RESUMO
Fluorescent dyes are widely used in histological studies and in intraoperative imaging, including surgical treatment of prostate cancer (PC), which is one of the most common types of cancerous tumors among men today. Targeted delivery of fluorescent conjugates greatly improves diagnostic efficiency and allows for timely correct diagnosis. In the case of PC, the protein marker is a prostate-specific membrane antigen (PSMA). To date, a large number of diagnostic conjugates targeting PSMA have been created based on modified urea. The review focuses on the conjugates selectively binding to PSMA and answers the following questions: What fluorescent dyes are already in use in the field of PC diagnosis? What factors influence the structure-activity ratio of the final molecule? What features should be considered when selecting a fluorescent tag to create new diagnostic conjugates? And what could be suggested to further development in this field at the present time?
Assuntos
Corantes Fluorescentes , Neoplasias da Próstata , Masculino , Humanos , Próstata , Neoplasias da Próstata/diagnóstico por imagem , Ligantes , Projetos de PesquisaRESUMO
Prostate-specific membrane antigen (PSMA) has been identified as a target for the development of theranostic agents. In our current work, we describe the design and synthesis of novel N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-L-lysine (DCL) urea-based PSMA inhibitors with a chlorine-substituted aromatic fragment at the lysine ε-nitrogen atom, a dipeptide including two phenylalanine residues in the L-configuration as the peptide fragment of the linker, and 3- or 4-(tributylstannyl)benzoic acid as a prosthetic group in their structures for radiolabeling. The standard compounds [127I]PSMA-m-IB and [127I]PSMA-p-IB for comparative and characterization studies were first synthesized using two alternative synthetic approaches. An important advantage of the alternative synthetic approach, in which the prosthetic group (NHS-activated esters of compounds) is first conjugated with the polypeptide sequence followed by replacement of the Sn(Bu)3 group with radioiodine, is that the radionuclide is introduced in the final step of synthesis, thereby minimizing operating time with iodine-123 during the radiolabeling process. The obtained DCL urea-based PSMA inhibitors were radiolabeled with iodine-123. The radiolabeling optimization results showed that the radiochemical yield of [123I]PSMA-p-IB was higher than that of [123I]PSMA-m-IB, which were 74.9 ± 1.0% and 49.4 ± 1.2%, respectively. The radiochemical purity of [123I]PSMA-p-IB after purification was greater than 99.50%. The initial preclinical evaluation of [123I]PSMA-p-IB demonstrated a considerable affinity and specific binding to PC-3 PIP (PSMA-expressing cells) in vitro. The in vivo biodistribution of this new radioligand [123I]PSMA-p-IB showed less accumulation than [177Lu]Lu-PSMA-617 in several normal organs (liver, kidney, and bone). These results warrant further preclinical development, including toxicology evaluation and experiments in tumor-bearing mice.
Assuntos
Radioisótopos do Iodo , Neoplasias da Próstata , Humanos , Masculino , Animais , Camundongos , Ureia/farmacologia , Distribuição Tecidual , Neoplasias da Próstata/metabolismo , Glutamato Carboxipeptidase II/metabolismo , Antígenos de Superfície/metabolismo , Compostos Radiofarmacêuticos/química , Linhagem Celular TumoralRESUMO
Prostate cancer is the second most common cancer among men. We designed and synthesized new ligands targeting prostate-specific membrane antigen and suitable for bimodal conjugates with diagnostic and therapeutic agents. In vitro studies of the affinity of the synthesized compounds to the protein target have been carried out. Based on these ligands, a series of bimodal conjugates with a combination of different mitosis inhibitors and antiandrogenic drugs were synthesized. The cytotoxicity of the compounds obtained in vitro was investigated on three different cell lines. The efficacy of the two obtained conjugates was evaluated in vivo in xenograft models of prostate cancer. These compounds have been shown to be highly effective in inhibiting the growth of PSMA-expressing tumors.
