor the OA progression level during treatment through a real-time detection of MMP13.Therefore,ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.

Branched-chain amino acid transaminase 1 confers EGFRTKI resistance through epigenetic glycolytic activation

Third-generation EGFR tyrosine kinase inhibitors(TKIs),exemplified by osimertinib,have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer(NSCLC).Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application(NDA)submission in China.Despite substantial progress,acquired resistance to EGFR-TKIs remains a significant challenge,impeding the long-term effectiveness of therapeutic approaches.In this study,we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models,and found a notable upregulation of branched-chain amino acid transaminase 1(BCAT1)expression in both osimertinib-and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors.Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs.Mechanistically,upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid(BCAA)metabolism and promoted alpha ketoglutarate(α-KG)-dependent demethylation of lysine 27 on histone H3(H3K27)and subsequent transcriptional derepression of glycolysis-related genes,thereby enhancing glycolysis and promoting tumor progression.Moreover,we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression.In summary,our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC,thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.