The specific sizes that determine optimal nanoparticle tumor accumulation, penetration, and treatment remain inconclusive because many studies compared nanoparticles with multiple physicochemical variables (e.g., chemical structures, shapes, and other physical properties) in addition to the size. In this study, we synthesized amphiphilic block copolymers of 7-ethyl-10-hydroxylcamptothecin (SN38) prodrug and fabricated micelles with sizes ranging from 20 to 300 nm from a single copolymer. The as-prepared micelles had exactly the same chemical structures and similar physical properties except for size, which provided an ideal platform for a systematic investigation of the size effects in cancer drug delivery. We found that the micelle's blood circulation time and tumor accumulation increased with the increase in their diameters, with optimal diameter range of 100 to 160 nm. However, the much higher tumor accumulation of the large micelles (100 nm) did not result in significantly improved therapeutic efficacy, because the large micelles had poorer tumor penetration than the small ones (30 nm). An optimal size that balances drug accumulation and penetration in tumors is critical for improving the therapeutic efficacy of nanoparticulate drugs.

A prodrug forms nanocapsules responsive to tumor GSH/ROS heterogeneity releasing the parent drug SN38 via thiolysis in the presence of GSH (glutathione) or via enhanced hydrolysis due to ROS (reactive oxygen species)-oxidation of the linker, giving rise to high in vitro cytotoxicity and in vivo anticancer therapeutic activity. The nanocapsules are a suitable size for tumor targeting by means of the EPR effect and have a fixed SN38 loading content of 35 wt%, ideal for translational nanomedicine.

Glucose-responsive insulin delivery systems that mimic pancreatic endocrine function could enhance health and improve quality of life for people with type 1 and type 2 diabetes with reduced β-cell function. However, insulin delivery systems with rapid in vivo glucose-responsive behaviour typically have limited insulin-loading capacities and cannot be manufactured easily. Here, we show that a single removable transdermal patch, bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix, and fabricated via in situ photopolymerization, regulated blood glucose in insulin-deficient diabetic mice and minipigs (for minipigs >25kg, glucose regulation lasted >20h with patches of ~5 cm 2 ). Under hyperglycaemic conditions, phenylboronic acid units within the polymeric matrix reversibly form glucose-boronate complexes that-owing to their increased negative charge-induce the swelling of the polymeric matrix and weaken the electrostatic interactions between the negatively charged insulin and polymers, promoting the rapid release of insulin. This proof-of-concept demonstration may aid the development of other translational stimuli-responsive microneedle patches for drug delivery.Diabetes-a chronic disease that often leads to severe secondary complications-affects over 425 million people around the world 1,2 . Insulin therapy is required for life in the setting of type 1 diabetes and is often used in type 2 diabetes with reduced islet β-cell function. It generally involves frequent monitoring of blood glucose levels and multiple subcutaneous injections daily or infusion to allow dose adjustment for safety and efficacy 1,3 . However, such treatment strategies are burdensome and often complicated by inadequate control and life-threatening hypoglycaemia resulting from miscalculated dose.

Neuromorphic computing simulates the operation of biological brain function for information processing and can potentially solve the bottleneck of the von Neumann architecture. This computing is realized based on memristive hardware neural networks in which synaptic devices that mimic biological synapses of the brain are the primary units. Mimicking synaptic functions with these devices is critical in neuromorphic systems. In the last decade, electrical and optical signals have been incorporated into the synaptic devices and promoted the simulation of various synaptic functions. In this review, these devices are discussed by categorizing them into electrically stimulated, optically stimulated, and photoelectric synergetic synaptic devices based on stimulation of electrical and optical signals. The working mechanisms of the devices are analyzed in detail. This is followed by a discussion of the progress in mimicking synaptic functions. In addition, existing application scenarios of various synaptic devices are outlined. Furthermore, the performances and future development of the synaptic devices that could be significant for building efficient neuromorphic systems are prospected.

