177Lu-Bombesin-PLGA (paclitaxel): A targeted controlled-release nanomedicine for bimodal therapy of breast cancer

The gastrin-releasing peptide receptor (GRPr) is overexpressed in>75% of breast cancers. 177Lu-Bombesin (177Lu-BN) has demonstrated the ability to target GRPr and facilitate efficient delivery of therapeutic radiation doses to malignant cells. Poly(D,L‑lactide‑co‑glycolide) acid (PLGA) nanoparticles can work as smart drug controlled- release systems activated through pH changes. Considering that paclitaxel (PTX) is a first-line drug for cancer treatment, this work aimed to synthesize and chemically characterize a novel polymeric PTX-loaded nanosystem with grafted 177Lu-BN and to evaluate its performance as a targeted controlled-release nanomedicine for concomitant radiotherapy and chemotherapy of breast cancer. PLGA(PTX) nanoparticles were synthesized using the single emulsification-solvent evaporation method with PVA as a stabilizer in the presence of PTX. Thereafter, the activation of PLGA carboxylic groups for BN attachment through the Lys1-amine group was performed. Results of the chemical characterization by FT-IR, DLS, HPLC and SEM/TEM demonstrated the successful synthesis of BN-PLGA(PTX) with a hydrodynamic diameter of 163.54 ± 33.25 nm. The entrapment efficiency of paclitaxel was 92.8 ± 3.6%. The nanosystem showed an adequate controlled release of the anticancer drug, which increased significantly due to the pH change from neutral (pH=7.4) to acidic conditions (pH=5.3). After labeling with 177Lu and purification by ultrafiltration, 177Lu-BN-PLGA(PTX) was obtained with a radiochemical purity of 99 ± 1%. In vitro and in vivo studies using MDA-MB-231 breast cancer cells (GRPr-positive) demonstrated a 177Lu-BNPLGA( PTX) specific uptake and a significantly higher cytotoxic effect for the radiolabeled nanosystem than the unlabeled BN-PLGA(PTX) nanoparticles. Using a pulmonary micrometastasis MDA-MB-231 model, the added value of 177Lu-BN-PLGA(PTX) for tumor imaging was confirmed. The 177Lu-BN-PLGA(PTX) nanomedicine is suitable as a targeted paclitaxel delivery system with concomitant radiotherapeutic effect for the treatment of GRPr-positive breast cancer.This study was partially supported by the National Council of Science and Technology (CONACyT-CB-A1S38087) and the International Atomic Energy Agency (CRP-F22064, Contract 18358). It was carried out as part of the activities of the “Laboratorio Nacional de Investigación y Desarrollo de Radiofármacos, CONACyT

52gMn production route for multi-modal imaging applications

The radionuclide 52gMn is of significant medical interest for the innovative PET-MRI multimodal imaging technique. In this study we compare its standard cyclotron production route natCr(p, x)52gMn with the alternative reaction natV(α, x)52gMn. The theoretical calculations are performed by a suitable tuning of the nuclear level density parameters of the TALYS reaction code, with the aim to obtain a good agreement with the experimental cross sections. The production route with natV results in a more favorable radionuclidic purity than with natCr. Dosimetric studies are performed to establish the time frame in which 52gMn can be used with an acceptable dose to the patient

Therapeutic application of a mixture of 64/67Cu radioisotopes

Copper radioisotopes, such as 64Cu and 67Cu, could be useful tools for diagnosis and therapy of cancers, due to the increased accumulation of Cu2+ ions in the tumor site. While 64Cu can be produced with high specific activity using low-energy biomedical cyclotrons and it is already commercially available, 67Cu production is more challenging, due to the difficulties to obtain a high yield without the co-production of other Cu-isotopes, especially 64Cu. Due to the favorable decay characteristics of both 64/67Cu radioisotopes, in this work the possibility of using a mixture of them for therapeutic purposes has been evaluated

A feasibility study of the Therapeutic Application of a Mixture of 67/64Cu Radioisotopes produced by cyclotrons with proton irradiation

