Targeted Radionuclide Therapy Using Auger Electron Emitters: The Quest for the Right Vector and the Right Radionuclide

Auger electron emitters (AEEs) are attractive tools in targeted radionuclide therapy to specifically irradiate tumour cells while sparing healthy tissues. However, because of their short range, AEEs need to be brought close to sensitive targets, particularly nuclear DNA, and to a lower extent, cell membrane. Therefore, radioimmunoconjugates (RIC) have been developed for specific tumour cell targeting and transportation to the nucleus. Herein, we assessed, in A-431CEA-luc and SK-OV-31B9 cancer cells that express low and high levels of HER2 receptors, two 111In-RIC consisting of the anti-HER2 antibody trastuzumab conjugated to NLS or TAT peptides for nuclear delivery. We found that NLS and TAT peptides improved the nuclear uptake of 111In-trastuzumab conjugates, but this effect was limited and non-specific. Moreover, it did not result in a drastic decrease of clonogenic survival. Indium-111 also contributed to non-specific cytotoxicity in vitro due to conversion electrons (30% of the cell killing). Comparison with [125I]I-UdR showed that the energy released in the cell nucleus by increasing the RIC’s nuclear uptake or by choosing an AEE that releases more energy per decay should be 5 to 10 times higher to observe a significant therapeutic effect. Therefore, new Auger-based radiopharmaceuticals need to be developed.

New Peptide-Based Pharmacophore Activates 20S Proteasome

The proteasome is a pivotal element of controlled proteolysis, responsible for the catabolic arm of proteostasis. By inducing apoptosis, small molecule inhibitors of proteasome peptidolytic activities are successfully utilized in treatment of blood cancers. However, the clinical potential of proteasome activation remains relatively unexplored. In this work, we introduce short TAT peptides derived from HIV-1 Tat protein and modified with synthetic turn-stabilizing residues as proteasome agonists. Molecular docking and biochemical studies point to the α1/α2 pocket of the core proteasome α ring as the binding site of TAT peptides. We postulate that the TATs’ pharmacophore consists of an N-terminal basic pocket-docking “activation anchor” connected via a β turn inducer to a C-terminal “specificity clamp” that binds on the proteasome α surface. By allosteric effects—including destabilization of the proteasomal gate—the compounds substantially augment activity of the core proteasome in vitro. Significantly, this activation is preserved in the lysates of cultured cells treated with the compounds. We propose that the proteasome-stimulating TAT pharmacophore provides an attractive lead for future clinical use.

Mitochondrial Drug Delivery for the Liver Diseases: Comprehensive Review

The role of mitochondria in liver targeting has been reviewed, which mainly focuses on acute and chronic. This is due to ethanol consumption, which causes liver damage. And how ethanol consumption affects liver disease. Autophagy, which explains the ROS production, in oxygen species, the changes that take place in it have been reviewed below and also helps us to understand the methods and drugs used in targeting the mitochondria differently. The mainly 2 types of targeting has been focused upon that is the active and passive targeting. The other different types of targeting are Hepatic stellate cells (HSCs) targeting, Hepatocytes, the drug is targeted, Polymeric micelles, the mitochondrial membranes are affected by the proteins, and the Nanosystems used for the delivery. The other drugs used for the study are lipophilic cation, liposomes, and the TAT peptides. The herbal treatment can also be used for the treatment of liver damage. The herbal extracts that are based on the phytosomes and the anti-oxidants that target on the hepatocytes cells

Cell-penetrating peptide modified AIE polymeric nanoparticles by miniemulsion polymerization and application for cell fluorescence imaging

AIE polymeric nanoparticles surface-modified with HIV Tat peptides for cell fluorescence imaging are efficiently prepared through miniemulsion polymerization, carbodiimide reaction, and thiol-maleimide click reaction in sequence.

Molecular mechanism of HIV-1 TAT peptide and its conjugated gold nanoparticles translocating across lipid membranes

It is demonstrated that the translocation of TAT peptides and TAT–AuNP complexes across lipid membranes is related to the peptide concentration and the number of grafted TAT peptides on the particle surface, respectively, which is mainly driven by electrostatic interactions.