Radiopharmaceuticals are pharmaceutical preparations composed of an artificial radionuclide, the active principle, chelated by a suitable ligand, in the case of a metallic radionuclide, and conjugated to proper molecules that act as vector s. By ‘nuclide’ we mean a single chemical species, characterized by an atomic number Z, the number of protons equal to the number of electrons, a mass number A, the number of proton plus neutron, and a particular energy state. Not all radionuclides are stable: usually a nuclide with a large number of protons and neutrons tends to be unstable, due to the high electrostatic repulsions between protons. To acquire greater stability, they tend to decay, producing a new and more stable nuclide. There are three different modes of decay: α, β and γ. In order to use the active principle, the metallic radioisotopes, we need to sequester them from an aqueous solution and covalently linked to a vector. Chelation is a chemical reaction in which a metal cation binds to a chemical species, called ligand. The metal behaves like a Lewis acid, as it tends to accept electrons due to the partially or completely empty orbitals, while the ligand behaves like a Lewis base, as it has electron doublets that can be shared. After the radiocomplex is formed it is necessary to evaluate its thermodynamic and kinetic stability, considering however that in vivo kinetic stability is the most important characteristic to prevent the complex to being transchelated by a multitude of endogenous molecules, present in enormous quantities in the body. The vector has the task to transport the active principle to the site of interest. The transport could be active or passive, but it must be as efficient as possible. The different vectors used in nuclear medicine are divided in three different categories: Antibodies, organic and inorganic nanoparticles. Of all the categories and subcategories analysed, the most important and analysed vectors are those based on human serum albumin (HSA). From the HSA it is possible to obtain a series of vectors, like nano and macro colloid of albumin. These vectors are a colloidal suspension on nanoparticle of different sizes. The nanocolloids (NC) are mainly used for the scan of sentinel lymph nodes, involved in different types of cancer: melanoma, breast cancer, etc. however, a careful control of the dimensions is necessary, because if the particles are too small they leave the lymphatic system, if they are too large they cannot penetrate it. They are generally supplied in kits together with SnCl2*2H2O, for the reduction of the pertechnetation ion, used with an activity of Tc no more than 5500 MBq/5 mL. Itnis also known that the percentage of radioisotope bound by the individual nanoparticles is proportional to their size. Macrocolloids, or macro-aggregate of albumin (MAA), are instead commonly used for pulmonary perfusion, loaded with Technetium with an activity of no more than 3700 MBq/5 mL. Their enormous size allows embolization in the first precapillary filter that they find just after being injected into the patient, allowing lung scintigraphy. Their dimensions can be very different: they start from about 10 μm up to 100 μm, with only 0.2% larger than 100 μm. They are commonly used, almost every day, in Nuclear Medicine, but little is known about their actual conformation or the type of bond that is established with Technetium and Gallium. The scope of the work is the characterization of the type of bond that is created between MAA (macroaggregate of HSA) and NC (nanocolloid of HSA) and the two radioisotopes Tc- 99m and Ga-68, commonly used in Nuclear Medicine. This work looks at a broader project of San Matteo polyclinic aimed to being able to predict if a different radioisotope could be used with this vector/chelator for different use.
I radiofarmaci sono preparati farmaceutici composti da un radionuclide artificiale, il principio attivo, chelato da un opportuno ligando, nel caso di un radionuclide metallico, e coniugato a opportune molecole che agiscono da vettori. Per "nuclide" si intende una singola specie chimica, caratterizzata da un numero atomico Z, un numero di massa A, e un particolare stato energetico. Non tutti i radionuclidi sono stabili: solitamente un nuclide con un gran numero di protoni e neutroni tende ad essere instabile, a causa delle elevate repulsioni elettrostatiche tra i protoni. Per acquisire una maggiore stabilità, tendono a decadere, producendo un nuovo e più stabile nuclide. Esistono tre diverse modalità di decadimento: α, β e γ. Per poter utilizzare il principio attivo, i radioisotopi metallici, occorre sequestrarli da una soluzione acquosa e legati covalentemente ad un vettore. La chelazione è una reazione chimica in cui un catione metallico si lega a una specie chimica, chiamata ligando. Il metallo si comporta come un acido di Lewis, in quanto tende ad accettare elettroni a causa degli orbitali parzialmente o completamente vuoti, mentre il ligando si comporta come una base di Lewis, in quanto ha doppietti di elettroni che possono essere condivisi. Una volta formato il radiocomplesso è necessario valutarne la stabilità termodinamica e cinetica, considerando però che la stabilità cinetica in vivo è la caratteristica più importante per evitare che il complesso venga transcelato da una moltitudine di molecole endogene, presenti in enormi quantità nell'organismo. Il vettore ha il compito di trasportare il principio attivo nel sito di interesse. Il trasporto può essere attivo o passivo, ma deve essere il più efficiente possibile. I diversi vettori utilizzati nella medicina nucleare si dividono in tre diverse categorie: Anticorpi, nanoparticelle organiche e inorganiche. Di tutte le categorie e sottocategorie analizzate, i vettori più importanti e analizzati sono quelli basati sull'albumina sierica umana (HSA). Dall'HSA è possibile ottenere una serie di