DM1 Loaded Ultrasmall Gold Nanoparticles Display Significant Efficacy and Improved Tolerability in Murine Models of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide with poor prognosis and limited options for treatment. Life expectancy after diagnosis is short; the currently available treatments are not well tolerated and have limited clinical benefit. There is a clear unmet clinical need for the development of new treatments. In this study, ultrasmall, 2 nm gold core nanoparticles (MidaCore) conjugated with the potent maytansine analogue DM1 (MTC-100038) were assessed as a systemic nanomedicine for the treatment of hepatocellular carcinoma. The platform improved overall tolerability of DM1, permitting ∼3-fold higher levels of drug to be administered compared to free drug. Dose for dose, MTC-100038 also facilitated delivery of ∼2.0-fold higher ( p = 0.039) levels of DM1 to the tumor compared to free DM1. MTC-100038 produced significant efficacy (tumor growth index ∼102%; p = <0.0001), in several murine xenograft models of HCC, and was superior to both free DM1 and the current standard of care, sorafenib. Furthermore, MTC-100038 displayed potent (nM) in vitro activity in various HCC primary patient derived cell lines and across various other different cancer cell types. These data demonstrate the potential of MidaCore nanoparticles to enhance tumor delivery of cytotoxic drugs and indicate MTC-100038 is worthy of further investigation as a potential treatment for HCC and other cancer types.

Targeting Ultrasmall Gold Nanoparticles with cRGD Peptide Increases the Uptake and Efficacy of Cytotoxic Payload.

Cyclic arginyl-glycyl-aspartic acid peptide (cRGD) peptides show a high affinity towards αVß3 integrin, a receptor overexpressed in many cancers. We aimed to combine the versatility of ultrasmall gold nanoparticles (usGNP) with the target selectivity of cRGD peptide for the directed delivery of a cytotoxic payload in a novel design. usGNPs were synthesized with a modified Brust-Schiffrin method and functionalized via amide coupling and ligand exchange and their uptake, intracellular trafficking, and toxicity were characterized. Our cRGD functionalized usGNPs demonstrated increased cellular uptake by αVß3 integrin expressing cells, are internalized via clathrin-dependent endocytosis, accumulated in the lysosomes, and when loaded with mertansine led to increased cytotoxicity. Targeting via cRGD functionalization provides a mechanism to improve the efficacy, tolerability, and retention of therapeutic GNPs.

Reduced plasma apelin levels in patients with autistic spectrum disorder.

BACKGROUND: Dysregulation of the vasopressin (AVP) system has been implicated in the pathogenesis of autistic spectrum disorder (ASD). Apelin is a recently discovered neuropeptide that could counteract AVP actions and whose receptors are colocalized with vasopressin in hypothalamic magnocellular neurons. Aims of the present study were to investigate circulating levels of apelin in patients with ASD and to assess their correlation with plasma AVP concentrations. METHODS: Plasma levels of apelin and AVP were measured in a total of 18 patients with ASD and 21 age- and gender-matched healthy comparison subjects. The Childhood Autism Rating Scale (CARS) was used to assess the severity of autistic symptoms. RESULTS: Significantly reduced levels of apelin (p < 0.001) and elevated concentrations of AVP (p = 0.02) were found in ASD patients as compared to controls. Additionally, a significant inverse correlation between apelin and AVP levels was found within the ASD group (r = -0.61; p = 0.007), but not in healthy participants (r = -0.26; p = 0.25). Multivariate linear regression analysis showed that only AVP concentrations independently predicted apelin values in ASD individuals (beta = -0.42, t = 2.63, p = 0.014). No correlation was seen between apelin levels and CARS scores (r = -0.10; p = 0.68). CONCLUSIONS: Our findings of a significantly reduced peripheral level of apelin coupled with elevated AVP point to a subtle but definite vasopressinergic dysfunction in autism that could play a role in the etiopathophysiology of this disorder in humans.