Purine nucleosides as selective inhibitors of butyrylcholinesterase - a multidisciplinary study.

The computational study of the most relevant interactions of the nanomolar purine nucleoside BuChE selective inhibitor has shown that the benzyl group at position 2 and the purine acetamido group are required for activity. In addition, the synthesis of a 6-iodinated radiolabelled analogue and the study of bioavailability have shown a low percentage of uptake by the brain after 1 hour. These results encouraged the synthesis of a small library of new compounds, focussing on deoxygenation at other positions aiming to access active and more bioavailable structures.

Molecular determinants for brain targeting by peptides: a meta-analysis approach with experimental validation.

Blood-brain barrier (BBB) peptide-shuttles (BBBpS) are able to translocate the BBB and reach the brain. Despite the importance of brain targeting in pharmacology, BBBpS are poorly characterized. Currently, their development relies on the empiric assumption that cell-penetrating peptides (CPPs), with proven ability to traverse lipid membranes, will likewise behave as a BBBpS.

Targeting of G-quadruplex DNA with Tc(I)/Re(I) Tricarbonyl Complexes Carrying Pyridostatin Derivatives.

The main goal of this work was to elucidate the potential relevance of (radio)metal chelates of Tc and Re targeting G-quadruplex structures for the design of new tools for cancer theranostics. Tc provides the complexes with the ability to perform single-photon-emission computed tomography imaging studies, while the Re complexes should act as anticancer agents upon interaction with specific G4 DNA or RNA structures present in tumor tissues. Towards this goal, we have developed isostructural Tc(I) and Re(I) tricarbonyl complexes anchored by a pyrazolyl-diamine (Pz) chelator carrying a pendant pyridostatin (PDS) fragment as the G4-binding motif.

Panobinostat-loaded folate targeted liposomes as a promising drug delivery system for treatment of canine B-cell lymphoma.

Introduction: Cancer is a major public health problem with over 19 million cases reported in 2020. Similarly to humans, dogs are also largely affected by cancer, with non-Hodgkin's lymphoma (NHL) among the most common cancers in both species. Comparative medicine has the potential to accelerate the development of new therapeutic options in oncology by leveraging commonalities between diseases affecting both humans and animals.

Rabbit derived VL single-domains as promising scaffolds to generate antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are among the fastest-growing classes of therapeutics in oncology. Although ADCs are in the spotlight, they still present significant engineering challenges. Therefore, there is an urgent need to develop more stable and effective ADCs.

Image-Guided Nanodelivery of Pt(IV) Prodrugs to GRP-Receptor Positive Tumors.

Over the last decades, gold nanoparticles (AuNPs) have proven to be remarkable tools for drug delivery and theranostic applications in cancer treatment. On the other hand, Pt(IV) prodrugs have been employed as an interesting alternative to the more common Pt(II) complexes, such as cisplatin, for cancer chemotherapy. Searching to design an image-guided nanocarrier to deliver selectively Pt(IV) prodrugs to tumors expressing the gastrin releasing peptide receptor (GRPR), we have synthesized small core AuNPs carrying a thiolated DOTA derivative, a GRPR-targeting bombesin analog (BBN[7-14]) and a Pt(IV) prodrug attached to the AuNPs without () or with a PEGylated linker ( and ).

Bioorthogonal Chemistry Approach for the Theranostics of GRPR-Expressing Cancers.

Several gastrin-releasing peptide receptor (GRPR) antagonists with improved in vivo behavior have been recently developed and tested in the clinic. However, despite the generally mild side effects of peptide receptor radionuclide therapy (PRRT), toxicity has been observed due to high doses delivered to nontarget tissues, especially in the kidneys and pancreas. Previous experiences with radiolabeled peptides opened a unique opportunity to explore GRPR pretargeting using clickable bombesin antagonists.

Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management.

The aggressiveness of melanoma and lack of effective therapies incite the discovery of novel strategies. Recently, a new dual acting hybrid molecule (HM), combining a triazene and a ʟ-tyrosine analogue, was synthesized. HM was designed to specifically be activated by tyrosinase, the enzyme involved in melanin biosynthesis and overexpressed in melanoma.

Gd and Ga complexes with a new tris-3,4-HOPO ligand as new imaging probes: complex stability, magnetic properties and biodistribution.

The development of metal-based multimodal imaging probes is a highly challenging field in coordination chemistry. In this context, we have developed a bifunctional hexadentate tripodal ligand (HL2) with three 3,4-HOPO moieties attached to a flexible tetrahedral carbon bearing a functionalizable nitro group. Complexes formed with different metal ions have potential interest for diagnostic applications, namely magnetic resonance imaging (MRI) and positron emission tomography (PET).

