февраля 2021 года ЯрославльУчастники: • Насонов Евгений Львович -академик РАН, д. м.н., профессор, Заслуженный деятель науки РФ, президент Общероссийской общественной организации «Ассоциация ревматологов России», главный внештатный специалист-ревматолог Минздрава России. • Мазуров Вадим Иванович -академик РАН, д. м.н., профессор, Заслуженный деятель науки РФ, Первый вице-президент Общероссийской общественной организации «Ассоциация ревматологов России», главный специалист-ревматолог Северо-Западного федерального округа и г. Санкт-Петербурга, директор НИИ ревматологии ФГБОУ ВО «Северо-Западный государственный медицинский университет им. И. И. Мечникова» Минздрава России. • Лила Александр Михайлович -д. м.н., профессор, директор ФГБНУ «Научно-исследовательский институт ревматологии им. В. А. Насоновой». • Дубинина Татьяна Васильевна -к. м.н., и. о. генерального секретаря Общероссийской общественной организации «Ассоциация ревматологов России», главный внештатный специалист (Центральный федеральный округ), секретарь профильной комиссии, заведующая лабораторией медикосоциальных проблем ревматологии ФГБНУ «Научноисследовательский институт ревматологии им. В. А. Насоновой». • Коротаева Татьяна Викторовна -д. м.н., заведующая лабораторией спондилоартритов и спориатического артрита ФГБНУ «Научно-исследовательский институт ревматологии им. В. А. Насоновой». • Лапшина Светлана Анатольевна -к. м.н., доцент кафедры госпитальной терапии ФГБОУ ВО «Казанский государственный медицинский университет» Минздрава России. • Гайдукова Инна Зурабиевна -д. м.н., профессор кафедры терапии, ревматологии, экспертизы временной нетрудоспособности и качества медицинской помощи
The purpose of this study was to develop Cu-labeled trastuzumab with improved pharmacokinetics for human epidermal growth factor receptor 2. Trastuzumab was conjugated with SCN-Bn-NOTA and radiolabeled with Cu. Serum stability and immunoreactivity ofCu-NOTA-trastuzumab were tested. Small animal PET imaging and biodistribution study were performed in HER2-positive breast cancer xenograft model (BT-474). Internal dosimetry of experimental animals was performed using the image-based approach with the Monte Carlo N-Particle Code. Cu-NOTA-trastuzumab was prepared with high radiolabel yield and radiochemical purity (>98%) and showed high stability in serum and good immunoreactivity. Uptake of Cu-NOTA-trastuzumab was highest at 48 h after injection determined by PET imaging and biodistribution results in BT-474 tumors. The blood radioactivity concentrations ofCu-NOTA-trastuzumab decreased bi-exponentially with time in both mice with and without BT-474 tumor xenografts. The calculated absorbed dose of Cu-NOTA-trastuzumab was 0.048 mGy/MBq for the heart, 0.079 for the liver and 0.047 for the spleen.Cu-NOTA-trastuzumab was effectively targeted to the HER2-expressing tumor and, and it exhibited relatively low absorbed dose due to short residence time. Therefore, Cu-NOTA-trastuzumab could be applied to select the right patients/right timing for HER2 therapy, to monitor the treatment response after HER2-targeted therapy, and to detect distal or metastatic spread.
Immuno-PET provides valuable information about tumor location, phenotype, susceptibility to therapy, and treatment response, especially to targeted radioimmunotherapy. In this study, we prepared antiepidermal growth factor receptor (EGFR) antibody via identical chelator, 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-trience-3,6,9,-triacetic acid (PCTA), labeled with 64 Cu or 177 Lu to evaluate the EGFR expression levels using immuno-PET and the feasibility of radioimmunotherapy in an esophageal squamous cell carcinoma (ESCC) model. Methods: Cetuximab was conjugated with p-SCN-Bn-PCTA and radiolabeled with 64 Cu or 177 Lu. In vitro EGFR expression levels were determined and compared using flow cytometry and cell binding assay. In vivo EGFR expression levels were evaluated via immuno-PET imaging of 64 Cu-cetuximab and biodistribution analysis. Micro-SPECT/CT imaging, biodistribution, and radioimmunotherapy studies of 177 Lu-cetuximab were performed in the ESCC model. Therapeutic responses were monitored using 18 F-FDG PET and immunohistochemical staining. Results: 64 Cu-or 177 Lu-labeled antibodies showed high radiolabeling yield (.98%), stability (.90%), and favorable immunoreactivity. In vitro EGFR status measured by cell binding assay was correlated with the flow cytometry data. Immuno-PET, micro-SPECT/CT, and biodistribution demonstrated specific uptake in ESCC tumors depending on the EGFR expression levels. Tumor accumulation of 64 Cu-and 177 Lu-cetuximab was peaked at 48 and 120 h, respectively. Radioimmunotherapy with 177 Lu-cetuximab showed significant inhibition of tumor growth (P , 0.01) and marked reduction of 18 F-FDG SUV compared with that of control (P , 0.05). Terminal deoxynucleotidyl transferase dUTP nick-end labeling positivity and Ki-67 staining indices increased and decreased, respectively, in the radioimmunotherapy group compared with other groups (P , 0.01). Conclusion: 64 Cu-cetuximab immuno-PET represented EGFR expression levels in ESCC tumors, and 177 Lu-cetuximab radioimmunotherapy effectively inhibited the tumor growth. The diagnostic and therapeutic convergence radiopharmaceutical 64 Cu-/ 177 Lu-PCTA-cetuximab may be useful as a diagnostic tool in patient selection and a potent radioimmunotherapy agent in EGFR-positive ESCC tumors.
Many aptamers have been evaluated for their ability as drug delivery vehicles to target ligands, and a variety of small interfering RNAs (siRNAs) have been tested for their anti-cancer properties. However, since these two types of molecules have similar physicochemical properties, it has so far been difficult to formulate siRNA-encapsulating carriers guided by aptamers. Here, we propose aptamer-coupled lipid nanocarriers encapsulating quantum dots (QDs) and siRNAs for theragnosis of triple-negative breast cancer (TNBC). Methods: Hydrophobic QDs were effectively incorporated into lipid bilayers, and then therapeutic siRNAs were complexed with QD-lipid nanocarriers (QLs). Finally, anti-EGFR aptamer-lipid conjugates were inserted into the QLs for TNBC targeting (aptamo-QLs). TNBC-targeting aptamo-QLs were directly compared to anti-EGFR antibody-coupled immuno-QLs. The in vitro delivery of therapeutic siRNAs and QDs to target cells was assessed by flow cytometry and confocal microscopy. The in vivo targeting of siRNAs to tumors and their therapeutic efficacy were evaluated in mice carrying MDA-MB-231 tumors. Results: Both types of EGFR-targeting QLs showed enhanced delivery to target cancer cells, resulting in more effective gene silencing and enhanced tumor imaging compared to non-targeting control QLs. Moreover, combinatorial therapy with Bcl-2 and PKC-ι siRNAs loaded into the anti-EGFR QLs was remarkably effective in inhibiting tumor growth and metastasis. Conclusion: In general, the aptamo-QLs showed competitive in vivo delivery and therapeutic efficacy compared to immuno-QLs under the same experimental conditions. Our results show that the anti-EGFR aptamer-guided lipid carriers may be a potential theranostic delivery vehicle for RNA interference and fluorescence imaging of TNBCs.
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