Assuntos
Antagonistas de Androgênios , Neoplasias da Próstata , Masculino , Humanos , Antagonistas de Androgênios/uso terapêutico , Citotoxinas/uso terapêutico , Próstata/patologia , Ligantes , Linhagem Celular Tumoral , Glutamato Carboxipeptidase II/metabolismo , Antígenos de Superfície/metabolismo , Neoplasias da Próstata/metabolismoRESUMO
Novel variously substituted thiohydantoin-based dispiro-indolinones were prepared using a regio- and diastereoselective synthetic route from 5-arylidene-2-thiohydantoins, isatines, and sarcosine. The obtained molecules were subsequently evaluated in vitro against the cancer cell lines LNCaP, PC3, HCTwt, and HCT(-/-). Several compounds demonstrated a relatively high cytotoxic activity vs. LNCaP cells (IC50 = 1.2-3.5 µM) and a reasonable selectivity index (SI = 3-10). Confocal microscopy revealed that the conjugate of propargyl-substituted dispiro-indolinone with the fluorescent dye Sulfo-Cy5-azide was mainly localized in the cytoplasm of HEK293 cells. P388-inoculated mice and HCT116-xenograft BALB/c nude mice were used to evaluate the anticancer activity of compound 29 in vivo. Particularly, the TGRI value for the P388 model was 93% at the final control timepoint. No mortality was registered among the population up to day 31 of the study. In the HCT116 xenograft model, the compound (170 mg/kg, i.p., o.d., 10 days) provided a T/C ratio close to 60% on day 8 after the treatment was completed. The therapeutic index-estimated as LD50/ED50-for compound 29 in mice was ≥2.5. Molecular docking studies were carried out to predict the possible binding modes of the examined molecules towards MDM2 as the feasible biological target. However, such a mechanism was not confirmed by Western blot data and, apparently, the synthesized compounds have a different mechanism of cytotoxic action.
Assuntos
Antineoplásicos , Humanos , Animais , Camundongos , Relação Estrutura-Atividade , Oxindóis/farmacologia , Simulação de Acoplamento Molecular , Camundongos Nus , Células HEK293 , Antineoplásicos/química , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Estrutura MolecularRESUMO
Over the past two decades, mesenchymal stem cells (MSCs) have shown promising therapeutic effects both in preclinical studies (in animal models of a wide range of diseases) and in clinical trials. However, the efficacy of MSC-based therapy is not always predictable. Moreover, despite the large number of studies, the mechanisms underlying the regenerative potential of MSCs are not fully elucidated. Recently, it has been reliably established that transplanted MSCs can undergo rapid apoptosis and clearance from the recipient's body, still exhibiting therapeutic effects, especially those associated with their immunosuppressive/immunomodulating properties. The mechanisms underlying these effects can be mediated by the efferocytosis of apoptotic MSCs by host phagocytic cells. In this concise review, we briefly describe three types of MSC-generated extracellular vesicles, through which their therapeutic functions can potentially be carried out; we focused on reviewing recent data on apoptotic MSCs and MSC-derived apoptotic bodies (MSC-ApoBDs), their functions, and the mechanisms of their therapeutic effects.
RESUMO
Mesenchymal stem cells (MSCs) have a pronounced therapeutic potential in various pathological conditions. Though therapeutic effects of MSC transplantation have been studied for a long time, the underlying mechanisms are still not clear. It has been shown that transplanted MSCs are rapidly eliminated, presumably by apoptosis. As the mechanisms of MSC apoptosis are not fully understood, in the present work we analyzed MSC sensitivity to Fas-induced apoptosis using MSCs isolated from the biopsies of liver fibrosis patients (L-MSCs). The level of cell death was analyzed by flow cytometry in the propidium iodide test. The luminescent ATP assay was used to measure cellular ATP levels; and the mitochondrial membrane potential was assessed using the potential-dependent dye JC-1. We found that human L-MSCs were resistant to Fas-induced cell death over a wide range of FasL and anti-Fas mAb concentrations. At the same time, intrinsic death signal inducers CoCl2 and staurosporine caused apoptosis of L-MSCs in a dose-dependent manner. Despite the absence of Fas-induced cell death treatment of L-MSCs with low concentrations of FasL or anti-Fas mAb resulted in a cellular ATP level decrease, while high concentrations of the inducers caused a decline of the mitochondrial membrane potential. Pre-incubation of L-MSCs with the pro-inflammatory cytokine TNF-α did not promote L-MSC cell death. Our data indicate that human L-MSCs have increased resistance to receptor-mediated cell death even under inflammatory conditions.