Purpose: 64Cu and 67Cu radioisotopes have nuclear characteristics suitable for nuclear medicine applications. The production of 64Cu is already well-established. However, the production of 67Cu in quantities suitable to conduct clinical trials is more challenging as it leads to the co-production of other Cu-isotopes, in particular 64Cu. The aim of this study is to investigate the possibility of using a CuCl2 solution with a mixture of 67/64Cu radioisotopes for therapeutic purposes, providing an alternative solution for the cyclotron production problem. Methods: Copper radioisotopes activities were calculated by considering proton beam irradiation of the following targets: i) 70Zn in the energy range 70-45 MeV; ii) 68Zn in the energy range 70-35 MeV; iii) a combination of 70Zn (70-55 MeV) and 68Zn (55-35 MeV). The contribution of each copper radioisotope to the human absorbed dose was estimated with OLINDA/EXM software using the biokinetic model for CuCl2 published by ICRP 53. The total absorbed dose generated by the 67/64CuCl2 mixture, obtained through different production routes, was calculated at different times after the end of the bombardment (EOB). A simple spherical model was used to simulate tumours of different sizes containing uniformly distributed 67/64Cu mixture and to calculate the absorbed dose of self-irradiation. The biological damage produced by 67Cu and 64Cu was also evaluated through cellular dosimetry and cell surviving fraction assessment using the MIRDcell code, considering two prostate cancer cell lines with different radiosensitivity. Results: The absorbed dose to healthy organs and the effective dose (ED) per unit of administered activity of 67CuCl2 are higher than those of 64CuCl2. Absorbed dose values per unit of administered activity of 67/64CuCl2 mixture increase with time after the EOB, because the amount of 67Cu in the mixture increases. Survival data showed that the biological damage caused per each decay of 67Cu is greater than that of 64Cu, assuming that radionuclides remain accumulated in the cell cytoplasm. Sphere model calculations demonstrated that 64Cu administered activity must be about five times higher than that of 67Cu to obtain the same absorbed dose for tumour mass between 0.01 g and 10 g and about ten times higher for very small spheres. Consequently, the 64CuCl2 absorbed dose to healthy organs will reach higher values than those of 67CuCl2. The supplemental activity of the 67/64CuCl2 mixture, required to get the same tumour absorbed dose produced by 67CuCl2, triggers a dose increment in healthy organs. The waiting time post-EOB necessary to keep this dose increment below 10% (t10%) depends on the irradiation methods employed for the production of the 67/64CuCl2 mixture. Conclusions: A mixture of cyclotron produced 67/64Cu radioisotopes proved to be an alternative solution for the therapeutic use of CuCl2 with minimal dose increment to healthy organs compared to pure 67Cu. Irradiation of a 70Zn+68Zn target in the 70-35 MeV proton energy range for 185 h appears to be the best option from among all the production routes investigated, as it gives the maximum amount of activity, the shortest t10% (10 h), and less than 1% of 61Cu and 60Cu impurities

Impact of Different [Tc(N)PNP]-Scaffolds on the Biological Properties of the Small cRGDfK Peptide: Synthesis, In Vitro and In Vivo Evaluations

Background: The [Tc-99m][Tc(N)(PNP)] system, where PNP is a bisphosphinoamine, is an interesting platform for the development of tumor 'receptor-specific' agents. Here, we compared the reactivity and impact of three [Tc(N)(PNP)] frameworks on the stability, receptor targeting properties, biodistribution, and metabolism of the corresponding [Tc-99m][Tc(N)(PNP)]-tagged cRGDfK peptide to determine the best performing agent and to select the framework useful for the preparation of [Tc-99m][Tc(N)(PNP)]-housing molecular targeting agents. Methods: cRGDfK pentapeptide was conjugated to Cys and labeled with each [Tc(N)(PNP)] framework. Radioconjugates were assessed for their lipophilicity, stability, in vitro and in vivo targeting properties, and performance. Results: All compounds were equally synthetically accessible and easy to purify (RCY >= 95%). The main influences of the synthon on the targeting peptide were observed in in vitro cell binding and in vivo. Conclusions: The variation in the substituents on the phosphorus atoms of the PNP enables a fine tuning of the biological features of the radioconjugates. ws[Tc-99m][Tc(N)(PNP3OH)]- and [Tc-99m][Tc(N)(PNP3)]- are better performing synthons in terms of labeling efficiency and in vivo performance than the [Tc-99m][Tc(N)(PNP43)] framework and are therefore more suitable for further radiopharmaceutical purposes. Furthermore, the good labeling properties of the ws[Tc-99m][Tc(N)(PNP3OH)]- framework can be exploited to extend this technology to the labeling of temperature-sensitive biomolecules suitable for SPECT imaging