RESUMO
The synthesis of bioinspired metal-organic frameworks (MOFs) performed in mild conditions with a high quality is greatly demanded. Moreover, the influence of the morphology and structure of bio-MOFs on the cell interaction and toxicity is important to determine. In this work, we developed an ultrasound (US)-assisted synthesis of HKUST-1 MOFs under mild conditions and investigated the influence of the parameters of synthesis on the morphology, structure, and biological properties of the developed MOFs. It was found that the US power, reaction time, temperature, and type of solvent composition would affect the morphology, size, and yield of the obtained crystals. Employing the optimal synthetic conditions, five types of HKUST-1 MOFs were prepared, achieving highest yields (67.8-96.2%) and different morphologies (octahedral, dodecahedral, icosahedral). The relationship between the morphological features and biological properties of developed bio-MOFs was evaluated and discussed. The cellular association and cytotoxicity of MOF@US and MOF@US-PARG were studied on various cell cultures, i.e. normal mouse embryonic fibroblasts (MEF NF2), chronic myeloid leukemia (K562), and mouse melanoma (B16-F10). The experimental results showed that MOF@US-PARG has a higher percentage of association compared to MOF@US. It has also been shown that the cytotoxicity depends on the concentration and surface modification of the developed MOFs.
Assuntos
Materiais Biocompatíveis , Teste de Materiais , Estruturas Metalorgânicas , Tamanho da Partícula , Camundongos , Animais , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Estruturas Metalorgânicas/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/síntese química , Humanos , Sobrevivência Celular/efeitos dos fármacos , Ondas Ultrassônicas , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Propriedades de Superfície , Proliferação de Células/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
Although small molecule drugs are widely used in chemotherapy, their low bioavailability, low-concentrated dose in the tumor zone, systemic toxicity, and chemoresistance can significantly limit the therapeutic outcome. These drawbacks can be overcome by two main strategies: (i) development of novel therapeutic molecules with more significant antitumor activity than currently available drugs and (ii) loading chemotherapeutic agents into drug delivery systems. In this study, we aimed to encapsulate a highly prospective small molecule drug based on substituted 2-aminothiophene (2-AT) into calcium carbonate (CaCO3) microparticles (MPs) for the treatment of melanoma tumors. In particular, we have optimized the encapsulation of 2-AT into MPs (2-AT@MPs), studied drug release efficiency, investigated cellular uptake, and evaluated in vivo biodistribution and tumor inhibition efficiency. In vitro results revealed that 2-AT@MPs were able to penetrate into tumor spheroids, leading to prolonged release of 2-AT. By performing intratumoral injection of 2-AT@MPs we observed significant melanoma suppressions in murine models: â¼0.084 cm3 for 2-AT@MPs at a dose of 0.4 g kg-1versus â¼1.370 cm3 for untreated mice. In addition, the 2-AT@MPs showed negligible in vivo toxicity towards major organs such as heart, lung, liver, kidney, and spleen. Thus, this work provided an efficient strategy for the improved chemotherapy of solid tumors by using an encapsulated form of small molecule drugs.
