Modelo de Despliegue

The increasing number of radioisotopes in nuclear medicine has necessitated the corresponding increase in the development of the novel chelators to suit the requirement of the complex’s stability in terms of thermodynamic stability and kinetic inertness. Each radiometal ion has different physical and chemical properties like; ligand donor atom preferences (e.g. N, O, S), size, oxidation state, coordination number and coordination geometry. As result of this, a correct choice of the chelator suiting the attributes of the chosen radioisotope has to be made so that the resulting complex exhibits optimal characteristics suitable for the in vivo stability. Broadly, the chelators have been classified as linear or acyclic and macrocyclic. In the context of this doctoral thesis, the key radiometals/metals that are of interest for theranostic applications include Gadolinium/Gd (for MRI and radiosensitization), Copper 64/⁶⁴Cu (for PET) and Indium-111/¹¹¹In (for SPECT). As a result, only those chelators useful for the complexation of above radiometals will be discussed. A detailed account of the chelators used in radiochemistry has been outlined in an excellent review by Price and Orvig [14].

32 Table I-3: Properties of the chelators used in this thesis for theranostic applications.

Chelator Radiometal/

The table has been adapted from [14, 34, 35]. Green-Best match; Orange-moderate match; Red-poor match.

DTPA is one of the oldest and most widely used acyclic chelator in radiochemistry and can be radiolabelled with many radiometal ions at room temperature within few minutes. However, the complexes of DTPA suffer from potential stability issues in vivo and are not as stable as

Chapter 1. Introduction

Multifunctional platforms for cancer theranosis 33

the ones formed with macrocyclic chelators. As a result of this, there is a decrease in its use which is gradually being replaced by chelators like DOTA and NOTA derivatives [36].

Nonetheless, DTPA has been successfully used in the FDA approved SPECT agent OctreoScan^TM(¹¹¹In-DTPA-octreotide), a somatostatin-targeting peptide-conjugate used for imaging neuroendocrine tumors [37]. DTPA (Gd complexed) based contrast agents for MRI have been approved and marketed under different brand names (Table I-4). Also, the first-generation gold nanoparticles from our group were based on the bifunctional chelator (BFC);

DTDTPA (thiolated DTDTPA) and are currently being upgraded to the advanced form by use of the BFC based on DOTA and NOTA.

Table I-4: Gadolinium based contrast agents marketed in US and Europe [34].

Chemical Name Generic Name Trade/Product Name Acyclic Chelators

Gd-DTPA Gadopentetate Dimeglumine Magnevist®

Gd-DTPA-BMA Gadodiamide Omniscan®

Gd-DTPA-BMEA Gadoversetamide Optimark®

Gd-BOPTA Gadobenate Disodium Multihance®

Gd-EOB-DTPA Gadoxetate Disodium Primovist®

MS-325 Gadofosveset Trisodium Vasovist®

Macrocyclic Chelators

Gd-DOTA Gadoterate Meglumine Dotarem®

Gd-HP-DO3A Gadoteridol Prohance®

Gd-DO3A-Butrol Gadobutrol Gadovist®

DOTA is the most versatile and widely used chelator and is of significant value for MRI as several marketed products are based on the gadolinium complex of the DOTA in its different forms as can be seen from the Table I-4. Due to relatively lower stability, the DTPA based contrast agents are more likely to release the Gd⁺³ in vivo. This can have implications in potential kidney toxicity that can result in Nephrogenic Systemic Fibrosis (NSF) and hence are being widely replaced by DOTA based complexes [38]. DOTA has been gold standard for some of the radioisotopes and forms stable complexes with ¹¹¹In, ¹⁷⁷Lu, ^86/90Y, ²²⁵Ac, and

44/47Sc. Owing to the lack of geometric fit, DOTA does not form very stable complexes with PET isotopes like ⁶⁴Cu and ⁶⁸Ga, which can be addressed by deployment of NOTA. NOTA is a hexadentate N3O3chelator and has been successfully used as chelator of choice for^67/68Ga and ⁶⁴Cu. NOTA is now considered to be the ‘‘gold standard’’ for ⁶⁴Cu⁺² and Ga³⁺ chelation, with facile and favourable radiolabelling conditions (RT, 30–60 minutes) and excellent in

34 vivo stability [39, 40].

Table I-1 summarizes the properties of the key chelators that are relevant to the research work described in this thesis.

I-3.1.1 Influence of the chelator on the properties and stability of the theranostics:

Selection of the correct combination of the chelator and metal is key to the successful development of theranostics. In vivo kinetic inertness of the metal–chelate complex is of utmost consideration in identifying the right match between the chelator and metal. Although, thermodynamic stability constants (KML= [ML]/[M][L]) can be a useful gauge for the initial level comparisons, but they do not necessarily predict the in vivo stability. Experiments like acid dissociation and competitive radiolabelling have been proposed but they are not representative and do not reflect the environment encountered at physiological conditions.

Challenge studies can be performed by incubating the chelate-metal complex with ions like Na⁺, K⁺, Ca²⁺, Mg²⁺, Cu²⁺ or Fe³⁺ to identify the trans-chelation mediated instabilities.

Alternatively, the complex can be subjected to EDTA challenge assays to mimic the potential endogenous chelators. Ultimately, the correct match can only be justified by performing the in vitro stability assessment in serum and performing in vivo studies focussing on biodistribution and pharmacokinetics.

Despite the stability and inertness with a given radiometal (e.g. NOTA vs. DOTA for ⁶⁸Ga), it may not be the optimal match for a certain application (e.g. a specific peptide vector). For instance, NOTA forms a more stable complex with ⁶⁸Ga than does DOTA, but owing to differences in charge and physical properties (e.g. neutral vs. charged complex), DOTA may provide superior in vivo properties with certain vectors [41]. This exemplifies the complex set of variables that need due consideration when constructing radiometal-based radiopharmaceuticals. Another interesting feature related to the influence of chelator, is that they can modulate the binding affinity of the peptide based radiopharmaceuticals. Findings by Maecke et al., claim that ‘The chelate makes difference’ in the context of peptide based imaging agents. It has been demonstrated that the combination of the chelate and metal can have a substantial effect on the binding affinity as well as the tumor localization in animal models [42].

In the view of the multimodality, it is necessary to use the right form of the bifunctional chelators so as to conjugate it to the multimodal assembly. This necessitates the use of the bifunctional chelator so that properties of the base chelators are unaffected. One of the strategies in offering the bifunctionality to the chelator (e.g: DOTA and NOTA) is to append a side arm containing two carboxylate groups on the macrocyclic ring. This can be done for instance, by employing the glutaric arm during the macrocycle synthesis so that the original

Chapter 1. Introduction

Multifunctional platforms for cancer theranosis 35

coordination sphere of the chelator remains intact yet offering a site for conjugation (e.g:

DOTAGA and NODAGA) [42-44]. Thus, chelator remains an integral and important component in development of a multimodal theranostics.