Highly Specific Blood-Brain Barrier Transmigrating Single-Domain Antibodies Selected by an In Vivo Phage Display Screening.

A major bottleneck in the successful development of central nervous system (CNS) drugs is the discovery and design of molecules that can cross the blood-brain barrier (BBB). Nano-delivery strategies are a promising approach that take advantage of natural portals of entry into the brain such as monoclonal antibodies (mAbs) targeting endogenous BBB receptors. However, the main selected mAbs rely on targeting broadly expressed receptors, such as the transferrin and insulin receptors, and in selection processes that do not fully mimic the native receptor conformation, leading to mistargeting and a low fraction of the administered dose effectively reaching the brain.

The HIV-1 Matrix Protein p17 Does Cross the Blood-Brain Barrier.

Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorder (HAND) remains an important neurological manifestation in HIV-1-infected (HIV) patients. Furthermore, detection of the HIV-1 matrix protein p17 (p17) in the central nervous system (CNS) and its ability to form toxic assemblies in the brain have been recently confirmed. Here, we show for the first time, using both an blood-brain barrier (BBB) model and biodistribution studies in healthy mice, that p17 can cross the BBB.

Clickable Radiocomplexes With Trivalent Radiometals for Cancer Theranostics: and Studies.

Pre-targeting approaches based on the inverse-electron-demand Diels-Alder (iEDDA) reaction between strained trans-cyclooctenes (TCO) and electron-deficient tetrazines (Tz) have emerged in recent years as valid alternatives to classic targeted strategies to improve the diagnostic and therapeutic properties of radioactive probes. To explore these pre-targeting strategies based on click chemistry, a small family of clickable chelators was synthesized and radiolabelled with medically relevant trivalent radiometals. The structure of the clickable chelators was diversified to modulate the pharmacokinetics of the resulting [In]In-radiocomplexes, as assessed upon injection in healthy mice.

Gallium and indium complexes with new hexadentate bis(semicarbazone) and bis(thiosemicarbazone) chelators.

The synthesis of two new hexadentate potentially tetra-anionic acyclic chelators, an N2O4-donor bis(semicarbazone) (H4bsc) and an N2O2S2-donor bis(thiosemicarbazone) (H4btsc), is described. Coordination reactions of the ligands with gallium and indium precursors were investigated and yielded the complexes [Ga(Hbsc)] (1) and [In(Hbtsc)] (2), respectively. Ligands and complexes structures were confirmed by several techniques, including FTIR, NMR (1H, 13C, COSY, HSQC), ESI(+)-MS and single crystal X-ray diffraction analysis.

Bioconjugate Supramolecular Pd Metallacages Penetrate the Blood Brain Barrier and .

The biomedical application of discrete supramolecular metal-based structures, specifically self-assembled metallacages, is still an emergent field of study. Capitalizing on the knowledge gained in recent years on the development of 3-dimensional (3D) metallacages as novel drug delivery systems and agents, we explore here the possibility to target [PdL] cages (L = 3,5-bis(3-ethynylpyridine)phenyl ligand) to the brain. In detail, a new water-soluble homoleptic cage () tethered to a blood brain barrier (BBB)-translocating peptide was synthesized by a combination of solid-phase peptide synthesis (SPPS) and self-assembly procedures.

Anti-HIV-1 Activity of pepRF1, a Proteolysis-Resistant CXCR4 Antagonist Derived from Dengue Virus Capsid Protein.

There is an urgent need for the development of new anti-HIV drugs that can complement existing medicines to be used against resistant strains. Here, we report the anti-HIV-1 peptide pepRF1, a human serum-resistant peptide derived from the Dengue virus capsid protein. , pepRF1 shows a 50% inhibitory concentration of 1.

In Vivo Pretargeting Based on Cysteine-Selective Antibody Modification with IEDDA Bioorthogonal Handles for Click Chemistry.

Pretargeted imaging has emerged as an effective multistep strategy aiming to improve imaging contrast and reduce patient radiation exposure through decoupling of the radioactivity from the targeting vector. The inverse electron-demand Diels-Alder (IEDDA) reaction between a -cyclooctene (TCO)-conjugated antibody and a labeled tetrazine holds great promise for pretargeted imaging applications due to its bioorthogonality, rapid kinetics under mild conditions, and formation of stable products. Herein, we describe the use of functionalized carbonylacrylic reagents for site-specific incorporation of TCO onto a human epidermal growth factor receptor 2 (HER2) antibody (THIOMAB) containing an engineered unpaired cysteine residue, generating homogeneous conjugates.

Biological evaluation of new TEM1 targeting recombinant antibodies for radioimmunotherapy: In vitro, in vivo and in silico studies.