Assuntos
Antineoplásicos , Carbonato de Cálcio , Portadores de Fármacos , Melanoma , Tiofenos , Animais , Carbonato de Cálcio/química , Carbonato de Cálcio/administração & dosagem , Camundongos , Tiofenos/química , Tiofenos/administração & dosagem , Tiofenos/farmacologia , Tiofenos/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Melanoma/tratamento farmacológico , Melanoma/patologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Distribuição Tecidual , Humanos , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BLRESUMO
A new efficient and versatile one-pot three-component synthesis of substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives has been developed. It is based on a multistep cascade reaction from 2-aminothiophenes and 2-hydroxy-4-oxobut-2-enoic acids, and derivatives of cyanoacetic acid catalyzed by diisopropylethylamine. As a result, novel pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives (21 compounds) were synthesized in a mild reaction conditions with a high yield. The structures of the developed compounds were confirmed by NMR and elemental analysis. The influence of electron-withdrawing or electron-donor substituents on the antitumor activity of the developed compounds has been identified. In vitro screening analysis of 21 compounds revealed six lead candidates (12aa, 12dc, 12hc, 12ic, 12lb, and 12mb) that demonstrated the most significant antitumor activity against B16-F10, 4T1 and CT26 cells. Necrosis/apoptosis assay showed that apoptosis was the predominant mechanism of cell death. Molecular docking analysis revealed several potential targets for tested compounds, i.e. phosphatidylinositol 5-phosphate 4-kinase (PI5P4K2C), proto-oncogene serine/threonine-protein kinase (Pim-1), nicotinamide phosphoribosyltransferase (NAMPT) and dihydrofolate reductase (DHFR). The lead compound (12aa) can effectively induce cell apoptosis, possesses a high yield (98 %) and requires low-cost starting chemicals for its synthesis. In vivo experiments with melanoma-bearing mice confirmed that 12aa compound resulted in the significant tumor inhibition on 15 d after the therapy. In particular, tumor volume was â¼0.19 cm3 for 50 mg/kg versus â¼2.39 cm3 in case of untreated mice and tumor weight was â¼71.6 mg for 50 mg/kg versus â¼452.4 mg when considered untreated mice. Thus, our results demonstrated the high potential of the 12aa compound in the treatment of melanoma and can be recommended for further preclinical studies.
Assuntos
Antineoplásicos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pirimidinas , Pirróis , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Animais , Pirimidinas/química , Pirimidinas/síntese química , Pirimidinas/farmacologia , Camundongos , Relação Estrutura-Atividade , Estrutura Molecular , Humanos , Pirróis/química , Pirróis/farmacologia , Pirróis/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Proto-Oncogene Mas , Apoptose/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Melanoma Experimental/metabolismoRESUMO
The design and synthesis of nano- and microcarriers for preclinical and clinical imaging are highly attractive due to their unique features, for example, multimodal properties. However, broad translation of these carriers into clinical practice is postponed due to the unknown biological reactivity of the new components used for their synthesis. Here, we have developed microcarriers (â¼2-3 µm) and nanocarriers (<200 nm) made of barium carbonate (BaCO3) for multiple imaging applications in vivo. In general, barium in the developed carriers can be used for X-ray computed tomography, and the introduction of a diagnostic isotope (99mTc) into the BaCO3 structure enables in vivo visualization using single-photon emission computed tomography. The bioimaging has shown that the radiolabeled BaCO3 nano- and microcarriers had different biodistribution profiles and tumor accumulation efficiencies after intratumoral and intravenous injections. In particular, in the case of intratumoral injection, all the types of used carriers mostly remained in the tumors (>97%). For intravenous injection, BaCO3 microcarriers were mainly localized in the lung tissues. However, BaCO3 NPs were mainly accumulated in the liver. These results were supported by ex vivo fluorescence imaging, direct radiometry, and histological analysis. The BaCO3-based micro- and nanocarriers showed negligible in vivo toxicity towards major organs such as the heart, lungs, liver, kidneys, and spleen. This study provides a simple strategy for the design and fabrication of the BaCO3-based carriers for the development of dual bioimaging.
Assuntos
Bário , Carbonatos , Tomografia Computadorizada de Emissão de Fóton Único , Animais , Camundongos , Carbonatos/química , Bário/química , Tomografia Computadorizada por Raios X , Tamanho da Partícula , Nanopartículas/química , Humanos , Distribuição TecidualRESUMO
Many methods for cancer treatment have been developed. Among them photothermal therapy (PTT) has drawn the most significant attention due to its noninvasiveness, remote control activation, and low side effects. However, a limited depth of light penetration of PTT is the main drawback. To improve the therapeutic efficiency, the development of combined PTT with other therapeutic agents is highly desirable. In this work, we have designed multifunctional composite carriers based on polylactic acid (PLA) particles decorated with gold nanorods (Au NRs) as nanoheaters and selenium nanoparticles (Se NPs) for reactive oxygen species (ROS) production in order to perform a combined PTT against B16-F10 melanoma. To do this, we have optimized the synthesis of PLA particles modified with Se NPs and Au NRs (PLA-Se:Au), studied the cellular interactions of PLA particles with B16-F10 cells, and analyzed in vivo biodistribution and tumor inhibition efficiency. The results of in vitro and in vivo experiments demonstrated the synergistic effect from ROS induced by Se NPs and the heating from Au NRs. In melanoma tumor-bearing mice, intratumoral injection of PLA-Se:Au followed by laser irradiation leads to almost complete elimination of tumor tissues. Thus, the optimal photothermal properties and ROS-generating capacity allow us to recommend PLA-Se:Au as a promising candidate for the development of the combined PTT against melanoma.