vettori, come il nano e il macro colloide dell'albumina. Questi vettori sono una sospensione colloidale su nanoparticelle di diverse dimensioni.I nanocolloidi (NC) vengono utilizzati principalmente per la scansione dei linfonodi sentinella, coinvolti in diversi tipi di cancro: melanoma, cancro al seno, ecc. Tuttavia è necessario un attento controllo delle dimensioni, perché se le particelle sono troppo piccole se ne vanno il sistema linfatico, se sono troppo grandi non riescono a penetrarlo. Sono generalmente forniti in kit insieme a SnCl2 * 2H2O, per la riduzione dello ione pertecnetazione, utilizzato con un'attività di Tc non superiore a 5500 MBq / 5 mL. È anche noto che la percentuale di radioisotopo legato dalle singole nanoparticelle è proporzionale alla loro dimensione. I macrocolloidi, o macroaggregati di albumina (MAA), sono invece comunemente usati per la perfusione polmonare, caricati con tecnezio con un'attività non superiore a 3700 MBq / 5 mL. Le loro enormi dimensioni consentono l'embolizzazione nel primo filtro precapillare che trovano subito dopo essere stati iniettati nel paziente, consentendo la scintigrafia polmonare. Le loro dimensioni possono essere molto diverse: partono da circa 10 μm fino a 100 μm, con solo lo 0,2% maggiori di 100 μm. Sono comunemente usati, quasi tutti i giorni, in Medicina Nucleare, ma poco si sa sulla loro effettiva conformazione o sul tipo di legame che si instaura con Tecnezio e Gallio. Lo scopo del lavoro è la caratterizzazione del tipo di legame che si crea tra MAA (macroaggregato di HSA) e NC (nanocolloide di HSA) e i due radioisotopi Tc-99m e Ga-68, comunemente usati in Medicina Nucleare. Questo lavoro esamina un progetto più ampio del policlinico San Matteo volto a poter prevedere se un diverso radioisotopo potrebbe essere utilizzato con questo vettore / chelante per usi diversi.
Marcatura di nanocolloidi e macroaggregati di Albumina con isotopi radioattivi: studio della cinetica e caratterizzazione del legame
CANZIANI, LETIZIA
2019/2020
Abstract
Radiopharmaceuticals are pharmaceutical preparations composed of an artificial radionuclide, the active principle, chelated by a suitable ligand, in the case of a metallic radionuclide, and conjugated to proper molecules that act as vector s. By ‘nuclide’ we mean a single chemical species, characterized by an atomic number Z, the number of protons equal to the number of electrons, a mass number A, the number of proton plus neutron, and a particular energy state. Not all radionuclides are stable: usually a nuclide with a large number of protons and neutrons tends to be unstable, due to the high electrostatic repulsions between protons. To acquire greater stability, they tend to decay, producing a new and more stable nuclide. There are three different modes of decay: α, β and γ. In order to use the active principle, the metallic radioisotopes, we need to sequester them from an aqueous solution and covalently linked to a vector. Chelation is a chemical reaction in which a metal cation binds to a chemical species, called ligand. The metal behaves like a Lewis acid, as it tends to accept electrons due to the partially or completely empty orbitals, while the ligand behaves like a Lewis base, as it has electron doublets that can be shared. After the radiocomplex is formed it is necessary to evaluate its thermodynamic and kinetic stability, considering however that in vivo kinetic stability is the most important characteristic to prevent the complex to being transchelated by a multitude of endogenous molecules, present in enormous quantities in the body. The vector has the task to transport the active principle to the site of interest. The transport could be active or passive, but it must be as efficient as possible. The different vectors used in nuclear medicine are divided in three different categories: Antibodies, organic and inorganic nanoparticles. Of all the categories and subcategories analysed, the most important and analysed vectors are those based on human serum albumin (HSA). From the HSA it is possible to obtain a series of vectors, like nano and macro colloid of albumin. These vectors are a colloidal suspension on nanoparticle of different sizes. The nanocolloids (NC) are mainly used for the scan of sentinel lymph nodes, involved in different types of cancer: melanoma, breast cancer, etc. however, a careful control of the dimensions is necessary, because if the particles are too small they leave the lymphatic system, if they are too large they cannot penetrate it. They are generally supplied in kits together with SnCl2*2H2O, for the reduction of the pertechnetation ion, used with an activity of Tc no more than 5500 MBq/5 mL. Itnis also known that the percentage of radioisotope bound by the individual nanoparticles is proportional to their size. Macrocolloids, or macro-aggregate of albumin (MAA), are instead commonly used for pulmonary perfusion, loaded with Technetium with an activity of no more than 3700 MBq/5 mL. Their enormous size allows embolization in the first precapillary filter that they find just after being injected into the patient, allowing lung scintigraphy. Their dimensions can be very different: they start from about 10 μm up to 100 μm, with only 0.2% larger than 100 μm. They are commonly used, almost every day, in Nuclear Medicine, but little is known about their actual conformation or the type of bond that is established with Technetium and Gallium. The scope of the work is the characterization of the type of bond that is created between MAA (macroaggregate of HSA) and NC (nanocolloid of HSA) and the two radioisotopes Tc- 99m and Ga-68, commonly used in Nuclear Medicine. This work looks at a broader project of San Matteo polyclinic aimed to being able to predict if a different radioisotope could be used with this vector/chelator for different use.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/13103