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1.
Yakugaku Zasshi ; 140(10): 1199-1206, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999198

RESUMO

Potential risks to the fetus or infant should be considered prior to medication during pregnancy and lactation. It is essential to evaluate the exposure levels of drugs and their related factors in addition to toxicological effects. Epilepsy is one of the most common neurological complications in pregnancy; some women continue to use antiepileptic drugs (AEDs) to control seizures. Benzodiazepines (BZDs) are widely prescribed for several women who experience symptoms such as anxiety and insomnia during the postpartum period. In this review, we describe the 1) transport mechanisms of AEDs across the placenta and the effects of these drugs on placental transporters, and 2) the transfer of BZDs into breast milk. Our findings indicated that carrier systems were involved in the uptake of gabapentin (GBP) and lamotrigine (LTG) in placental trophoblast cell lines. SLC7A5 was the main contributor to GBP transport in placental cells. LTG was transported by a carrier that was sensitive to chloroquine, imipramine, quinidine, and verapamil. Short-term exposure to 16 AEDs had no effect on folic acid uptake in placental cells. However, long-term exposure to valproic acid (VPA) affected the expression of folate carriers (FOLR1, SLC46A1). Furthermore, VPA administration changed the expression levels of various transporters in rat placenta, suggesting that sensitivity to VPA differed across gestational stages. Lastly, we developed a method for quantifying eight BZDs in human breast milk and plasma using LC/MS/MS, and successfully applied it to quantify alprazolam in breast milk and plasma donated by a lactating woman.


Assuntos
Anticonvulsivantes/metabolismo , Benzodiazepinas/metabolismo , Transporte Biológico/genética , Aleitamento Materno , Gabapentina/metabolismo , Lactação/metabolismo , Lamotrigina/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/fisiologia , Troca Materno-Fetal , Leite Humano/metabolismo , Placenta/metabolismo , Ácido Valproico/metabolismo , Anticonvulsivantes/efeitos adversos , Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Linhagem Celular , Epilepsia/tratamento farmacológico , Feminino , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Gabapentina/efeitos adversos , Expressão Gênica/efeitos dos fármacos , Humanos , Lamotrigina/efeitos adversos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Transportador de Folato Acoplado a Próton/genética , Transportador de Folato Acoplado a Próton/metabolismo , Ácido Valproico/efeitos adversos
2.
Int J Nanomedicine ; 15: 4899-4918, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764924

RESUMO

Purpose: The use of chemotherapeutic agents to combat cancer is accompanied by high toxicity due to their inability to discriminate between cancer and normal cells. Therefore, cancer therapy research has focused on the targeted delivery of drugs to cancer cells. Here, we report an in vitro study of folate-poly(ethylene glycol)-poly(propylene succinate) nanoparticles (FA-PPSu-PEG-NPs) as a vehicle for targeted delivery of the anticancer drug paclitaxel in breast and cervical cancer cell lines. Methods: Paclitaxel-loaded-FA-PPSu-PEG-NPs characterization was performed by in vitro drug release studies and cytotoxicity assays. The NPs cellular uptake and internalization mechanism were monitored by live-cell imaging in different cancer cell lines. Expression of folate receptor-α (FOLR1) was examined in these cell lines, and specific FOLR1-mediated entry of the FA-PPSu-PEG-NPs was investigated by free folic acid competition. Using inhibitors for other endocytic pathways, alternative, non-FOLR1 dependent routes for NPs uptake were also examined. Results: Drug release experiments of Paclitaxel-loaded PPSu-PEG-NPs indicated a prolonged release of Paclitaxel over several days. Cytotoxicity of Paclitaxel-loaded PPSu-PEG-NPs was similar to free drug, as monitored in cancer cell lines. Live imaging of cells treated with either free Paclitaxel or Paclitaxel-loaded PPSu-PEG-NPs demonstrated tubulin-specific cell cycle arrest, with similar kinetics. Folate-conjugated NPs (FA-PPSu-PEG-NPs) targeted the FOLR1 receptor, as shown by free folic acid competition of the FA-PPSu-PEG-NPs cellular uptake in some of the cell lines tested. However, due to the differential expression of FOLR1 in the cancer cell lines, as well as the intrinsic differences between the different endocytic pathways utilized by different cell types, other mechanisms of nanoparticle cellular entry were also used, revealing that dynamin-dependent endocytosis and macropinocytosis pathways mediate, at least partially, cellular entry of the FA-PPSu-PEG NPs. Conclusion: Our data provide evidence that Paclitaxel-loaded-FA-PPSu-PEG-NPs can be used for targeted delivery of the drug, FA-PPSu-PEG-NPs can be used as vehicles for other anticancer drugs and their cellular uptake is mediated through a combination of FOLR1 receptor-specific endocytosis, and macropinocytosis. The exploration of the different cellular uptake mechanisms could improve treatment efficacy or allow a decrease in dosage of anticancer drugs.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Ácido Fólico/química , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Receptor 1 de Folato/metabolismo , Ácido Fólico/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Paclitaxel/química , Paclitaxel/farmacologia
3.
Nat Rev Clin Oncol ; 17(6): 349-359, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32152484

