A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization

Glioma is a primary aggressive brain tumor with high recurrence rate. The poor efficiency of chemotherapeutic drugs crossing the blood‒brain barrier (BBB) is well-known as one of the main challenges for anti-glioma therapy. Moreover, massive infiltrated tumor-associated macrophages (TAMs) in glioma further thwart the drug efficacy. Herein, a therapeutic nanosystem (SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera (PROTAC) ARV-825 into the complex micelle (SPP) composed of substance P (SP) peptide-modified poly(ethylene glycol)-poly(d,l-lactic acid)(SP-PEG-PDLLA) and methoxy poly(ethylene glycol)-poly(d,l-lactic acid) (mPEG-PDLLA, PP), which could penetrate BBB and target brain tumor. Subsequently, released drug engenders antitumor effect via attenuating cells proliferation, inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6, STAT3 and AKT. Taken together, our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma, which may provide a novel strategy for glioma therapy in future.

Modified atlantooccipital decompression combined with occipitocervical internal fixation in treatment of Chiari malformation type I with syringomyelia and atlantoaxial dislocation / 中华神经医学杂志

Objective:To investigate the clinical effect of modified atlantooccipital decompression combined with occipitocervical internal fixation on Chiari type I malformation combined with syringomyelia and atlantoaxial dislocation.Methods:Twenty-five patients with Chiari I malformation combined with syringomyelia and atlantoaxial dislocation accepted by modified atlantooccipital decompression combined with occipitocervical internal fixation in our hospital from January 2011 to March 2019. The clinical data of these patients were retrospectively analyzed. The changes of peak velocity of cerebrospinal fluid in the dorsal part of the spinal cord, electrophysiological results, atlantodental interval (ADI) values, sizes of syringomyelia, and Chicago Chiari outcome scale (CCOS) scores before and after operation were compared.Results:The peak velocity of cerebrospinal fluid in the dorsal spinal cord after surgery ([3.25±0.47] cm/s) was statistically higher in these patients than that before surgery ([2.13±0.19] cm/s, P<0.05). As compared with the preoperative results, ADI values, sizes of syringomyelia, and proportion of patients with abnormal electrophysiological monitoring at 6 months after surgery were significantly decreased, and CCOS scores at 6 months after surgery were significantly increased ( P<0.05). There were no new nerve function damage, infection, cerebrospinal fluid leakage, paralysis, respiratory failure or death. Conclusions:Modified atlantooccipital decompression combined with occipitocervical internal fixation plays effective role in atlantooccipital decompression and atlantoaxial anatomical reduction in patients with Chiari malformation type I combined with syringomyelia and atlantoaxial dislocation. The remission rate of syringomyelia is high, the symptoms and signs improve obviously, and the postoperative complications are less.