Design, development and bio-evaluation of a novel radio-ligand 99mTc-THQ-DTPA as a sigma 2 receptor specific breast tumor imaging agent.

Over-expression of sigma-2 receptor in cancer cells provides an opportunity to develop molecular probes for diagnosis, even for non-receptor specific malignancies like triple negative breast cancers. In this work, a novel sigma-2 receptor ligand [THQ-DTPA] has been synthesized and characterized using 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (THQ) and diethylenetriaminepentaacetic acid (DTPA). The ligand is further chelated with 99mTc for application as metal based radiotracer [99mTc-THQ-DTPA]. Radiolabelling with 99mTc was achieved in an excellent yield of 98.0 ± 0.5% using stannous chloride as a reducing agent. The radioligand was found to be stable in human serum up-to 24 h, bio-compatible with less than 4% hemolysis, and exhibited high binding with sigma receptors isolated from rat liver membrane (Kd of 16.32 ± 4.93 nM and Bmax of 0.5232 ± 0.06 pmol/mg). Bio-distribution studies in triple-negative breast tumor bearing nude mice showed high tumor uptake after 30 min of injection with tumor/muscle (T/M) ratio of 3.58 ± 0.09. At 240 min, the T/M ratio (2.84 ± 0.20) decreased by 35% when administered in sigma blocked tumor bearing mice (1.81 ± 0.16) suggesting the selectivity of the ligand. Tumor imaging in gamma camera indicated a contrast of 3.56 at 30 min p.i. The above findings indicate that the ligand 99mTc-THQ-DTPA binds to sigma-2 receptors with high affinity and has potential for triple-negative breast tumor imaging.

Concept of lipid droplet biogenesis.

Lipid droplets (LD) are functionally conserved fat storage organelles found in all cell types. LDs have a unique structure comprising of a hydrophobic core of neutral lipids (fat), triacylglycerol (TAG) and cholesterol esters (CE) surrounded by a phospholipid monolayer. LD surface is decorated by a multitude of proteins and enzymes rendering this compartment functional. Accumulating evidence suggests that LDs originate from discrete ER-subdomains, demarcated by the lipodystrophy protein seipin, however, the mechanisms of which are not well understood. LD biogenesis factors together with biophysical properties of the ER membrane orchestrate spatiotemporal regulation of LD nucleation and growth at specific ER subdomains in response to metabolic cues. Defects in LD formation manifests in several human pathologies, including obesity, lipodystrophy, ectopic fat accumulation, and insulin resistance. Here, we review recent advances in understanding the molecular events during initial stages of eukaryotic LD assembly and discuss the critical role of factors that ensure fidelity of this process.