Low-density lipoprotein encapsulated thiosemicarbazone metal complexes is active targeting vehicle for breast,lung, and prostate cancers

Cancer is a leading cause of death worldwide and affects society in terms of the number of lives lost. Current cancer treatments are based on conventional chemotherapy which is nonspecific in targeting cancer. Therefore, intensive efforts are underway to better target cancer-specific cells while minimizing the side effects on healthy tissues by using LDL particles as active drug delivery vehicles. The goal is to encapsulate anticancer agents thiosemicarbazone metal-ligand complexes into LDL particles to increase the cytotoxic effect of the agent by internalization through LDL receptors into MCF7, A549, and C42 cancer cell lines as segregate models for biological evaluations targeting tubulin. Zeta potential data of LDL-particles encapsulated anticancer agents showed an acceptable diameter range between 66–91 nm and uniform particle morphology. The results showed cell proliferation reduction in all tested cell lines. The IC₅₀ values of LDL encapsulated thiosemicarbazone metal-ligand complexes treated with MCF7, A549, and C42 ranged between 1.18–6.61 µM, 1.17–9.66 µM, and 1.01–6.62 µM, respectively. Western blot analysis showed a potent decrease in tubulin expression when the cell lines were treated with LDL particles encapsulated with thiosemicarbazone metal-ligand complexes as anticancer agents. In conclusion, the data provide strong evidence that LDL particles are used as an active drug delivery strategy for cancer therapy.     

Excitatory Synaptic Function and Plasticity is Persistently Altered in Ventral Tegmental Area Dopamine Neurons after Prenatal Ethanol Exposure

Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction propensity (risk). However, the neuronal mechanisms underlying this effect remain unknown. We examined whether increased excitatory synaptic transmission in ventral tegmental area (VTA) dopamine (DA) neurons, which is associated with drug addiction, was impacted by PE. Pregnant rats were exposed to ethanol (0 or 6 g/kg/day) via intragastric intubation from gestational day 8–20. Amphetamine self-administration, whole-cell recordings, and electron microscopy were performed in male offspring between 2 and 12-week-old. The results showed enhanced amphetamine self-administration in PE animals. In PE animals, we observed a persistent augmentation in calcium-permeable AMPA receptor (CP-AMPAR) expression, indicated by increased rectification and reduced decay time of AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), enhanced depression of AMPAR-EPSCs by NASPM (a selective CP-AMPAR antagonist), and increased GluA3 subunits in VTA DA neuron dendrites. Increased CP-AMPAR expression in PE animals led to enhanced excitatory synaptic strength and the induction of CP-AMPAR-dependent long-term potentiation (LTP), an anti-Hebbian form of LTP. These observations suggest that, in PE animals, increased excitatory synaptic strength in VTA DA neurons might be susceptible to further strengthening even in the absence of impulse flow. The PE-induced persistent increase in CP-AMPAR expression, the resulting enhancement in excitatory synaptic strength, and CP-AMPAR-dependent LTP are similar to effects observed after repeated exposure to drugs of abuse, conditions known to increase addiction risk. Therefore, these mechanisms could be important neuronal substrates underlying PE-induced enhancement in amphetamine self-administration and increased addiction risk in individuals with fetal alcohol spectrum disorders.