Evolution from small molecule to nano-drug delivery systems:An emerging approach for cancer therapy of ursolic acid

Ursolic acid(UA),a natural pentacyclic triterpenoid,possesses widespread biological and pharmacological activities.However,drawbacks such as low bioavailability,poor targeting and rapid metabolism greatly hinder its further clinical application.Recently,with the development of nanotechnology,various UA nanosystems have emerged as promising strategies for effective cancer therapy.This article reviews various types of UA-based nanodelivery systems,primarily with emphasis placed on novel UA-based carrier-free nanodrugs,which are considered to be innovative methods for cancer therapy.Moreover,this review presents carrier-free nano-drugs that co-assembled of UA and photosensitizers that displayed synergistic antitumor performance.Finally,the article also describes the development and challenges of UA nanosystems for future research in this field.Overall,the information presented in this review will provide new insight into the rational utilization of nano-drugs in cancer therapy.

Recent advances of sorafenib nanoformulations for cancer therapy:Smart nanosystem and combination therapy

Sorafenib,a molecular targeted multi-kinase inhibitor,has received considerable interests in recent years due to its significant profiles of efficacy in cancer therapy.However,poor pharmacokinetic properties such as limited water solubility,rapid elimination and metabolism lead to low bioavailability,restricting its further clinical application.Over the past decade,with substantial progress achieved in the development of nanotechnology,various types of smart sorafenib nanoformulations have been developed to improve the targetability as well as the bioavailability of sorafenib.In this review,we summarize various aspects from the preparation and characterization to the evaluation of antitumor efficacy of numerous stimuli-responsive sorafenib nanodelivery systems,particularly with emphasis on their mechanism of drug release and tumor microenvironment response.In addition,this review makes great effort to summarize the nanosystem-based combination therapy of sorafenib with other antitumor agents,which can provide detailed information for further synergistic cancer therapy.In the final section of this review,we also provide a detailed discussion of future challenges and prospects of designing and developing ideal sorafenib nanoformulations for clinical cancer therapy.

金属佐剂在肿瘤免疫治疗领域的研究进展

Immunotherapy with immune checkpoint inhibitors,chimeric antigen receptor-T cells,and cancer vaccines has made breakthrough in clinical cancer treatment[1].Cancer immunotherapy can enhance the antitumor immunity of the tumor microenvironment by activating and maintaining the cancer-immune cycle to eradicate tumor cells[2,3].Among above immunotherapeutics.

Unintended Results:Inter-Provincial Differences in Environmental Protection Tax Rates and Relocation Strategies of Polluting Enterprises

The Environmental Protection Tax Law that took effect in 2018 gave local authorities a certain amount of discretionary power to set the local rates for environmental protection tax.The inter-provincial gradient tax rates pattern may induce strategic relocation of enterprises,leading to unintended policy results.Combined with the data on trans-regional investment of listed companies,this paper employs the Difference-in-Difference(DID)approach to study the impact of inter-provincially different environmental tax rates on the trans-regional migration of polluting enterprises.The study shows that due to the regional differences in the tax rates,the polluting enterprises opt for the relocation strategy of"avoiding high tax rates and opting for low rates",setting up more subsidiaries in regions with relatively low tax rates.Further research demonstrates that the trans-regional migration induced by different tax rates can help reduce production costs and increase corporate profits,while dampening the corporate enthusiasm for green innovation in the short term and resulting in pollution transfer.This paper reveals the unintended policy effects that may derive from the environmental tax reform,providing concrete proof for the comprehensive evaluation and understanding of the actual policy effects of existing environmental tax reform.

An efficient way to enhance the total nitrogen removal efficiency of the Anammox process by S^0-based short-cut autotrophic denitrification

In order to reduce the amount of NO_3^-–N generated by the Anammox process, and alleviate the competition between denitrification and Anammox for NO_2^-–N in a single reactor, the preference of S^0 for reacting with coexisting NO_2^-–N and NO_3^-–N in the sulfur autotrophic denitrifying(SADN) process and the coupling effect of short-cut SADN and the Anammox process were studied. The results showed that S^0 preferentially reacted with NO_3^-to produce NO_2^-–N, and then reacted with NO_2^-–N when NO_3^-–N was insufficient, which could effectively alleviate the competition between SADN bacteria(SADNB) and Anammox bacteria(An AOB) for NO_2^-–N. After 170 days of operation, coupling between short-cut S^0-SADN and the Anammox process was first successfully achieved. SADNB converted the NO_3^-–N generated by the Anammox process into NO_2^-–N, which was once again available to An AOB. The total nitrogen removal efficiency eventually stabilized at over 95%, and the effluent NO_3^-–N was controlled within 10 mg/L, when high NH_4^+–N wastewater was treated by the Anammox process. Microbial community analysis further showed that Candidatus Brocadia and Thiobacillus were the functional microorganisms for An AOB and SADNB.

Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy

Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance.Herein,a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms.A disulfide bond-linked bispecific prodrug of NLG919 and JQ1(namely NJ) was synthesized and self-assembled into a prodrug nanoparticle,which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ.Upon tumor accumulation via passive tumor targeting,the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug.NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond.JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1.In contrast,NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment,which thus restores robust antitumor immune responses.Photodynamic therapy(PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells.The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.

Dual-targeting prodrug nanotheranostics for NIR-Ⅱfluorescence imaging-guided photo-immunotherapy of glioblastoma

Glioblastoma(GBM) therapy is severely impaired by the blood-brain barrier(BBB) and invasive tumor growth in the central nervous system.To improve GBM therapy,we herein presented a dual-targeting nanotheranostic for second near-infrared(NIR-Ⅱ) fluorescence imaging-guided photoimmunotherapy.Firstly,a NIR-Ⅱ fluorophore MRP bearing donor-acceptor-donor(D-A-D) backbone was synthesized.Then,the prodrug nanotheranostics were prepared by self-assembling MRP with a prodrug of JQ1(JPC) and T7 ligand-modified PEG5k-DSPE.T7 can cross the BBB for tumor-targeted delivery of JPC and MRP.JQ1 could be restored from JPC at the tumor site for suppressing interferon gamma-inducible programmed death ligand 1 expression in the tumor cells.MRP could generate NIR-Ⅱ fluorescence to navigate 808 nm laser,induce a photothermal effect to trigger in-situ antigen release at the tumor site,and ultimately elicit antitumor immunogenicity.Photo-immunotherapy with JPC and MRP dual-loaded nanoparticles remarkably inhibited GBM tumor growth in vivo.The dual-targeting nanotheranostic might represent a novel nanoplatform for precise photo-immunotherapy of GBM.