RESUMO

Folate receptor α (FRα) came into focus as an anticancer target many decades after the successful development of drugs targeting intracellular folate metabolism, such as methotrexate and pemetrexed. Binding to FRα is one of several methods by which folate is taken up by cells; however, this receptor is an attractive anticancer drug target owing to the overexpression of FRα in a range of solid tumours, including ovarian, lung and breast cancers. Furthermore, using FRα to better localize effective anticancer therapies to their target tumours using platforms such as antibody-drug conjugates, small-molecule drug conjugates, radioimmunoconjugates and, more recently, chimeric antigen receptor T cells could further improve the outcomes of patients with FRα-overexpressing cancers. FRα can also be harnessed for predictive biomarker research. Moreover, imaging FRα radiologically or in real time during surgery can lead to improved functional imaging and surgical outcomes, respectively. In this Review, we describe the current status of research into FRα in cancer, including data from several late-phase clinical trials involving FRα-targeted therapies, and the use of new technologies to develop FRα-targeted agents with improved therapeutic indices.


Assuntos
Antineoplásicos/uso terapêutico , Receptor 1 de Folato/metabolismo , Imunoconjugados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imagem Molecular , Neoplasias/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Epitelial do Ovário/diagnóstico por imagem , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/terapia , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/terapia , Feminino , Corantes Fluorescentes , Ácido Fólico , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Imunoterapia Adotiva , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Maitansina/análogos & derivados , Maitansina/uso terapêutico , Mesotelioma/diagnóstico por imagem , Mesotelioma/metabolismo , Mesotelioma/terapia , Terapia de Alvo Molecular , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Imagem Óptica , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/terapia , Cintilografia , Nanomedicina Teranóstica , Moduladores de Tubulina/uso terapêutico
4.
Cancer Sci ; 111(5): 1794-1804, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32154964

RESUMO

Folate receptor alpha (FRα) is overexpressed in >80% of epithelial ovarian cancer (EOC). Accordingly, folate is attracting attention as a targeting ligand for EOC. For EOC patients, paclitaxel (PTX) is generally used as a first-line chemotherapeutic agent in combination with platinum-based drugs. Cyclodextrin (CyD) is a potential new formulation vehicle for PTX that could replace Cremophor-EL, a traditional formulation vehicle that causes significant side effects, including neutropenia. Several years ago, folate-appended ß-CyD (Fol-c1 -ß-CyD) was developed as an FRα-targeting drug carrier, but its efficacy as a treatment for EOC remains to be determined. In this study, we assessed the antitumor activity of PTX in Fol-c1 -ß-CyD (PTX/Fol-c1 -ß-CyD) in EOC-derived cell lines. We found that PTX/Fol-c1 -ß-CyD killed not only FRα-expressing cells but also FRα-negative cells. In the FRα-negative A2780 cells, knockdown of proton-coupled folate transporter (PCFT) significantly decreased the cytotoxicity of PTX/Fol-c1 -ß-CyD, whereas knockdown of FRα did not. By contrast, knockdown of either FRα or proton-coupled folate transporter (PCFT) decreased the cytotoxicity of PTX/Fol-c1 -ß-CyD in FRα-expressing SK-OV-3 cells. Furthermore, the cytotoxicity of PTX/Fol-c1 -ß-CyD in A2780 cells was increased at acidic pH, and this increase was suppressed by PCFT inhibitor. In mice intraperitoneally inoculated with FRα-expressing or PCFT-expressing EOC cells, intraperitoneal administration of PTX/Fol-c1 -ß-CyD significantly suppressed the growth of both types of EOC cells relative to PTX alone, without inducing a significant change in the neutrophil/white blood cell ratio. Our data suggest that Fol-c1 -ß-CyD targets not only FRα but also PCFT, and can efficiently deliver anticancer drugs to EOC cells in the peritoneal cavity.


