Ozone Dosage is the Key Factor of Its Effect in Biological Systems

The applications of ozone are not only restricted to environmental remediation or industrial areas. This gas has been applied in medicine to treat several diseases, where positive effects have been confirmed by many clinical studies. According to the European Medical Society of Ozone and the National Center of Scientific Investigation in Cuba, it has not been possible to validate ozone’s effectiveness by traditional analytical methods. Thus, this investigation proposed evaluating the effect that ozone has on biological substrates (murine models with induced carcinogenic tumors, inflammation, and wounds), studying the variations that ozone (dissolved in physiological solution or ozonated vegetable oils) provokes over the total unsaturation of lipids (TUL), and by using the so-called method double bond index (DB-index), make a correlation with the dynamic reactions obtained by several analytical methods according to each experimental stage considered in this study

Synthesis and Evaluation of 177Lu-DOTA-DN(PTX)-BN for Selective and Concomitant Radio and Drug—Therapeutic E ect on Breast Cancer Cells

The peptide-receptor radionuclide therapy (PRRT) is a successful approach for selectively delivering radiation within tumor sites through specific recognition of radiolabeled peptides by overexpressed receptors on cancer cell surfaces. The e cacy of PRRT could be improved by using polymeric radio- and drug- therapy nanoparticles for a concomitant therapeutic e ect on malignant cells. This research aimed to prepare and evaluate, a novel drug and radiation delivery nanosystem based on the 177Lu-labeled polyamidoamine (PAMAM) dendrimer (DN) loaded with paclitaxel (PTX) and functionalized on the surface with the Lys1Lys3(DOTA)-bombesin (BN) peptide for specific targeting to gastrin-releasing peptide receptors (GRPr) overexpressed on breast cancer cells. DN was first conjugated covalently to BN and DOTA (chemical moiety for lutetium-177 complexing) and subsequently loaded with PTX. The characterization by microscopic and spectroscopic techniques, in-vitro drug delivery tests as well as in in-vitro and in-vivo cellular uptake of 177Lu-DOTA-DN(PTX)-BN by T47D breast cancer cells (GRPr-positive), indicated the formation of an improved delivery nanosystem with target-specific recognition by GRPr. Results of the 177Lu-DOTA-DN(PTX)-BN e ect on T47D cell viability (1.3%, compared with 10.9% of 177Lu-DOTA-DN-BN and 14.0% of DOTA-DN-(PTX)-BN) demonstrated the concomitant radiotherapeutic and chemotherapeutic properties of the polymeric nanosystem as a potential agent for the treatment of GRPr-positive tumors.This study was supported by the grant CONACyT-CB-A1S38087 and the International Atomic Energy Agency (CRP-F2264). It was performed as part of the activities of the “Laboratorio Nacional de Investigación y Desarrollo de Radiofármacos, CONACyT”

Development of 177Lu-scFvD2B as a Potential Immunotheranostic Agent for Tumors Overexpressing the Prostate Specific Membrane Antigen

The clinical translation of theranostic 177Lu-radiopharmaceuticals based on inhibitors of the prostate-specific membrane antigen (PSMA) has demonstrated positive clinical responses in patients with advanced prostate cancer (PCa). However, challenges still remain, particularly regarding their pharmacokinetic and dosimetric properties. We developed a potential PSMA-immunotheranostic agent by conjugation of a single-chain variable fragment of the IgGD2B antibody (scFvD2B) to DOTA, to obtain a 177Lu-labelled agent with a better pharmacokinetic profile than those previously reported. The labelled conjugated 177Lu-scFvD2B was obtained in high yield and stability. In vitro, 177Lu-scFvD2B disclosed a higher binding and internalization in LNCaP (PSMA-positive) compared to PC3 (negative control) human PCa cells. In vivo studies in healthy nude mice revealed that 177Lu-scFvD2B present a favorable biokinetic profile, characterized by a rapid clearance from non-target tissues and minimal liver accumulation, but a slow wash-out from kidney. Micro-SPECT/CT imaging of mice bearing pulmonary microtumors evidenced a slow uptake by LNCaP tumors, which steadily rose up to a maximum value of 3.6 SUV at 192 h. This high and prolonged tumor uptake suggests that 177Lu-scFvD2B has great potential in delivering ablative radiation doses to PSMA-expressing tumors, and warrants further studies to evaluate its preclinical therapeutic efficacy