Assuntos
Hipertermia Induzida , Melanoma , Nanopartículas Metálicas , Animais , Camundongos , Melanoma/terapia , Espécies Reativas de Oxigênio , Distribuição Tecidual , Nanopartículas Metálicas/uso terapêutico , PoliésteresRESUMO
The size of drug carriers strongly affects their biodistribution, tissue penetration, and cellular uptake in vivo. As a result, when such carriers are loaded with therapeutic compounds, their size can influence the treatment outcomes. For internal α-radionuclide therapy, the carrier size is particularly important, because short-range α-emitters should be delivered to tumor volumes at a high dose rate without any side effects, i.e. off-target irradiation and toxicity. In this work, we aim to evaluate and compare the therapeutic efficiency of calcium carbonate (CaCO3) microparticles (MPs, >2 µm) and nanoparticles (NPs, <100 nm) labeled with radium-223 (223Ra) for internal α-radionuclide therapy against 4T1 breast cancer. To do this, we comprehensively study the internalization and penetration efficiency of these MPs and NPs, using 2D and 3D cell cultures. For further therapeutic tests, we develop and modify a chelator-free method for radiolabeling of CaCO3 MPs and NPs with 223Ra, improving their radiolabeling efficiency (>97%) and radiochemical stability (>97%). After intratumoral injection of 223Ra-labeled MPs and NPs, we demonstrate their different therapeutic efficiencies against a 4T1 tumor. In particular, 223Ra-labeled NPs show a tumor inhibition of approximately 85%, which is higher compared to 60% for 223Ra-labeled MPs. As a result, we can conclude that 223Ra-labeled NPs have a more suitable biodistribution within 4T1 tumors compared to 223Ra-labeled MPs. Thus, our study reveals that 223Ra-labeled CaCO3 NPs are highly promising for internal α-radionuclide therapy.
Assuntos
Neoplasias da Mama , Nanopartículas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Neoplasias da Mama/patologia , Carbonato de Cálcio/química , Distribuição Tecidual , Portadores de Fármacos/química , Nanopartículas/química , Radioisótopos/uso terapêuticoRESUMO
Considering the clinical limitations of individual approaches against metastatic lung cancer, the use of combined therapy can potentially improve the therapeutic effect of treatment. However, determination of the appropriate strategy of combined treatment can be challenging. In this study, combined chemo- and radionuclide therapy has been realized using radionuclide carriers (177Lu-labeled core-shell particles, 177Lu-MPs) and chemotherapeutic drug (cisplatin, CDDP) for treatment of lung metastatic cancer. The developed core-shell particles can be effectively loaded with 177Lu therapeutic radionuclide and exhibit good radiochemical stability for a prolonged period of time. In vivo biodistribution experiments have demonstrated the accumulation of the developed carriers predominantly in lungs. Direct radiometry analysis did not reveal an increased absorbance of radiation by healthy organs. It has been shown that the radionuclide therapy with 177Lu-MPs in mono-regime is able to inhibit the number of metastatic nodules (untreated mice = 120 ± 12 versus177Lu-MPs = 50 ± 7). The combination of chemo- and radionuclide therapy when using 177Lu-MPs and CDDP further enhanced the therapeutic efficiency of tumor treatment compared to the single therapy (177Lu-MPs = 50 ± 7 and CDDP = 65 ± 10 versus177Lu-MPs + CDDP = 37 ± 5). Thus, this work is a systematic research on the applicability of the combination of chemo- and radionuclide therapy to treat metastatic lung cancer.