The tumour endothelial marker 1 (TEM1/endosialin/CD248) is a receptor overexpressed in several human solid tumours and silenced in normal adult tissues, representing a suitable and potentially safe target for radioimmunotherapy of sarcoma. To develop new tools with improved TEM1 targeting properties, a new panel of antibody fragments was for the first time evaluated preclinically following I radiolabelling. The antibody fragment 1C1m-Fc, with the highest human/murine TEM1 binding affinity, was extensively characterized in vitro and in vivo in a Ewing's sarcoma human xenograft mouse model.

Imaging probes for non-invasive tumoral detection and functional monitoring of cancer multidrug resistance.

Several cationic radiotracers originally developed as myocardial perfusion agents have shown potential for both early detection of cancer and non-invasive monitoring of multiple drug resistance (MDR) by single photon emission computed tomography. We have introduced two cationic complexes, Tc-DMEOP [di-methoxy-tris-pyrazolyl-Tc-(CO)] and Tc-TMEOP [tri-methoxy-tris-pyrazolyl-Tc-(CO)], which showed excellent preclinical results as cardiac imaging probes, namely a persistent heart uptake with rapid blood and liver clearance. This study aimed at the evaluation of their usefulness for tumoral detection and functional assessment of MDR.

Dual Imaging Gold Nanoplatforms for Targeted Radiotheranostics.

Gold nanoparticles (AuNPs) are interesting for the design of new cancer theranostic tools, mainly due to their biocompatibility, easy molecular vectorization, and good biological half-life. Herein, we report a gold nanoparticle platform as a bimodal imaging probe, capable of coordinating Gd for Magnetic Resonance Imaging (MRI) and Ga for Single Photon Emission Computed Tomography (SPECT) imaging. Our AuNPs carry a bombesin analogue with affinity towards the gastrin releasing peptide receptor (GRPr), overexpressed in a variety of human cancer cells, namely PC3 prostate cancer cells.

Chemical and biological studies of Re(I)/Tc(I) thiosemicarbazonate complexes relevant for the design of radiopharmaceuticals.

Five thiosemicarbazones (HL) derived from 4,6-diacetylresorcinol (n = 1-4) and salicylaldehyde (n = 5) have been synthesized and spectroscopically characterized. Single crystal X-ray diffraction studies on some of them show that the molecular structure is dominated by intramolecular hydrogen bonds involving the O(1)-H group of the resorcinol/salicylaldehyde group and the azomethinic nitrogen atom and sulfur atom of the thiosemicarbazone arm. All of the ligands react with fac-[ReBr(CO)(CHCN)] in the presence of NEt to form the stable anionic complexes [NHEt][fac-[Re(L)(CO)] (1-5).

New strong extrafunctionalizable tris(3,4-HP) and bis(3,4-HP) metal sequestering agents: synthesis, solution and in vivo metal chelation.

Finding new multifunctional metal binders to be potentially used in diagnosis or therapy has been a subject of major challenge. Hydroxypyridinones have long been recognized as privileged chelating structures for the design of metal chelating drugs, especially towards hard metal ions, in view of their decorporation in metal overload disorders. Thus, pursuing our strategy of engineering new polydentate 3-hydroxy-4-pyridinones (3,4-HP) with extrafunctionalization capacity for sensing or targeting purposes, we report herein the synthesis and full characterization of a hexadentate (tris-3,4-HP) and a tetradentate (bis-3,4-HP) ligand, possessing three and two 3,4-HP arms N-attached to an aminomethanetrispropionic acid backbone, respectively.

Antitumour and Toxicity Evaluation of a Ru(II)-Cyclopentadienyl Complex in a Prostate Cancer Model by Imaging Tools.

Background: Ruthenium complexes have been extensively investigated for their prospective value as alternatives to cisplatin. Recently, we reported the in vitro anticancer properties of a family of organometallic ruthenium( II)-cyclopentadienyl complexes and have explored their mechanism of action.

Objective: The purpose of this study was to evaluate the in vivo antitumour efficacy and toxicity of one of these Ru(II) compounds, [RuCp(mTPPMSNa)(2,2'-bipy)][CF3SO2] (TM85) which displayed an interesting spectrum of activity against several cancer cells.

A new tripodal kojic acid derivative for iron sequestration: Synthesis, protonation, complex formation studies with Fe, Al, Cu and Zn, and in vivo bioassays.

This work presents the simple and low cost synthesis of a new tripodal ligand, in which three units of kojic acid are coupled to a tris(2-aminoethyl)amine (tren) backbone molecule. The protonation equilibria, together with the complex formation equilibria of this ligand with Fe, Al, Cu and Zn ions were studied. The complementary use of potentiometric, spectrophotometric and NMR techniques, and of Density Functional Theory (DFT) calculations, has allowed a thorough characterization of the different species involved in equilibrium.