Synergism through combination of chemotherapy and oxidative stress-induced autophagy in A549 lung cancer cells using redox-responsive nanohybrids: A new strategy for cancer therapy

A combination of various therapeutic approaches has emerged as a promising strategy for cancer treatment. A safe and competent nano-delivery system is thus in urgent demand to facilitate the simultaneous transport of various therapeutic agents to cancer cells and a tumor region to achieve synergistic effect. Gold nanoparticles (GNPs) and mesoporous silica nanoparticle (MSNs) were fabricated herein as potential candidates for drug delivery. Serving as gatekeepers, GNPs (5 nm in diameter) were attached onto the amino-functionalized MSNs (denoted as NMSNs) via a relatively weak gold–nitrogen bonding. The resulting nanohybrids (denoted as GCMSNs) were uptaken by cells, and the detachment of GNPs and subsequent intracellular drug release from NMSNs were achieved by competitive binding of intracellular glutathione to GNPs. In addition to the function of gatekeeping, GNPs also play another role as the oxidative stress elicitor. Our in vitro studies revealed that GCMSNs induced higher oxidative stress in lung cancer cells (A549) than in normal cells (3T3-L1). This growth inhibitory effect found in the cancer cells was likely induced by mitochondria dysfunction originated from the GCMSN-induced, oxidative stress-triggered mitochondria-mediated autophagy. The redox-responsive nanohybrids were further loaded with camptothecin and the intensified synergistic therapeutic effects were observed associated with combined chemotherapy and oxidative stress strategy. The results clearly demonstrate that such unique nanohybrids hold great promise for selective and effective cancer treatments.     

AuNP flares-capped mesoporous silica nanoplatform for MTH1 detection and inhibition

The human mutT homologue MTH1, a nucleotide pool sanitizing enzyme, represents a vulnerability factor and an attractive target for anticancer therapy. However, there is currently a lack of selective and effective platforms for the detection and inhibition of MTH1 in cells. Here, we demonstrate for the first time a gold nanoparticle (AuNP) flares-capped mesoporous silica nanoparticle (MSN) nanoplatform that is capable of detecting MTH1 mRNA and simultaneously suppressing MTH1 activity. The AuNP flares are made from AuNPs that are functionalized with a dense shell of MTH1 recognition sequences hybridized to short cyanine (Cy5)-labeled reporter sequences and employed to seal the pores of MSN to prevent the premature MTH1 inhibitors (S-crizotinib) release. Just like the pyrotechnic flares that produce brilliant light when activated, the resulting AuNP flares@MSN (S-crizotinib) undergo a significant burst of red fluorescence enhancement upon MTH1 mRNA binding. This hybridization event subsequently induces the opening of the pores and the release of S-crizotinib in an mRNA-dependent manner, leading to significant cytotoxicity in cancer cells and improved therapeutic response in mouse xenograft models. We anticipate that this nanoplatform may be an important step toward the development of MTH1-targeting theranostics and also be a useful tool for cancer phenotypic lethal anticancer therapy.     

Greater Visceral Fat but No Difference in Measures of Total Body Fat in Ambulatory Children With Spastic Cerebral Palsy Compared to Typically Developing Children

Background: Individuals with cerebral palsy (CP) are at increased risk for obesity and obesity-related complications. Studies of total body fat in those with CP are inconsistent and studies of abdominal fat are lacking in children with CP. The objective of this study was to determine if ambulatory children with spastic CP have greater central adiposity compared to typically developing children. Methodology: Eighteen ambulatory children with spastic CP (n = 5 girls; 8.6 ± 2.9 yr) and 18 age-, sex-, and race-matched typically developing children (controls; 8.9 ± 2.1 yr) participated in this cross-sectional study. Children with CP were classified as I or II using the Gross Motor Function Classification System. Dual-energy X-ray absorptiometry assessed body composition, including total body, trunk and abdominal fat mass, fat-free mass, fat mass index (FMI), and fat-free mass index (FFMI). Results: There were no group differences in fat mass, fat-free mass, FMI, and FFMI in the total body, fat mass, fat-free mass, and FFMI in the trunk, or fat mass, visceral fat mass, and subcutaneous fat mass in the abdomen (p > 0.05). Compared to controls, children with CP had higher trunk FMI, abdominal FMI, and visceral FMI (p < 0.05). Although marginally insignificant (p = 0.088), children with CP had higher subcutaneous FMI. Conclusions: Ambulatory children with spastic CP have elevated central adiposity, especially in the visceral region, despite no differences in measures of total body fat. How this relates to cardiometabolic disease progression in those with CP requires further investigation.