Hybridization of Tumor Homing and Mitochondria-Targeting Peptide Domains to Design Novel Dual-Imaging Self-Assembled Peptide Nanoparticles for Theranostic Applications

A unique dual-targeting dual-imaging peptide-based nanoprobe was successfully designed by investigating the cyclic heptapeptide having Arg-Gly-Asp-Lys-Leu-Ala-Lys sequence composed of RGD homing motif and KALK mitochondria targeting motif linked via amide bond. The designed peptide was further modified through covalent linkage, characterized and self-assembled to form spherical nanoparticles. The novel Cy5.5-SAPD-99mTc nanoparticles were tested in vitro for cytotoxicity, cellular uptake, biocompatibility and apoptosis inducing functionalities. The cellular internalization, enhanced cytotoxicity and selective receptor binding capabilities against U87MG cells, excellent dual-imaging potential, improved apoptosis inducing feature by damaging mitochondria and in vivo preclinical investigations suggested that our newly designed novel dual-targeting dual-imaging nanoparticles may serve as an admirable theranostic probe to treat brain tumor glioblastoma multiforme.

A Brief Review of the Structure, Cytotoxicity, Synthesis, and Biodegradation of Microcystins

Harmful cyanobacterial blooms pose an environmental health hazard due to the release of water-soluble cyanotoxins. One of the most prevalent cyanotoxins in nature is microcystins (MCs), a class of cyclic heptapeptide hepatotoxins, and they are produced by several common cyanobacteria in aquatic environments. Once released from cyanobacterial cells, MCs are subjected to physical chemical and biological transformations in natural environments. MCs can also be taken up and accumulated in aquatic organisms and their grazers/predators and induce toxic effects in several organisms, including humans. This brief review aimed to summarize our current understanding on the chemical structure, exposure pathway, cytotoxicity, biosynthesis, and environmental transformation of microcystins.

Molecular Dynamics Study of Surfactin Interaction with Lipid Bilayer Membranes

Background: Surfactin is a cyclic heptapeptide that is closed by a β-hydroxy fatty acid chain. This potent biosurfactant is produced by different Bacillus subtilis strains. This lipopeptide has numerous attractive biological activities, including antibacterial, antiviral, antimycoplasma, hemolytic, and other different and powerful surface and interface activities. Methods: Understanding how surfactin binds to different membranes and its mechanism of action can help us modify and optimize its structure to improve the potential efficacy of this lipopeptide in the future. For this purpose, we studied the interaction of this lipopeptide with two types of lipid bilayer models, including palmitoyl-oleoyl-glycero- phosphocholine (POPC) and palmitoyl-oleoyl-phosphtidylglycerol (POPG) as the prokaryotic and eukaryotic membrane models, respectively. Results: The obtained data have shown that the tendency of surfactin for these membranes is different. According to the analysis, this molecule binds to both membranes peripherally, and its interaction with the negative membrane is also more potent compared to the zwitterionic membrane. Moreover, we found that surfactin destabilized POPG more than POPC. This suggests that surfactin may act by modifying the membrane’s bulk physical properties. Conclusions: As a final point, this study has shown that surfactin has different behaviors in the eukaryotic and prokaryotic cell membranes and can modify and amplify its action in order to use it for antibacterial drugs.

Cucurbituril Ameliorates Liver Damage Induced by Microcystis aeruginosa in a Mouse Model

Microcystis aeruginosa is a cyanobacterium that produces a variety of cyclic heptapeptide toxins in freshwater. The protective effects of the macromolecular container cucurbit[7]uril (CB7) were evaluated using mouse models of cyanotoxin-induced liver damage. Biochemical analysis of liver function was performed to gauge the extent of liver damage after exposure to cyanobacterial crude extract [CCE; LD50 = 35 mg/kg body weight; intraperitoneal (i.p.)] in the absence or presence of CB7 (35 mg/kg body weight, i.p.). CCE injection resulted in liver enlargement, potentiated the activities of alanine aminotransferase (ALT) and glutathione S-transferase (GST), increased lipid peroxidation (LPO), and reduced protein phosphatase 1 (PP1) activity. CCE-induced liver enlargement, ALT and GST activities, and LPO were significantly reduced when CB7 was coadministered. Moreover, the CCE-induced decline of PP1 activity was also ameliorated in the presence of CB7. Treatment with CB7 alone did not affect liver function, which exhibited a dose tolerance of 100 mg/kg body wt. Overall, our results illustrated that the addition of CB7 significantly reduced CCE-induced hepatotoxicity (P < 0.05).

High Cell Permeability Does Not Predict Oral Bioavailability for Analogues of Cyclic Heptapeptide Sanguinamide A

The cyclic heptapeptide derivative, sanguinamide A, is a model scaffold for studying how component amino acids, heterocycles, and N-methylation influence membrane permeability and oral bioavailability. Membrane permeable sanguinamide A analogues have been reported, but there is limited data on their pharmacokinetic properties invivo. Here we report pharmacokinetic properties for highly cell and membrane permeable sanguinamide A analogues in rats and find that there is no correlation between reported permeability invitro and oral bioavailability invivo. We show that N-methylation of sanguinamide A analogues gives compounds with greater flexibility, greater susceptibility to degradation by rat liver microsomes, and lower oral bioavailability in rats.