Engineered rHDL Nanoparticles as a Suitable Platform for Theranostic Applications

Reconstituted high-density lipoproteins (rHDLs) can transport and specifically release drugs and imaging agents, mediated by the Scavenger Receptor Type B1 (SR-B1) present in a wide variety of tumor cells, providing convenient platforms for developing theranostic systems. Usually, phospholipids or Apo-A1 lipoproteins on the particle surfaces are the motifs used to conjugate molecules for the multifunctional purposes of the rHDL nanoparticles. Cholesterol has been less addressed as a region to bind molecules or functional groups to the rHDL surface. To maximize the efficacy and improve the radiolabeling of rHDL theranostic systems, we synthesized compounds with bifunctional agents covalently linked to cholesterol. This strategy means that the radionuclide was bound to the surface, while the therapeutic agent was encapsulated in the lipophilic core. In this research, HYNIC-S-(CH2)3-S-Cholesterol and DOTA-benzene-p-SC-NH-(CH2)2-NH-Cholesterol derivatives were synthesized to prepare nanoparticles (NPs) of HYNIC-rHDL and DOTA-rHDL, which can subsequently be linked to radionuclides for SPECT/PET imaging or targeted radiotherapy. HYNIC is used to complexing 99mTc and DOTA for labeling molecules with 111, 113mIn, 67, 68Ga, 177Lu, 161Tb, 225Ac, and 64Cu, among others. In vitro studies showed that the NPs of HYNIC-rHDL and DOTA-rHDL maintain specific recognition by SR-B1 and the ability to internalize and release, in the cytosol of cancer cells, the molecules carried in their core. The biodistribution in mice showed a similar behavior between rHDL (without surface modification) and HYNIC-rHDL, while DOTArHDL exhibited a different biodistribution pattern due to the significant reduction in the lipophilicity of the modified cholesterol molecule. Both systems demonstrated characteristics for the development of suitable theranostic platforms for personalized cancer treatment.Consejo Nacional de Ciencia y Tecnología (CONACyT, Mexico), through Grant SEP-CONACyT-CB-2016-01-287217. the financing program for female scientists EDOMEX, Grant Number FICDTEM-2021-015

177Lu-Dendrimer conjugated to folate and bombesin with gold nanoparticles in the dendritic cavity: A potential theranostic radiopharmaceutical

177Lu-labeled nanoparticles conjugated to biomolecules have been proposed as a new class of theranostic radiopharmaceuticals. The aim of this research was to synthesize 177Lu-dendrimer(PAMAM-G4)-folate-bombesin with gold nanoparticles (AuNPs) in the dendritic cavity and to evaluate the radiopharmaceutical potential for targeted radiotherapy and the simultaneous detection of folate receptors (FRs) and gastrin-releasing peptide receptors (GRPRs) overexpressed in breast cancer cells. p-SCN-Benzyl-DOTA was conjugated in aqueous-basic medium to the dendrimer.The carboxylate groups of Lys1Lys3(DOTA)-bombesin and folic acid were activatedwithHATUand also conjugated to the dendrimer.The conjugate was mixed with 1%HAuCl4 followed by the addition of NaBH4 and purified by ultrafiltration. Elemental analysis (EDS), particle size distribution (DLS), TEM analysis, UV-Vis, and infrared and fluorescence spectroscopies were performed. The conjugate was radiolabeled using 177LuCl3 or 68GaCl3 and analyzed by radio-HPLC. Studies confirmed the dendrimer functionalization with high radiochemical purity (>95%). Fluorescence results demonstrated that the presence ofAuNPs in the dendritic cavity confers useful photophysical properties to the radiopharmaceutical for optical imaging. Preliminary binding studies in T47D breast cancer cells showed a specific cell uptake (41.15 ± 2.72%). 177Ludendrimer( AuNP)-folate-bombesin may be useful as an optical and nuclear imaging agent for breast tumors overexpressing GRPR and FRs, as well as for targeted radiotherapy.CONACYT-SEP-CB-2014-01-242443 International Atomic Energy Agency (Grant 18358) LaboratorioNacional de Investigaci´on yDesarrollo de Radiof´armacos, CONACy