Assuntos
Carcinoma Epitelial do Ovário/metabolismo , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Ácido Fólico/química , Neoplasias Ovarianas/metabolismo , Transportador de Folato Acoplado a Próton/metabolismo , beta-Ciclodextrinas/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , Feminino , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Ácido Fólico/administração & dosagem , Expressão Gênica , Humanos , Camundongos , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/química , Paclitaxel/farmacologia , Transportador de Folato Acoplado a Próton/genética , Ensaios Antitumorais Modelo de Xenoenxerto , beta-Ciclodextrinas/administração & dosagem
5.
Ann Clin Lab Sci ; 50(1): 73-78, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32161014

RESUMO

OBJECTIVE: Cervical cancer is the fourth most deadly women's cancer worldwide, and regular screening is essential to lower mortality rates. The folate receptor-mediated staining solution detection (FRD) has been suggested to be a rapid and cost-effective screening method. We aim to evaluate the validity of FRD testing in cervical cancer screening. METHODS: A total of 207 participants were enrolled in the study. The validity of screening by FRD, cytology screening, and a HPV test were compared using histopathology as the gold standard. Sensitivity, specificity, positive predictive value, negative predictive value, Kappa value, positive likelihood ratio, negative likelihood ratio, percent agreement, and positive detection rates were compared among the three screening methods. RESULTS: 83(40.1%) participants were diagnosed as NILM, 50(24.15%) were diagnosed as CIN1, and 74(35.74%) were diagnosed as CIN2+. For CIN2+, the detection rates for the FRD, cytology screening, and HPV were 75.68%, 82.09% and 93.22%, respectively. For CIN2+, the sensitivity of HPV testing (93.22%) was significantly higher than that of cytology screening (82.09%) and FRD (75.68%), while the specificity of FRD (63.91%) was higher than that of cytology screening (35.34%) and HPV test (7.56%). The percent agreement and Kappa value of FRD were significantly higher than those of the cytology screening and HPV test. In HPV-HC2+ and ASCUS patients, FRD was associated with a lower false positive rate compared to other screening methods. CONCLUSION: Our study indicates that FRD has a good sensitivity and high specificity in cervical cancer screening, and could be a rapid, valid and cost-effective screening test.


Assuntos
Neoplasia Intraepitelial Cervical/diagnóstico , Detecção Precoce de Câncer/métodos , Receptor 1 de Folato/metabolismo , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/diagnóstico , Adulto , Idoso , Neoplasia Intraepitelial Cervical/metabolismo , Neoplasia Intraepitelial Cervical/virologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Prognóstico , Estudos Prospectivos , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia , Esfregaço Vaginal , Adulto Jovem
6.
Biofactors ; 46(1): 136-145, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31621972

