No abstract

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy type with limited approaches for treatment. Additionally, inappropriate immune therapy indicates that the understanding the underlying mechanism of HCC is necessary. The aim of the present study was to investigate the influence of a novel circular RNA (circRNA), circRNA of AR-suppressed PABPC1 91 bp (CircARSP91), on immune surveillance induced by natural killer (NK) cells. An in vitro cell cytotoxicity assay was performed to determine the cytotoxicity of NK cells against HCC cells. A specific plasmid for circRNA overexpression was used to establish stable cell lines. Additionally, samples from patients with HCC were analyzed to determine the association between the present in vitro data and those of clinical settings. CircARSP91 could increase the susceptibility of HCC cells to NK cell cytotoxicity. Following screening multiple factors that could influence the activation of NK cells, it was determined that such a phenotype may be caused by upregulating UL16 binding protein 1 (ULBP1) expression in HCC cells at the mRNA and protein levels. Additionally, the data generated from patient samples significantly support a positive association between CircARSP91 and ULBP1. In conclusion, CircARSP91 could enhance innate immune surveillance by strengthening the cytotoxicity of NK cells, implying that circRNA may serve a role in tumor immunity.Abbreviations: CircARSP91, circRNA of AR-suppressed PABPC1 91 bp; NK cell, natural killer cell; E:T, effector cell:target cell; ULBP1, UL16 binding protein 1; HCC, hepatocellular carcinoma

The COVID‐19 pandemic has taken a significant toll on people worldwide, and there are currently no specific antivirus drugs or vaccines. Herein it is a therapeutic based on catalase, an antioxidant enzyme that can effectively breakdown hydrogen peroxide and minimize the downstream reactive oxygen species, which are excessively produced resulting from the infection and inflammatory process, is reported. Catalase assists to regulate production of cytokines, protect oxidative injury, and repress replication of SARS‐CoV‐2, as demonstrated in human leukocytes and alveolar epithelial cells, and rhesus macaques, without noticeable toxicity. Such a therapeutic can be readily manufactured at low cost as a potential treatment for COVID‐19.

No abstract

Well-defined water-soluble block copolymers poly(ethylene glycol)-b-poly(N-(2-hydroxypropyl) methacrylamide-co-N-methacryloylglycylglycine) (PEG-b-P(HPMA-co-MAGG)) and their doxorubicin (Dox) conjugates with different composition and molecular weight were synthesized. These Dox conjugates can form micelles in buffer solution. The physicochemical properties, in vivo biodistribution, blood clearance, and especially the tumor accumulation of copolymers and micelles were studied. Severe liver accumulation can be observed for PEG-b-PMAGG copolymers. This was quite different from their Dox conjugate for which decreased RES uptake and elevated kidney accumulation could be observed. When decrease the negative charge to an appropriate amount such as 8-10 mol %, both RES uptake and kidney accumulation could be suppressed. Obvious tumor accumulation could be achieved especially when the molecular weight were increased from ∼40 to ∼80 KDa. These results provided us with a guideline for the design of nanoscaled drug delivery system as well as a potential option for treating kidney-related cancers.

Novel poly(ethylene glycol) and poly(N-(2-hydroxypropyl)methacrylamide) block copolymer (PEG-b-PHPMA) with well-defined composition was synthesized by RAFT polymerization. Folate and doxorubicin (DOX) were quantitatively introduced into the copolymer. The influences of folate content and pH value on folate receptor (FR) mediated cell endocytosis and pH-responsive DOX release were studied. It has been demonstrated that minimum folate content is needed for the enrichment of hydrophobic folate on the hydrophilic part of polymer conjugates. The cytotoxicity of targetable polymer drug conjugates was much higher than that of non-targetable ones and free DOX. It could be concluded that the folate plays a significant role in targeting and internalization of the conjugates against bladder cancer cells.

To obtain high tumor-specific accumulation, strong tumor penetration and low off-target uptake, we developed a series of polymer therapeutics with different architectures, including random, block, and brush-like structure, based on the classic N-(2-hydroxypropyl) methacrylamide polymers. The influence of polymer architecture on biological properties such as cellular uptake, blood clearance, and biodistribution have been investigated. Besides small micelles whose sizes were determined by polymer architectures, large aggregates formed by micelle aggregation could also be observed. Although they had different architectures, the drug release rate, endocytic pathways and cellular uptake level of various conjugates have been proved to be identical. The polymer architecture of various conjugates lay great impact on the blood clearance, biodistribution and tumor growth inhibition. We assumed that the differences in in vivo biological properties were coordinately caused by the different size of the small aggregates and the formation and stability of large aggregates for different conjugates. Even though the reason was still unclear, the results inspired us that only by diblock conjugates with improved cellular uptake can we realize tumor specific accumulation, deep penetration, and efficient tumor inhibition.

PEG-b-PHPMA block copolymers with a precisely controlled composition were synthesized and showed a good biodistribution pattern and long circulation time.