Synthesis and Biochemical Evaluation of Samarium-153 Oxide Nanoparticles Functionalized with iPSMA-Bombesin Heterodimeric Peptide.

Developments in the design of lanthanide oxide nanoparticles (NPs) have unleashed a wide variety of biomedical applications. Several types of hepatic cancer cells overexpress two proteins: the gastrin-releasing peptide receptor (GRPr), which specifically recognizes the bombesin (BN) peptide, and the prostate-specific membrane antigen (PSMA), which specifically binds to several peptides that inhibit its activity (iPSMA). This research synthesized and physicochemically characterized Sm2O3 nanoparticles functionalized with the iPSMA-BN heterodimeric peptide and studied the effects on their structural, biochemical and preclinical properties after activation by neutron irradiation for possible use in molecular dual-targeted radiotherapy of hepatocellular carcinoma. The Sm2O3 NPs were synthesized by the precipitation-calcination method and functionalized with iPSMA-BN peptide using the DOTA macrocycle as a linking agent. Analysis of physicochemical characterization via TEM, EDS, XRD, UV-Vis, FT-IR, DSL, and zeta potential results showed the formation of Sm2O3-iPSMA-BN NPs (94.23 ± 5.98 nm), and their physicochemical properties were not affected after neutron activation. The nanosystem showed a high affinity with respect to PSMA and GRPr in HepG2 cells ( Kd = 6.6 ± 1.6 nM) and GRPr in PC3 cells ( Kd = 10.6 ± 1.9 nM). 153Sm2O3-iPSMA-BN NPs exhibited radioluminescent properties, making possible in vivo optical imaging of their biodistribution in mice. The results obtained from this research support further preclinical studies designed to evaluate the dosimetry and therapeutic efficacy of 153Sm2O3-iPSMA-BN nanoparticles for in vivo imaging and molecular dual-targeted radiotherapy of liver tumors overexpressing PSMA and/or GRPr proteins.

Synthesis, chemical and biochemical characterization of Lu2O3-iPSMA nanoparticles activated by neutron irradiation.

Among the nanomaterials, rare sesquioxides (lanthanide oxides such as Lu2O3) are of interest due to their adequate thermal conductivity, excellent chemical stability, and high light output. The prostate-specific membrane antigen (PSMA) is an integral multifunctional protein overexpressed in various types of cancer cells. The radiolabeled PSMA inhibitor peptides (iPSMA) have demonstrated their usefulness as specific probes in the treatment and detection of a wide variety of neoplasms, mainly due to their high in vivo recognition by the PSMA protein. The objective of this research was to synthesize Lu2O3-iPSMA nanoparticles (NPs) and characterize their physicochemical properties before and after neutron activation, as well as to assess their biodistribution profile and in vitro potential to target cells overexpressing PSMA. The Lu2O3 NPs were synthesized by the precipitation-calcination method and conjugated to the iPSMA peptide using DOTA (1,4,7,10-tetraazocyclodecane-N,N',N″,N‴-tetraacetic acid) as a linking agent. Results of the physicochemical characterization by FT-IR and UV-Vis spectroscopies, SEM, TEM, DLS, HRTEM, SAED, DSC-TGA, and X-ray diffraction indicated the formation of Lu2O3-iPSMA NPs (diameter of 29.98 ± 9.07 nm), which were not affected in their physicochemical properties after neutron activation. 177Lu2O3-iPSMA NPs showed high affinity (Kd = 5.7 ± 1.9 nM) for the PSMA protein, evaluated by the saturation assay on HepG2 hepatocellular carcinoma cells (PSMA-positive). The biodistribution profile of the nanosystem in healthy mice showed the main uptake in the liver. After irradiation, radioactive Lu2O3-iPSMA NPs exhibited radioluminescent properties, making the in vivo acquisition of their biodistribution, via optical imaging, possible. The results obtained from this research validate the execution of additional preclinical studies with the objective of evaluating the potential of the 177Lu2O3-iPSMA NPs for the targeted radiotherapy and in vivo imaging of tumors overexpressing the PSMA protein.

Tumoral fibrosis effect on the radiation absorbed dose of (177)Lu-Tyr(3)-octreotate and (177)Lu-Tyr(3)-octreotate conjugated to gold nanoparticles.

The aim of this work was to evaluate the tumoral fibrosis effect on the radiation absorbed dose of the radiopharmaceuticals (177)Lu-Tyr(3)-octreotate (monomeric) and (177)Lu-Tyr(3)-octreotate-gold nanoparticles (multimeric) using an experimental HeLa cells tumoral model and the Monte Carlo PENELOPE code. Experimental and computer micro-environment models with or without fibrosis were constructed. Results showed that fibrosis increases up to 33% the tumor radiation absorbed dose, although the major effect on the dose was produced by the type of radiopharmaceutical (112Gy-multimeric vs. 43Gy-monomeric).

Multifunctional radiolabeled nanoparticles for targeted therapy.

Nanoparticles can be near infrared (NIR)-fluorescent (e.g., gold nanoparticles, quantum dots or carbon nanotubes) or can have magnetic properties (e.g., iron oxide nanoparticles). These optical or magnetic properties can be exploited for use in thermal therapy and molecular imaging. Radiolabeled nanoparticles have proven to be promising tools in the diagnosis and therapy of malignant processes due to their multivalency and as multi-modal imaging agents. Furthermore, these radiopharmaceuticals may function simultaneously as both radiotherapy systems and thermal-ablation systems. This review examines the application of radiolabeled nanoparticles in the development of multifunctional nanosystems for targeted therapy.

Click chemistry for [(99m)Tc(CO)(3)] labeling of Lys(3)-bombesin.

(99m)Tc-HYNIC labeled Lys(3)-bombesin has shown specific binding to gastrin-releasing peptide receptors (GRP-r) over-expressed in cancer cells. Click chemistry offers an innovative functionalization strategy for biomolecules such as bombesin. The aim of this research was to apply a click chemistry approach for [(99m)Tc(CO)(3)] labeling of Lys(3)-bombesin and to compare the in vitro MCF7 breast cancer cell uptake and biodistribution profile in mice with that of (99m)Tc-EDDA/HYNIC-Lys(3)-bombesin. The results suggest a higher lipophilicity for (99m)Tc(CO)(3)-triazole-Lys(3)-bombesin which explains its higher in vivo hepatobiliary elimination. Pancreas-to-blood ratio for (99m)Tc(CO)(3)-triazole-Lys(3)-bombesin was 4.46 at 3 h and both bombesin radiopharmaceuticals showed specific recognition for GRP receptors in MCF7 cancer cells. Click chemistry is a reliable approach for [(99m)Tc(CO)(3)] labeling of Lys(3)-bombesin.

Gold nanoparticles conjugated to [Tyr3]octreotide peptide.

A multifunctional system of gold nanoparticles (AuNP) capped by the [Tyr(3)]Octreotide (TOC) peptide was prepared and characterized by transmission electron microscopy (TEM) and UV-Vis, infrared and fluorescence spectroscopy. AuNP and AuNP-TOC fluorescence emission spectra were obtained both in solution and in murine AR42J-tumor tissues. Results suggest that AuNP were functionalized with TOC through interactions with the N-terminal amine of the phenylalanine, the amide groups and possibly with the indole group of the tryptophan residue. The fluorescence analyses in tissue revealed a recognition of the AuNP-TOC conjugate for the neuroendocrine tumor because of the lower energy position of the fluorescence resonance (692 nm) with respect to that of the AuNP in the same tumoral tissue (684 nm). The emission band observed in the near-infrared region (692 nm) opens the possibility for AuNP-TOC use in bioimaging.