RESUMO

The present study was aimed to explore the functional role of microRNA (miR)-29b in colon cancer, as well as underlying mechanisms. Expressions of miR-29b and folate receptor 1 (FOLR1) were measured in both human colon tumor samples and cell lines. Colon cancer cell lines SW480 and SW620 were transfected with miR-29b mimic, antisense oligonucleotides (ASO)-miR-29b, small interfering (siRNA) against FOLR1 (si-FOLR1), or corresponding negative controls (NCs), and then were incubated with or without oxaliplatin (L-OHP). Thereafter, cell viability, cytotoxicity, cell apoptosis, and expression of FOLR1, ATP Binding Cassette Subfamily G Member 2 (ABCG2) and p-glycoprotein (p-gp) were analyzed. We found that miR-29b was significantly decreased, while FOLR1 was statistically elevated in colon cancer samples and cell lines compared to the nontumor samples and nontumourigenic immortalized human colon epithelial cell line FHC. Overexpression of miR-29b markedly inhibited cell viability, promoted sensitivity to L-OHP, stimulated cell apoptosis (all p < .05), and decreased the levels of ABCG2 and p-gp in cancer cells, whereas suppression of miR-29b showed contrary results. Moreover, we observed that FOLR1 was a direct target of miR-29b and was negatively regulated by miR-29b. In addition, the findings revealed that the effects of FOLR1 inhibition on cell viability, sensitivity to L-OHP, cell apoptosis, and the levels of ABCG2 and p-gp were similar to overexpression of miR-29b. Taken together, our study suggests that miR-29b inhibits cell growth and promotes sensitivity to L-OHP in colon cancer by targeting FOLR1.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Receptor 1 de Folato/genética , MicroRNAs/metabolismo , Oxaliplatina/uso terapêutico , Idoso , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Neoplasias do Colo/genética , Feminino , Receptor 1 de Folato/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade
7.
Mater Sci Eng C Mater Biol Appl ; 107: 110341, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31761235

RESUMO

Cancer theranostics represents a strategy that aims at combining diagnosis with therapy through the simultaneous imaging and targeted delivery of therapeutics to cancer cells. Recently, the folate receptor alpha has emerged as an attractive theranostic target due to its overexpression in multiple solid tumors and its great functional versatility. In fact, it can be incorporated into folate-conjugated nano-systems for imaging and drug delivery. Hence, it can be used along the line of personalized clinical strategies as both an imaging tool and a delivery method ensuring the selective transport of treatments to tumor cells, thus highlighting its theranostic qualities. In this review, we will explore these theranostic characteristics in detail and assess their clinical potential. We will also discuss the technological advances that have allowed the design of sophisticated folate-based nanocarriers harboring various chemical properties and suited for the transport of various therapeutic agents.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Ácido Fólico/química , Nanoestruturas/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Dendrímeros/química , Dendrímeros/farmacologia , Receptor 1 de Folato/metabolismo , Ácido Fólico/metabolismo , Ácido Fólico/farmacocinética , Humanos , Lipossomos/administração & dosagem , Terapia de Alvo Molecular/métodos , Nanoestruturas/química , Neoplasias/metabolismo , Microambiente Tumoral
8.
Nanoscale ; 12(2): 825-831, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31830181

RESUMO

Accurate, sensitive detection of cancer cells from clinical fluids is helpful for screening and early diagnosis of tumors. Here, we develop a facile approach for in situ growth of palladium nanoparticles in an aqueous stable carboxymethyl cellulose-modified covalent organic framework hydrogel (named Pd NPs/CMC-COF-LZU1). The resulting nanocomposite has been proven to show superior catalytic performance for the transformation of N-butyl-4-NHAlloc-1,8-naphthalimide (NNPH) into N-butyl-4-amido-1,8-naphthalimide (NPH), indicated by significant changes in both color and fluorescence. Based on these features, the designed nanocomposite was used as a signal transducer to develop a colorimetric assay and multicolor imaging for accurate and sensitive detection of cancer cells. The transformation of NNPH into NPH enabled the detection system to perform multicolor imaging of HeLa cells. By using folic acid (FA) as a recognition element, a total of 100 cancer cells (HeLa) can be distinguished in 1 mL culture medium with 10% FBS. We envision that these COF-based composite materials (Pd NPs/CMC-COF-LZU1) have tremendous potential applications in biotechnology and biological sciences.


Assuntos
Colorimetria/métodos , Nanopartículas Metálicas/química , Estruturas Metalorgânicas/química , Nanocompostos/química , Células Neoplásicas Circulantes/patologia , Paládio/química , Animais , Técnicas Biossensoriais , Carboximetilcelulose Sódica/química , Catálise , Receptor 1 de Folato/metabolismo , Ácido Fólico/química , Células HeLa , Humanos , Hidrogéis/química , Limite de Detecção , Camundongos , Microscopia Confocal , Células NIH 3T3 , Células Neoplásicas Circulantes/metabolismo
9.
J Pharm Biomed Anal ; 180: 113077, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31884393

