Acid-switchable nanoparticles induce self-adaptive aggregation for enhancing antitumor immunity of natural killer cells

Deficiency of natural killer (NK) cells shows a significant impact on tumor progression and failure of immunotherapy. It is highly desirable to boost NK cell immunity by upregulating active receptors and relieving the immunosuppressive tumor microenvironment. Unfortunately, mobilization of NK cells is hampered by poor accumulation and short retention of drugs in tumors, thus declining antitumor efficiency. Herein, we develop an acid-switchable nanoparticle with self-adaptive aggregation property for co-delivering galunisertib and interleukin 15 (IL-15). The nanoparticles induce morphology switch by a decomposition-metal coordination cascade reaction, which provides a new methodology to trigger aggregation. It shows self-adaptive size-enlargement upon acidity, thus improving drug retention in tumor to over 120 h. The diameter of agglomerates is increased and drug release is effectively promoted following reduced pH values. The nanoparticles activate both NK cell and CD8+ T cell immunity in vivo. It significantly suppresses CT26 tumor in immune-deficient BALB/c mice, and the efficiency is further improved in immunocompetent mice, indicating that the nanoparticles can not only boost innate NK cell immunity but also adaptive T cell immunity. The approach reported here provides an innovative strategy to improve drug retention in tumors, which will enhance cancer immunotherapy by boosting NK cells.

Comparison of the Effectiveness and Safety of Intensified Dose and Standard Dose of Mycophenolic Acids for Adult Renal Transplant Recipients ：A Meta-analysis / 中国药房

OBJECTIVE：To compare the effectiveness and safety of int ensified dose and standard dose of mycophenolic acids （MPA）for kidney transplant recipients ，and to provide evidence-based reference for clinical use of drugs. METHODS ：Retrieved from Embase ，PubMed，Cochrane library ，Clinical trials ，CNKI，Wanfang database and CBM ，randomized controlled trial （RCT） and cohort study about intensified dose and standard dose of clinical commonly used Mycophenotate mofetil （MMF） and Mycophenolate sodium enteric-coated tablet （EC-MPS）for adult kidney transplant recipients were collected during the inception to Mar. 2020. After literature screening and data extraction ，the quality of RCTs were evaluated with bias risk evaluation tool recommended by Cochrane system evaluator manual 5.0. The quality of cohort study was evaluated by NOS scale. Meta-analysis was performed by using Rev Man 5.3 software，and sensitivity analysis was conducted. RESULTS ：A total of 8 studies were included，involving 6 RCTs，2 cohort studies ，with 1 637 patients involved. Meta-analysis results showed that ，the incidence of biopsy-proven acute rejection （BPAR）[RR＝0.65，95％CI（0.48，0.89），P＝0.007] and cytomegalovirus （CMV）infection [RR ＝ 0.39，95％CI（0.17，0.91），P＝0.03] in intensified dose groupwere significantly lower than control group. Subgroup analysis by drug showed that the incidence of BPAR in MMF intensive dose group [RR ＝0.72，95％CI（0.53，0.99），P＝0.04] and EC-MPS intensive dose group [RR ＝0.19，95％ CI （0.04， 0.81），P＝0.03] was significantly lower than that in standard zhaorongsheng@bjmu.edu.cn dose group ； there was n o statistical significance in the incidence of CMV infection in MMF intensive dose group [RR ＝0.16，95％CI（0.02，1.33），P＝0.09] and EC-MPS intensive dose group [RR ＝0.51，95％CI（0.20，1.30），P＝0.16]，compared with standard dose group （P＞0.05）. There was no significant difference in the incidence of rejection，treatment failure ，graft loss ，termination of treatment ，death，overall adverse events ， infection（overall），BK virus infection ，urinary tract infection ，hematological adverse events （overall），leucopenia，anemia， thrombocytopenia，gastrointestinal adverse events （overall），nausea，vomiting or diarrhea between 2 groups（P＞0.05）. Sensitivity analysis showed that the incidence of rejection ，CMV infection and leukopenia were generally stable. CONCLUSIONS ：The efficacy and safety of early intensive dose of MPA in adult renal transplant recipients were similar to those of standard dose ，but the incidence of rejection ，CMV infection and leucopenia should be carefully interpreted.

Injectable peptide hydrogel as intraperitoneal triptolide depot for the treatment of orthotopic hepatocellular carcinoma

Chemotherapy is among the limited choices approved for the treatment of hepatocellular carcinoma (HCC) at intermediate and advanced stages. Preferential and prolonged drug exposure in diseased sites is required to maximize the therapeutic index of the drug. Here, we report an injectable supramolecular peptide hydrogel as an intraperitoneal depot for localized and sustained release of triptolide for the treatment of orthotopic HCC. We chose peptide amphiphile C-GNNQQNYKD-OH-based nanofibers as gelators and carriers for triptolide. Sustained triptolide release from the hydrogel was achieved over 14 days , with higher accumulation in and cytotoxicity against human HCC Bel-7402 in comparison with L-02 fetal hepatocytes. After intraperitoneal injection, the hydrogel showed prolonged retention over 13 days and preferential accumulation in the liver, realizing HCC growth inhibition by 99.7 ± 0.1% and animal median survival extension from 19 to 43 days, without causing noticeable pathological changes in the major organs. These results demonstrate that injectable peptide hydrogel can be a potential carrier for localized chemotherapy of HCC.