A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Metastatic melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NPs) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NPs are similarly sized (~48nm), with neutral, partially charged, or fully charged surface. The NPs are able to load ~2mg/mL of each drug and are stable for 24h. The NPs are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NPs were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NPs are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NPs are efficacious at the proximal LN, while the fully charged NPs have no effect on either LNs. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NPs have the highest potential in treating metastatic melanoma

The Impact of Emotional Abuse on Psychological Distress among Child Protective Services-Involved Adolescents with Borderline-to-Mild Intellectual Disability

DOI 10.1080/19361521.2011.574677Childhood maltreatment is a robust contributing factor to mental health problems in adolescents. The current study examines the impact of childhood emotional abuse on adolescent psychological distress in 48 youths with borderline-to-mild intellectual disability (ID), as compared to 117 peers with average intellectual functioning. Both emotional abuse and intellectual functioning predicted the severity of youth psychological distress. Childhood emotional abuse has an impact on adolescent distress, and maltreated child welfare-involved youth with lower IQ levels may be more vulnerable to distress than youth with average IQ. This raises a question regarding the detection of subtle manifestations of ID and the need to attend to mental health within this sub-population receiving child welfare services.Ontario Mental Health Foundatio