RESUMO
The biodistribution of chemotherapy compounds within tumor tissue is one of the main challenges in the development of antineoplastic drugs, and techniques for simple, inexpensive, sensitive, and selective detection of various analytes in tumors are of great importance. In this paper we propose the use of platinized carbon nanoelectrodes (PtNEs) for the electrochemical detection of platinum-based drugs in various biological models, including single cells and tumor spheroids in vitro and inside solid tumors in vivo. We have demonstrated the quantitative direct detection of Pt(II) in breast adenocarcinoma MCF-7 cells treated with cisplatin and a cisplatin-based DNP prodrug. To realize the potential of this technique in advanced tumor models, we measured Pt(II) in 3D tumor spheroids in vitro and in tumor-bearing mice in vivo. The concentration gradient of Pt(II) species correlated with the distance from the sample surface in MCF-7 tumor spheroids. We then performed the detection of Pt(II) species in tumor-bearing mice treated intravenously with cisplatin and DNP. We found that there was deeper penetration of DNP in comparison to cisplatin. This research demonstrates a minimally invasive, real-time electrochemical technique for the study of platinum-based drugs.
Assuntos
Antineoplásicos , Pró-Fármacos , Animais , Cisplatino/química , Cisplatino/farmacologia , Humanos , Células MCF-7 , Camundongos , Pró-Fármacos/química , Distribuição TecidualRESUMO
We report an improved series of ligands targeting prostate specific membrane antigen (PSMA). The new compounds were designed by the introduction of changes in the structure of the aromatic fragment at ε-nitrogen atom of lysine that resulted in improved biological parameters. Some of them demonstrated high selectivity and nanomolar IC50 values. We synthesized and tested two conjugates with a fluorescent label Sulfo-Cy5 as an example of the use of the obtained PSMA inhibitors as a basis for the creation of diagnostic preparations.
Assuntos
Lisina , Neoplasias da Próstata , Antígenos de Superfície , Linhagem Celular Tumoral , Glutamato Carboxipeptidase II , Humanos , Ligantes , Masculino , NitrogênioRESUMO
We report herein a Pt(IV) prodrug with metronidazole in axial positions Pt-Mnz. The nitroaromatic axial ligand was conjugated with a cisplatin scaffold to irreversibly reduce under hypoxic conditions, thereby retaining the Pt(IV) prodrug in the area of hypoxia. X-ray near-edge adsorption spectroscopy (XANES) on dried drug-preincubated tumor cell samples revealed a gradual release of cisplatin from the Pt-Mnz prodrug instead of rapid intracellular degradation. The ability of the prodrug to penetrate into three-dimensional (3D) spheroid cellular cultures was evaluated by a novel electrochemical assay via a platinum-coated carbon nanoelectrode, capable of single-cell measurements. Using a unique technique of electrochemical measurements in single tumor spheroids, we were able to both detect the real-time response of the axial ligand to hypoxia and establish the depth of penetration of the drug into the tumor model.
Assuntos
Antineoplásicos , Pró-Fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbono , Linhagem Celular Tumoral , Cisplatino/química , Humanos , Hipóxia , Ligantes , Metronidazol/farmacologia , Platina/química , Pró-Fármacos/química , Pró-Fármacos/farmacologiaRESUMO
Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to prostate cancer cells. In this study, we performed the synthesis of a novel small-molecule PSMA-targeted conjugate based on abiraterone. Cytotoxicity, the induction of intracellular reactive oxygen species, and P450-cytochrome species inhibition were investigated for this conjugate PSMA-abiraterone. The conjugate demonstrated a preferential effect on prostate tumor cells, remaining inactive at up to 100 µM in human fibroblast cells. In addition, it revealed preferential efficacy, specifically on PSMA-expressing lines with a 65% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts after 14-fold oral administration of PSMA-Abi at a single dose of 500 mg/kg (7.0 g/kg total dose) was observed. This compound showed significantly reduced acute toxicity with comparable efficacy compared to AbiAc.
Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Próstata/patologia , Antagonistas de Androgênios , Antígenos de Superfície , Androstenos/farmacologiaRESUMO
Herein, we describe the design, synthesis, and biological evaluation of novel betulin and N-acetyl-d-galactosamine (GalNAc) glycoconjugates and suggest them as targeted agents against hepatocellular carcinoma. We prepared six conjugates derived via the C-3 and C-28 positions of betulin with one or two saccharide ligands. These molecules demonstrate high affinity to the asialoglycoprotein receptor (ASGPR) of hepatocytes assessed by in silico modeling and surface plasmon resonance tests. Cytotoxicity studies in vitro revealed a bivalent conjugate with moderate activity, selectivity of action, and cytostatic properties against hepatocellular carcinoma cells HepG2. An additional investigation confirmed the specific engagement with HepG2 cells by the enhanced generation of reactive oxygen species. Stability tests demonstrated its lability to acidic media and to intracellular enzymes. Therefore, the selected bivalent conjugate represents a new potential agent targeted against hepatocellular carcinoma. Further extensive studies of the cellular uptake in vitro and the real-time microdistribution in the murine liver in vivo for fluorescent dye-labeled analogue showed its selective internalization into hepatocytes due to the presence of GalNAc ligand in comparison with reference compounds. The betulin and GalNAc glycoconjugates can therefore be considered as a new strategy for developing therapeutic agents based on natural triterpenoids.
Assuntos
Acetilgalactosamina/química , Antineoplásicos/farmacologia , Receptor de Asialoglicoproteína/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Triterpenos/química , Antineoplásicos/química , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Ressonância de Plasmônio de SuperfícieRESUMO
In this work, we have developed covalent and low molecular weight docetaxel delivery systems based on conjugation with N-acetyl-d-galactosamine and studied their properties related to hepatocellular carcinoma cells. The resulting glycoconjugates have an excellent affinity to the asialoglycoprotein receptor (ASGPR) in the nanomolar range of concentrations and a high cytotoxicity level comparable to docetaxel. Likewise, we observed the 21-75-fold increase in water solubility in comparison with parent docetaxel and prodrug lability to intracellular conditions with half-life values from 25.5 to 42 h. We also found that the trivalent conjugate possessed selective toxicity against hepatoma cells vs control cell lines (20-35 times). The absence of such selectivity in the case of monovalent conjugates indicates the effect of ligand valency. Specific ASGPR-mediated cellular uptake of conjugates was proved in vitro using fluorescent-labeled analogues. In addition, we showed an enhanced generation of reactive oxygen species in the HepG2 cells, which could be inhibited by the natural ligand of ASGPR. Overall, the obtained results highlight the potential of ASGPR-directed cytostatic taxane drugs for selective therapy of hepatocellular carcinoma.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Docetaxel/administração & dosagem , Glicoconjugados/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/administração & dosagem , Células A549 , Receptor de Asialoglicoproteína/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Portadores de Fármacos/química , Células HEK293 , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Células PC-3RESUMO
Acidification of the extracellular matrix, an intrinsic characteristic of many solid tumors, is widely exploited for physiologically triggered delivery of contrast agents, drugs, and nanoparticles to tumor. However, pH of tumor microenvironment shows intra- and inter-tumor variation. Herein, we investigate the impact of this variation on pH-triggered delivery of magnetic nanoparticles (MNPs) modified with pH-(low)-insertion peptide (pHLIP). Fluorescent flow cytometry, laser confocal scanning microscopy and transmission electron microscopy data proved that pHLIP-conjugated MNPs interacted with 4T1 cells in two-dimensional culture and in spheroids more effectively at pHâ¯6.4 than at pHâ¯7.2, and entered the cell via clathrin-independent endocytosis. The accumulation efficiency of pHLIP-conjugated MNPs in 4T1 tumors after their intravenous injection, monitored in vivo by magnetic resonance imaging, showed variation. Analysis of the tumor pH profiles recorded with implementation of original nanoprobe pH sensor, revealed obvious correlation between pH measured in the tumor with the amount of accumulated MNPs.
Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas de Magnetita/química , Proteínas de Membrana/farmacologia , Neoplasias/patologia , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Endocitose/efeitos dos fármacos , Feminino , Concentração de Íons de Hidrogênio , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita/ultraestrutura , Camundongos Endogâmicos BALB C , Neoplasias/diagnóstico por imagem , Polietilenoglicóis/química , Esferoides Celulares/efeitos dos fármacosRESUMO
A regio- and diastereoselective synthesis of two types of dispiro derivatives of 2-selenoxoimidazolidin-4-ones, differing in the position of the nitrogen atom in the central pyrrolidine ring of the spiro-fused system-namely, 2-selenoxodispiro[imidazolidine-4,3'-pyrrolidine-2',3â³-indoline]-2â³,5-diones (5a-h) and 2-senenoxodispiro[imidazolidine-4,3'-pyrrolidine-4',3â³-indoline]-2â³,5-diones (6a-m)-were developed based on a 1,3-dipolar cycloaddition of azomethine ylides generated from isatin and sarcosine or formaldehyde and sarcosine to 5-arylidene or 5-indolidene-2-selenoxo-tetrahydro-4H-imidazole-4-ones. Selenium-containing dispiro indolinones generally exhibit cytotoxic activity near to the activity of the corresponding oxygen and sulfur-containing derivatives. Compounds 5b, 5c, and 5e demonstrated considerable in vitro cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) test (concentration of compounds that caused 50% death of cells (CC50) 7.6-8.7 µM) against the A549 cancer cell line with the VA13/A549 selectivity index 5.2-6.9; some compounds (5 and 6) increased the level of intracellular reactive oxygen species (ROS) in the experiment on A549 and PC3 cells using platinized carbon nanoelectrode. The tests for p53 activation for compounds 5 and 6 on the transcriptional reporter suggest that the investigated compounds can only have an indirect p53-dependent mechanism of action. For the compounds 5b, 6b, and 6l, the ROS generation may be one of the significant mechanisms of their cytotoxic action.
Assuntos
Citotoxinas , Neoplasias/tratamento farmacológico , Pirrolidinas , Espécies Reativas de Oxigênio/metabolismo , Células A549 , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Células PC-3 , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
In vivo monitoring of reactive oxygen species (ROS) in tumors during treatment with anticancer therapy is important for understanding the mechanism of action and in the design of new anticancer drugs. In this work, a platinized nanoelectrode is placed into a single cell for detection of the ROS signal, and drug-induced ROS production is then recorded. The main advantages of this method are the short incubation time with the drug and its high sensitivity which allows the detection of low intracellular ROS concentrations. We have shown that our new method can measure the ROS response to chemotherapy in tumor-bearing mice in real-time. ROS levels were measured in vivo inside the tumor at different depths in response to doxorubicin. This work provides an effective new approach for the measurement of intracellular ROS by platinized nanoelectrodes.
Assuntos
Antineoplásicos/farmacologia , Técnicas Biossensoriais , Doxorrubicina/farmacologia , Técnicas Eletroquímicas , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Neoplasias Experimentais/diagnóstico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Células PC-3 , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismoRESUMO
Since the asialoglycoprotein receptor (also known as the "Ashwell-Morell receptor" or ASGPR) was discovered as the first cellular mammalian lectin, numerous drug delivery systems have been developed and several gene delivery systems associated with multivalent ligands for liver disease targeting are undergoing clinical trials. The success of these systems has facilitated the further study of new ligands with comparable or higher affinity and less synthetic complexity. Herein, we designed two novel trivalent ligands based on the esterification of tris(hydroxymethyl) aminomethane (TRIS) followed by the azide-alkyne Huisgen cycloaddition with azido N-acetyl-d-galactosamine. The presented triazolyl glycoconjugates exhibited good binding to ASGPR, which was predicted using in silico molecular docking and assessed by a surface plasmon resonance (SPR) technique. Moreover, we demonstrated the low level of in vitro cytotoxicity, as well as the optimal spatial geometry and the required amphiphilic balance, for new, easily accessible ligands. The conjugate of a new ligand with Cy5 dye exhibited selective penetration into HepG2 cells in contrast to the ASGPR-negative PC3 cell line.
