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RS achievements

CLICKABLE RADIOCOMPLEXES FOR RADIOIMMUNOTHERAPY

G1 1

 

The major goal of this project is to design multifunctional radioimmunoconjugates for the targeting of tumor endothelial marker 1 (TEM1/endosialin), a receptor overexpressed in several human cancers with minimal expression in normal tissues. For this purpose, Tb radioisotopes produced at the MEDICIS facility in CERN will be used. Terbium is an excellent candidate for theranostic applications possessing four clinically relevant radioisotopes (149Tb, 152Tb, 155Tb and 161Tb) for imaging and therapy. The final conjugates will be obtained by in vivo click reactions between macrocyclic Tb radiocomplexes carrying a tetrazine moiety and antibody fragments functionalized with trans-cyclooctene (TCO), expecting to reduce the systemic radiation exposure of the patients while maximizing the therapeutic efficacy. As a first step, we succeeded on the 125I-labelling of a small panel of TEM1 targeted antibody fragments and evaluated their specific TEM1 targeting ability, which allowed us to select the best candidates for further studies with the Tb radioisotopes.

INDIUM(III) COMPLEXES AS RADIOTHERANOSTIC AGENTS FOR DUAL TARGETING OF BREAST CANCER

G1 2

Despite the enhancement in the survival rate of breast cancer (BC) patients, there is still a need for more effective and personalized treatments to improve BC management. Radiotheranostics is particularly suitable for that purpose as the estrogen receptor (ER) status acquired by imaging can be used to targeted treatment. Thus, our approach combines into a single 111In-hybrid compound, a chelator simultaneously conjugated to an ER ligand (LXXLL peptide) and an antitumor agent (the DNA intercalating agent, acridine orange, AO) for dual targeting of BC cells aiming at the increase of therapeutic efficacy. The 111In-ER3AO is able to localize in the nucleus of BC cells and induce DNA damage in vitro. These features, along with a favourable biodistribution profile in tumor bearing mice with fast clearance from main organs and accumulation in target tissues, suggest that this hybrid radioconjugate has potential as theranostic agent.

64CU-BASED COMPOUNDS FOR CANCER IMAGING AND THERAPY

G1 3

Copper plays a critical role for cancer development and progression, and multiple copper isotopes are explored for cancer imaging and therapy. Studies using the simpler ionic form of the medically relevant copper radioisotope, 64Cu, have been conducted with promising results for prostate cancer theranostics. High levels of 64CuCl2 uptake were observed in prostate cancer cells, with a concomitant increase in DNA damage resulting from exposure to the compound (a work performed in collaboration with the RPS Group). We are currently studying whether this might correlate with the different expression of the native copper cellular transporters exhibited by those cell lines. Continuing our previous work on a family of cytotoxic bis(thiosemicarbazonato) copper(II) complexes (CuL1-CuL4), which presented significant uptake in cancer cells, we have found that such behavior is temperature-dependent, suggesting a predominant active or facilitated uptake of the metal complexes in those cell lines.

Multifunctional Gold Nanoparticles for Targeted Theranostics

 

G1 5

 

The aim of this project is to develop target-specific multifunctional gold nanoparticles (AuNPs) for simultaneous delivery of radionuclides and gadolinium to cancer cells, and explore their radiosensitizing properties. In this context, we have developed AuNPs stabilized with a thiolated DOTA derivative and decorated with a bombesin (BBN) for specific targeting of the gastrin releasing peptide receptor, which is overexpressed in a variety of cancers. These AuNPs were simultaneously coordinated with Gd and 67Ga to study their multimodal imaging capabilities. The relaxivity properties measured for the Gd-containing AuNPs make them potential candidates for T1- and T2- MR imaging. Biodistribution studies in prostate cancer PC-3 xenografts, performed by gamma-counting measurements of 67Ga, showed that the multimodal AuNPs have a reasonable tumor uptake. Additionally, in vitro studies using prostate cancer cells demonstrated that these nanoparticles have radiosensitization capabilities. Altogether, these data corroborate its promising potential for targeted cancer theranostics.

ACRIDINE ORANGE DERIVATIVES FOR DNA-TARGETING

G1 4

Applications using radioisotopes and radiopharmaceuticals are of major importance for cancer medicine and paved the way for the development of targeted radionuclide therapies and more advanced diagnostic techniques. Within targeted radionuclide therapies, Auger-emitting radiopharmaceuticals are considered best suited for the eradication of disseminated cancer metastases with minimization of deleterious effect to non-target surrounding tissues. To tackle this goal, we have been involved in the study of 125I- and 99mTc-containing acridine orange (AO) derivatives as potential Auger-emitting radiopharmaceuticals. In collaboration with the group of Carla Cruz (CICS-UBI, Covilhã), we have recently demonstrated that some of these AO derivatives are potent binders of G-quadruplex (G4) structures formed within the nuclease hypersensitive element of the KRAS promoter region. This finding might have great relevance for the design of innovative Auger-emitting radiopharmaceuticals targeted at KRAS, as KRAS is often found mutated in a variety of highly lethal cancers.

DESIGN OF HER2-SPECIFIC VIRUS-LIKE PARTICLES FOR IMAGE-GUIDED DRUG DELIVERY

G1 6

 

Modelling, docking and fitting of an HER2-specific single chain variable fragment with the transmembrane viral protein (gp41) was the key to define the best pairwise residues allowing the modeling of a fusion protein to be expressed onto the viral capsid. Considering this information, DNA recombinant technologies were used to prepare the retargeted VLP containing the fusion protein with Gp41. The tropism of the constructed HIV-based VLPs was manipulated and the particles were engineered for the specific delivery of drugs and/or radionuclides for theranostics of HER2 positive breast cancer.

  1. RADIOMETALLATED ANTIBODY FRAGMENTS FOR CENTRAL NERVOUS SYSTEM DRUG DESIGN
  2. A MOLECULAR IMAGING APPROACH TO CYSTIC FIBROSIS
  3. PRECLINICAL EVALUATION OF METALLODRUGS FOR ANTICANCER THERAPY
  4. COMPUTER-AIDED DRUG DESIGN APPROACHES IN NEURODEGENERATIVE DISEASES