Bridging Pharmaceutical Chemistry with Drug and Nanoparticle Targeting to Investigate the Role of the 18‐kDa Translocator Protein TSPO

Iacobazzi, Rosa Maria; Lopalco, Antonio; Cutrignelli, Annalisa; Laquintana, Valentino; Lopedota, Angela; Franco, Massimo; Denora, Nunzio

doi:10.1002/cmdc.201700322

Cited by 16 publications

(22 citation statements)

References 100 publications

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“…Only small molecules with adequate hydrophilic/lipophilic balance and molecular weight can be absorbed passively into the CNS, if not substrates for the ABC (ATP-binding cassette) transporters efflux pumps. Different methodologies have been developed to raise the delivery of therapeutics for CNS diseases, including the development of CNS-targeted pro-drugs or co-drugs [ 6 , 7 , 8 , 9 ] and functionalized nanocarriers with uptake-facilitating ligands [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Transferrin Functionalized Liposomes Loading Dopamine HCl: Development and Permeability Studies across an In Vitro Model of Human Blood–Brain Barrier

et al. 2018

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The transport of dopamine across the blood brain barrier represents a challenge for the management of Parkinson’s disease. The employment of central nervous system targeted ligands functionalized nanocarriers could be a valid tactic to overcome this obstacle and avoid undesirable side effects. In this work, transferrin functionalized dopamine-loaded liposomes were made by a modified dehydration–rehydration technique from hydrogenated soy phosphatidylcoline, cholesterol and 1,2-stearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(poly(ethylene glycol)-2000)]. The physical features of the prepared liposomes were established with successive determination of their endothelial permeability across an in vitro model of the blood-brain barrier, constituted by human cerebral microvascular endothelial cells (hCMEC/D3). Functionalized dopamine-loaded liposomes with encapsulation efficiency more than 35% were made with sizes in a range around 180 nm, polydispersity indices of 0.2, and positive zeta potential values (+7.5 mV). Their stability and drug release kinetics were also evaluated. The apparent permeability (Pe) values of encapsulated dopamine in functionalized and unfunctionalized liposomes showed that transferrin functionalized nanocarriers could represent appealing non-toxic candidates for brain delivery, thus improving benefits and decreasing complications to patients subjected to L-dopa chronical treatment.

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Section: Introductionmentioning

confidence: 99%

Transferrin Functionalized Liposomes Loading Dopamine HCl: Development and Permeability Studies across an In Vitro Model of Human Blood–Brain Barrier

et al. 2018

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“…Nevertheless, almost all the studies describing TSPO functions are based on the actions of TSPO ligands. These ligands constitute a broad range of endogenous and exogenous molecules, [ 17 , 18 , 19 ] used both to study TSPO involving functions, as well as TSPO tracers for diagnostic imaging [ 20 ]. These were originally classified as agonists or antagonists, following thermodynamics constraints [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Induction of ATP Release, PPIX Transport, and Cholesterol Uptake by Human Red Blood Cells Using a New Family of TSPO Ligands

Marginedas-Freixa

Álvarez

Moras

et al. 2018

IJMS

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Two main isoforms of the Translocator Protein (TSPO) have been identified. TSPO1 is ubiquitous and is mainly present at the outer mitochondrial membrane of most eukaryotic cells, whereas, TSPO2 is specific to the erythroid lineage, located at the plasma membrane, the nucleus, and the endoplasmic reticulum. The design of specific tools is necessary to determine the molecular associations and functions of TSPO, which remain controversial nowadays. We recently demonstrated that TSPO2 is involved in a supramolecular complex of the erythrocyte membrane, where micromolar doses of the classical TSPO ligands induce ATP release and zinc protoporphyrin (ZnPPIX) transport. In this work, three newly-designed ligands (NCS1016, NCS1018, and NCS1026) were assessed for their ability to modulate the functions of various erythrocyte’s and compare them to the TSPO classical ligands. The three new ligands were effective in reducing intraerythrocytic Plasmodium growth, without compromising erythrocyte survival. While NCS1016 and NCS1018 were the most effective ligands in delaying sorbitol-induced hemolysis, NCS1016 induced the highest uptake of ZnPPIX and NCS1026 was the only ligand inhibiting the cholesterol uptake. Differential effects of ligands are probably due, not only, to ligand features, but also to the dynamic interaction of TSPO with various partners at the cell membrane. Further studies are necessary to fully understand the mechanisms of the TSPO’s complex activation.

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“…Translocator protein 18 kDa (TSPO), a five-transmembrane domains receptor mainly located in the outer mithochondrial membrane (OMM), has recently become an attractive subcellular target since it participates in a wide range of cellular functions, including cholesterol transport, steroid hormone synthesis, mitochondrial respiration, permeability transition pore opening, apoptosis, and cell proliferation [19,20]. Variations in TSPO expression have been also correlated to different diseases, from tumors to endocrine and neurological disorders [21].…”

Section: Introductionmentioning

confidence: 99%

Green Fluorescent Terbium (III) Complex Doped Silica Nanoparticles for TSPO Targeting

Fanizza

Depalo

Fedorenko

et al. 2019

IJMS

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The low photostability of conventional organic dyes and the toxicity of cadmium-based luminescent quantum dots have prompted the development of novel probes for in vitro and in vivo labelling. Here, a new fluorescent lanthanide probe based on silica nanoparticles is fabricated and investigated for optically traceable in vitro translocator protein (TSPO) targeting. The targeting and detection of TSPO receptor, overexpressed in several pathological states, including neurodegenerative diseases and cancers, may provide valuable information for the early diagnosis and therapy of human disorders. Green fluorescent terbium(III)-calix[4]arene derivative complexes are encapsulated within silica nanoparticles and surface functionalized amine groups are conjugated with selective TSPO ligands based on a 2-phenylimidazo[1,2-a]pyridine acetamide structure containing derivatizable carboxylic groups. The photophysical properties of the terbium complex, promising for biological labelling, are demonstrated to be successfully conveyed to the realized nanoarchitectures. In addition, the high degree of biocompatibility, assessed by cell viability assay and the selectivity towards TSPO mitochondrial membrane receptors, proven by subcellular fractional studies, highlight targeting potential of this nanostructure for in vitro labelling of mitochondria.

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Bridging Pharmaceutical Chemistry with Drug and Nanoparticle Targeting to Investigate the Role of the 18‐kDa Translocator Protein TSPO

Cited by 16 publications

References 100 publications

Transferrin Functionalized Liposomes Loading Dopamine HCl: Development and Permeability Studies across an In Vitro Model of Human Blood–Brain Barrier

Transferrin Functionalized Liposomes Loading Dopamine HCl: Development and Permeability Studies across an In Vitro Model of Human Blood–Brain Barrier

Induction of ATP Release, PPIX Transport, and Cholesterol Uptake by Human Red Blood Cells Using a New Family of TSPO Ligands

Green Fluorescent Terbium (III) Complex Doped Silica Nanoparticles for TSPO Targeting

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