The clinical utility of doxorubicin (DOX) is restricted by its severe side effects. Continuous efforts are aimed at developing efficacious DOX-delivery systems that may overcome the drawbacks of existing ones. Herein, we report a self-assembling prodrug forming high drug loading nanoparticles for DOX delivery. A low molecular weight polyethylene glycol (PEG) chain as the hydrophilic part was anchored to hydrophobic DOX via an acid-cleavable hydrazone bond to form the amphiphilic prodrug PEG-DOX. In aqueous solution, PEG-DOX formed nanoparticles with a diameter of $125 nm and extremely high drug loading ($46 wt%). These nanoparticles were stable in PBS but released DOX in an acidic pH-triggered manner.Interestingly, taken up by cells via endocytosis, PEG-DOX bypassed the P-glycoprotein (P-gp)-mediated efflux of DOX, leading to drug accumulation in DOX-resistant human breast cancer cells (MCF-7/ADR).More importantly, PEG-DOX exhibited potent antitumor activity in vitro and in vivo, and showed significantly increased in vivo safety than free DOX. These encouraging data merit further preclinical and clinical development on PEG-DOX.

Platinum(IV) prodrug diaminedichlorodihydroxyplatinum (ACHP) conjugated with a histone deacetylase (HDAC) inhibitor valproic acid (VA), VAAP, exhibited strong synergistic cytotoxicity, about 50-100 times more cytotoxic than ACHP or its simple mixture with VA, against various human carcinoma cell lines. VAAP could be quickly absorbed in the cell membrane and diffused into the cytosol. VAAP loaded in polyethylene glycol-polycaprolactone micelles (PEG-PCL) was taken up via endocytosis. The cytosolic VAAP was intracellular reduced to Pt(II) and released VA eliciting a HDAC inhibitory effect and subsequently induced cell cycle arrest at the S phase in 24 h and cell apoptosis in a time-dependent manner. The in vivo antitumor experiment on A549-xenograft tumor model showed that VAAP dispersed in Tween 80 or loaded in PEG-PCL nanoparticles had long blood circulation times and thereby high accumulation in tumors and exerted a significant in vivo inhibitory effect on tumor growth with low systemic toxicity. Therefore, this novel conjugate is very promising for cancer chemotherapy.

Most human cancers develop from stem and progenitor cell populations through the sequential accumulation of various genetic and epigenetic alterations. Cancer stem cells have been identified from medulloblastoma (MB), but a comprehensive understanding of MB stemness, including the interactions between the tumor immune microenvironment and MB stemness, is lacking. Here, we employed a trained stemness index model based on an existent one‐class logistic regression (OCLR) machine‐learning method to score MB samples; we then obtained two stemness indices, a gene expression‐based stemness index (mRNAsi) and a DNA methylation‐based stemness index (mDNAsi), to perform an integrated analysis of MB stemness in a cohort of primary cancer samples (n = 763). We observed an inverse trend between mRNAsi and mDNAsi for MB subgroup and metastatic status. By applying the univariable Cox regression analysis, we found that mRNAsi significantly correlated with overall survival (OS) for all MB patients, whereas mDNAsi had no significant association with OS for all MB patients. In addition, by combining the Lasso‐penalized Cox regression machine‐learning approach with univariate and multivariate Cox regression analyses, we identified a stemness‐related gene expression signature that accurately predicted survival in patients with Sonic hedgehog (SHH) MB. Furthermore, positive correlations between mRNAsi and prognostic copy number aberrations in SHH MB, including MYCN amplifications and GLI2 amplifications, were detected. Analyses of the immune microenvironment revealed unanticipated correlations of MB stemness with infiltrating immune cells. Lastly, using the Connectivity Map, we identified potential drugs targeting the MB stemness signature. Our findings based on stemness indices might advance the development of objective diagnostic tools for quantitating MB stemness and lead to novel biomarkers that predict the survival of patients with MB or the efficacy of strategies targeting MB stem cells.

Based on the interaction between single-stranded probe DNA and graphene quantum dots (GQDs), we have designed a simple but smart electrochemical platform to detect HBV-DNA by using GQDs modified glassy carbon electrode coupled with probe DNA.