Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O→Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC 50 values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-Ras LSL/+ /Pten fl/fl ovarian cancer models with decreased systemicand nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a nextgeneration platinum-based agent in the clinics.chemotherapy | nanomedicine

Purpose Maternal lead exposure is associated with poor birth outcomes in populations with moderate to high blood levels. However, no studies have looked at exposure levels commonly experienced by US women. Methods We evaluated the relationship between maternal red blood cell (RBC) lead levels in mid-pregnancy and birth outcomes in 949 mother-child pairs in a pre-birth cohort. We used multiple linear regression and logistic regression, adjusted for potential confounders including maternal age, race, pre-pregnancy BMI and smoking, to relate maternal lead to infant birth size and risk for preterm birth (<37 weeks). Results Mean RBC lead level was 1.2 μg/dL (Range: 0.0, 5.0). Mean (SD) birthweight was 3505 (520) grams, birthweight for gestational age z-score 0.22 (0.93), and length of gestation 39.5 (1.7) weeks. Mothers in the highest vs. lowest lead quartile did not have higher odds (OR 1.85, 95% CI: 0.79, 4.34) of preterm delivery; after stratifying by child sex there was an association among males (OR: 5.51, 95% CI: 1.21, 25.15) but not females (OR 0.82, 95% CI: 0.24, 2.85). Maternal RBC lead was not associated with any continuous outcomes in combined or sex-stratified analyses. Conclusions Maternal lead exposure, even at very low levels, may adversely affect some child birth outcomes, particularly preterm birth among males.

BackgroundGiven mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism.MethodsArchived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: HFE [hemochromatosis], TF [transferrin], and ALAD [δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data.ResultsPercentage of participants carrying at least one copy of HFE C282Y, HFE H63D, TF P570S, and ALAD K59N variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either C282Y or H63D allele in HFE gene was 19.6%. Geometric mean (geometric standard deviation) manganese concentrations were 17.0 (1.5) μg/l. Women with any HFE variant allele had 12% lower blood manganese concentrations than women with no variant alleles (β = -0.12 [95% CI = -0.23 to -0.01]). TF and ALAD variants were not significant predictors of blood manganese. In animal models, Hfe-/- mice displayed a significant reduction in blood manganese compared with Hfe+/+ mice, replicating the altered manganese metabolism found in our human research.ConclusionsOur study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements.