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.