Fluorescent, Plasmonic, and Radiotherapeutic Properties of the 177Lu–Dendrimer-AuNP–Folate–Bombesin Nanoprobe Located Inside Cancer Cells

The integration of fluorescence and plasmonic properties into one molecule is of importance in developing multifunctional imaging and therapy nanoprobes. The aim of this research was to evaluate the fluorescent properties and the plasmonic–photothermal, therapeutic, and radiotherapeutic potential of 177Lu–dendrimer conjugated to folate and bombesin with gold nanoparticles in the dendritic cavity (177Lu–DenAuNP–folate–bombesin) when it is internalized in T47D breast cancer cells. The intense near-Infrared (NIR) fluorescence emitted at 825 nm from the conjugate inside cells corroborated the usefulness of DenAuNP–folate–bombesin for optical imaging. After laser irradiation, the presence of the nanosystem in cells caused a significant increase in the temperature of the medium (46.8oC, compared to 39.1oC without DenAuNP–folate–bombesin, P < 0.05), resulting in a significant decrease in cell viability (down to 16.51% + 1.52%) due to the 177Lu–DenAuNP–folate–bombesin plasmonic properties. After treatment with 177Lu–DenAuNP–folate–bombesin, the T47D cell viability decreased 90% because of the radiation-absorbed dose (63.16 + 4.20 Gy) delivered inside the cells. The 177Lu–DenAuNP–folate–bombesin nanoprobe internalized in cancer cells exhibited properties suitable for optical imaging, plasmonic–photothermal therapy, and targeted radiotherapy.CONACYT-SEP-CB-2014-01-24244

Synthesis and in vitro evaluation of an antiangiogenic cancerspecific dual-targeting 177Lu-Au-nanoradiopharmaceutical

The aim of this research was to synthesize and chemically characterize a cancer-specific 177Lu-Aunanoradiopharmaceutical based on gold nanoparticles (NPs), the nuclear localization sequence (NLS)-Arg-Gly- Asp peptide and an aptamer (HS-pentyl-pegaptanib) to target both the a(v)b(3) integrin and the vascular endothelial growth factor (VEGF) overexpressed in the tumor neovasculature, as well as to evaluate by the tube formation assay, the nanosystem capability to inhibit angiogenesis. 177Lu-NP-RGD-NLS-Aptamer was obtained with a radiochemical purity of 99 ± 1%. Complete inhibition of tube formation (angiogenesis) was demonstrated when endothelial cells (EA.hy926), cultured in a 3D-extracellular matrix support, were treated with the developed nanosystem.Mexican National Council of Science and Technology (CONACYT-SEP-CB-2014-01-242443)

Preparation and in vitro evaluation of 177Lu-iPSMA-RGD as a new heterobivalent radiopharmaceutical

This study aimed to synthesize a new 177Lu-iPSMA-RGD heterobivalent radiopharmaceutical, as well as to assess the in vitro radiopharmaceutical potential to target cancer cells overexpressing PSMA and a(v) b(3) integrins. The radiotracer prepared with a radiochemical purity of 98.8 ± 1.0% showed stability in human serum, specific recognition with suitable affinity to PSMA and a(v)b(3) integrins, and capability to inhibit cancer cell proliferation and VEGF signaling (antiangiogenic effect). Results warrant further preclinical studies to establish the 177Lu-iPSMA-RGD potential as a dual therapeutic radiopharmaceutical.CONACyT-CB-2016-01-28152

Innovación docente y creación de recursos educativos en abierto para Psicometría.

El objetivo del proyecto es el desarrollo de un banco de recursos educativos en abierto para dar soporte a metodologías docentes innovadoras en la asignatura de Psicometría y fomentar el papel activo del alumnado en su proceso de aprendizaje.Depto. de Psicobiología y Metodología en Ciencias del ComportamientoFac. de PsicologíaFALSEsubmitte

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