Assuntos
Receptor de Asialoglicoproteína/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Alcinos/química , Receptor de Asialoglicoproteína/química , Azidas , Técnicas de Química Sintética , Desenho de Fármacos , Esterificação , Galactosamina/química , Células Hep G2 , Humanos , Ligantes , Metano/síntese química , Metano/química , Metano/metabolismo , Metano/farmacologia , Simulação de Acoplamento Molecular , Células PC-3 , Conformação ProteicaRESUMO
An attractive strategy for C-Se bond formation by Ullmann-type copper(I)-promoted cross-coupling is developed. A wide range of aryliodides reacts with various disubstituted 2-selenohydantoins under mild conditions and provides Se-arylated imidazolines in moderate to high yields. Computational mechanistic studies show the oxidative addition/intramolecular reductive elimination likely to be the lowest-energy pathway. Cytotoxic activity of all 43 reaction products has been tested in vitro against MCF7 and A549 cancer cell lines with VA13 and MCF10a control cells.
Assuntos
Hidantoínas , Imidazolinas , Catálise , Cobre , Hidantoínas/farmacologiaRESUMO
Three new and complementary approaches to S-arylation of 2-thiohydantoins have been developed: copper-catalyzed cross coupling with either arylboronic acids or aryl iodides under mild conditions, or direct nucleophilic substitution in activated aryl halides. For 38 diverse compounds, reaction yields for all three methods have been determined. Selected by molecular docking, they have been tested on androgen receptor activation, and p53-Mdm2 regulation, and A549, MCF7, VA13, HEK293T, PC3, LnCAP cell lines for cytotoxicity, Two of them turned out to be promising as androgen receptor activators (likely by allosteric regulation), and another one is shown to activate the p53 cascade. It is hoped that 2-thiohydantoin S-arylidenes are worth further studies as biologically active compounds.
Assuntos
Androgênios/química , Androgênios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Tioidantoínas/química , Tioidantoínas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Androgênios/síntese química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Receptores Androgênicos/metabolismo , Tioidantoínas/síntese química , Proteína Supressora de Tumor p53/metabolismoRESUMO
A strategy for stereoselective synthesis of molecular platform for targeted delivery of bimodal therapeutic or theranostic agents to the prostate-specific membrane antigen (PSMA) receptor was developed. The proposed platform contains a urea-based, PSMA-targeting Glu-Urea-Lys (EuK) fragment as a vector moiety and tripeptide linker with terminal amide and azide groups for subsequent addition of two different therapeutic and diagnostic agents. The optimal method for this molecular platform synthesis includes (a) solid-phase assembly of the polypeptide linker, (b) coupling of this linker with the vector fragment, (c) attachment of 3-aminopropylazide, and (d) amide and carboxylic groups deprotection. A bimodal theranostic conjugate of the proposed platform with a cytostatic drug (docetaxel) and a fluorescent label (Sulfo-Cy5) was synthesized to demonstrate its possible sequential conjugation with different functional molecules.
Assuntos
Antígenos de Superfície/administração & dosagem , Carbocianinas/química , Docetaxel/química , Portadores de Fármacos/química , Glutamato Carboxipeptidase II/administração & dosagem , Peptídeos/química , Sequência de Aminoácidos , Técnicas de Química Sintética , Sistemas de Liberação de Medicamentos , Estrutura Molecular , Peptídeos/síntese químicaRESUMO
A novel approach to the synthesis of pH-sensitive prodrugs has been proposed: thiourea drug modification. Resulting prodrugs can release the cytotoxic agent and the biologically active 2-thiohydantoin in the acidic environment of tumor cells. The concept of acid-catalyzed cyclization of thioureas to 2-thiohydantoins has been proven using a FRET model. Dual prodrugs of model azidothymidine, cytotoxic doxorubicin, and 2-thiohydantoin albutoin were obtained, which release the corresponding drugs in the acidic environment. The resulting doxorubicin prodrug was tested on prostate cancer cells and showed that the thiourea-modified prodrug is less cytotoxic (average IC50 ranging from 0.5584 to 0.9885 µM) than doxorubicin (IC50 ranging from 0.01258 to 0.02559 µM) in neutral pH 7.6 and has similar toxicity (average IC50 ranging from 0.4970 to 0.7994 µM) to doxorubicin (IC50 ranging from 0.2303 to 0.8110 µM) under mildly acidic conditions of cancer cells. Cellular and nuclear accumulation in PC3 tumor cells of Dox prodrug is much higher than accumulation of free doxorubicin.