Hepatocellular carcinoma (HCC) develops predominantly in the inflammatory environment of a cirrhotic liver caused by hepatitis, toxin exposure, or chronic liver disease. A targeted therapeutic approach is required to enable cancer killing without causing toxicity and liver failure. Poly(beta-amino-ester) (PBAE) nanoparticles (NPs) were used to deliver a completely CpG-free plasmid harboring mutant herpes simplex virus type 1 sr39 thymidine kinase (sr39) DNA to human HCC cells. Transfection with sr39 enables cancer cell killing with the prodrug ganciclovir and accumulation of 9-(4- 18 F-fluoro-3-hydroxymethylbutyl)guanine ( 18 F-FHBG) for in vivo imaging. Targeting was achieved using a CpG-free human alpha fetoprotein (AFP) promoter (CpGf-AFP-sr39). Expression was restricted to AFP-producing HCC cells, enabling selective transfection of orthotopic HCC xenografts. CpGf-AFP-sr39 NP treatment resulted in 62% reduced tumor size, and therapeutic gene expression was detectable by positron emission tomography (PET). This systemic nanomedicine achieved tumor-specific delivery, therapy, and imaging, representing a promising platform for targeted treatment of HCC.

Despite initial promise, tumor necrosis factor-related apoptosisinducing ligand (TRAIL)-based approaches to cancer treatment have yet to yield a clinically approved therapy, due to delivery challenges, a lack of potency, and drug resistance. To address these challenges, we have developed poly(beta-amino ester) (PBAE) nanoparticles (NPs), as well as an engineered cDNA sequence encoding a secretable TRAIL (sTRAIL) protein, to enable reprogramming of liver cancer cells to locally secrete TRAIL protein. We show that sTRAIL initiates apoptosis in transfected cells and has a bystander effect to non-transfected cells. To address TRAIL resistance, NP treatment is combined with histone deacetylase inhibitors, resulting in >80% TRAILmediated cell death in target cancer cells and significantly slowed xenograft tumor growth. This anti-cancer effect is specific to liver cancer cells, with up to 40-fold higher cell death in HepG2 cancer cells over human hepatocytes. By combining cancer-specific TRAIL NPs with small-molecule-sensitizing drugs, this strategy addresses multiple challenges associated with TRAIL therapy and offers a new potential approach for cancer treatment.

Purpose Hepatocellular carcinoma (HCC) has limited treatment options, and modest survival after systemic chemotherapy or procedures such as transarterial chemoembolization (TACE). There is therefore a need to develop targeted therapies to address HCC. Gene therapies hold immense promise in treating a variety of diseases, including HCC, though delivery remains a critical hurdle. This study investigated a new approach of local delivery of polymeric nanoparticles (NPs) via intra-arterial injection for targeted local gene delivery to HCC tumors in an orthotopic rat liver tumor model. Methods Poly(beta-amino ester) (PBAE) nanoparticles were formulated and assessed for GFP transfection in N1-S1 rat HCC cells in vitro. Optimized PBAE NPs were next administered to rats via intra-arterial injection with and without orthotopic HCC tumors, and both biodistribution and transfection were assessed. Results In vitro transfection of PBAE NPs led to >50% transfected cells in adherent and suspension culture at a variety of doses and weight ratios. Administration of NPs via intra-arterial or intravenous injection demonstrated no transfection of healthy liver, while intra-arterial NP injection led to transfection of tumors in an orthotopic rat HCC model. Conclusion Hepatic artery injection is a promising delivery approach for PBAE NPs and demonstrates increased targeted transfection of HCC tumors compared to intravenous administration, and offers a potential alternative to standard chemotherapies and TACE. This work demonstrates proof of concept for administration of polymeric PBAE nanoparticles via intra-arterial injection for gene delivery in rats.

The best ways to reduce the risk of infection with COVID-19, in addition to vaccination, are properly using medical masks, frequent hand washing, and discouraging face touching.Many parents have questions about proper mask use for their children. The safest masks for children are surgical masks and N95 respirators. Cloth masks offer less protection but are better than not masking at all. All children 2 years and older should wear one of these masks when indoors. Children younger than 2 years should not use masks because their small airways make it harder to breathe. They also cannot communicate breathing difficulties to parents and are less likely to keep the mask on. You should ensure that masks fit properly, especially for smaller children who cannot fit into adult-sized masks. Neck gaiters, scarves tied around the mouth, or any masks with valves are not recommended. Surgical masks should be discarded after 6 hours of use or if they become wet or damaged. Cloth masks should be hand or machine washed after every use with warm water and laundry detergent.Masks prevent inhalation of airborne virus released while others talk, breathe, and cough. Children should keep their masks on even while coughing or sneezing. Parents should also emphasize the importance of frequent handwashing, hand sanitization, and avoidance of touching the nose, eyes, and mouth. Children should wash or sanitize their hands before wearing or removing masks and before eating. When in public or at school, a child should only remove their mask to eat or drink. When eating, they should stay at least 6 ft away from their classmates.Younger children may not remember a time before the COVID-19 pandemic, while older children may be growing impatient with daily masking. Both groups will take cues from their parents. We suggest always wearing a mask in public and affirming routine use to your children.For younger children, try offering this explanation about the importance of wearing masks: You want to play in the rain with your friends, but we will only let you go if you stay dry. If you use an umbrella, there is a good chance that you can remain dry, but what happens if your friend does not have an umbrella? When they get close to you, you could get wet. If you and your friends all have umbrellas, you can all play and still stay dry. The umbrella is like a mask. If used correctly, you will all be safe (dry), but if someone around you doesn't have one on, you could still get sick (wet). That's why you need to keep your distance from people who don't have a mask on so that you can stay healthy! Recently, the Delta variation of COVID-19 caused a 240% surge in pediatric infections. During the summer of 2021, the number of children younger than 4 years who were hospitalized because of COVID-19 increased 10-fold. As children return to in-person schools across the country, parents must do everything they can to reduce their own and their children's risk of getting sick with COVID-19. Please encourage your children to wear their masks.