RESUMO

A novel fluorescent probe for detection of HT 29 cancer cells was developed based on terbium-doped dendritic fibrous nanosilica functionalized by folic acid (Tb@KCC-1-NH2-FA). Using this probe, fluorescence signals was emitted by Tb@KCC-1-NH2-FA at 490 nm by applying 380 nm as excitation wavelength. The reported probe is based on the interaction between FA decorated on the surface of Tb@KCC-1-NH2-FA and folate receptor (FR) which is overexpressed on the surface of the most of cancer cells. Fluorescence microscopy and flow cytometry were utilized to verify the uptake of Tb@KCC-1-NH2-FA with FR-positive HT 29 cancer cells. The specificity of Tb@KCC-1-NH2-FA towards FR-positive cells was approved by staining HEK 293 cells as FR-negative cells with Tb@KCC-1-NH2-FA which obtained results approved selective differentiation of normal cells with the FA-decorated nanomaterials. The cytotoxicity of Tb@KCC-1-NH2-FA was evaluated by MTT assay which confirmed their biocompatible nature. Under optimum conditions, this cytosensor is able to detect HT 29 colon cancer from 500 to 6.5 × 103 cells/mL with lower limit of detection (LLOQ) of 500 cells/mL. Due to the room temperature stability of Tb@KCC-1-NH2-FA, this cytosensor could be developed in a simple way with exceptional specificity which may show potential applications for early stage detection of colon cancer.


Assuntos
Técnicas Biossensoriais/métodos , Neoplasias Colorretais/patologia , Citodiagnóstico/métodos , Ácido Fólico/química , Nanoestruturas/química , Dióxido de Silício/química , Térbio/química , Técnicas Biossensoriais/instrumentação , Técnicas de Cultura de Células , Neoplasias Colorretais/metabolismo , Citodiagnóstico/instrumentação , Citometria de Fluxo , Corantes Fluorescentes/química , Receptor 1 de Folato/metabolismo , Células HEK293 , Células HT29 , Humanos , Microscopia de Fluorescência , Sensibilidade e Especificidade , Espectrometria de Fluorescência , Propriedades de Superfície
10.
Bioorg Med Chem ; 27(23): 115125, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31679978

RESUMO

We previously showed that classical 6-substituted pyrrolo[2,3-d]pyrimidine antifolates bind to folate receptor (FR) α and the target purine biosynthetic enzyme glycinamide ribonucleotide formyltransferase (GARFTase) with different cis and trans conformations. In this study, we designed novel analogs of this series with an amide moiety in the bridge region that can adopt both the cis and trans lowest energy conformations. This provides entropic benefit, by restricting the number of side-chain conformations of the unbound ligand to those most likely to promote binding to FRα and the target enzyme required for antitumor activity. NMR of the most active compound 7 showed both cis and trans amide bridge conformations in ~1:1 ratio. The bridge amide group in the best docked poses of 7 in the crystal structures of FRα and GARFTase adopted both cis and trans conformations, with the lowest energy conformations predicted by Maestro and evidenced by NMR within 1 kcal/mol. Compound 7 showed ~3-fold increased inhibition of FRα-expressing cells over its non-restricted parent analog 1 and was selectively internalized by FRα over the reduced folate carrier (RFC), resulting in significant in vitro antitumor activity toward FRα-expressing KB human tumor cells. Antitumor activity of 7 was abolished by treating cells with adenosine but was incompletely protected by 5-aminoimidazole-4-carboxamide (AICA) at higher drug concentrations, suggesting GARFTase and AICA ribonucleotide formyltransferase (AICARFTase) in de novo purine biosynthesis as the likely intracellular targets. GARFTase inhibition by compound 7 was confirmed by an in situ cell-based activity assay. Our results identify a "first-in-class" classical antifolate with a novel amide linkage between the scaffold and the side chain aryl L-glutamate that affords exclusive selectivity for transport via FRα over RFC and antitumor activity resulting from inhibition of GARFTase and likely AICARFTase. Compound 7 offers significant advantages over clinically used inhibitors of this class that are transported by the ubiquitous RFC, resulting in dose-limiting toxicities.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/farmacologia , Piridinas/química , Piridinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Amidas/química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Antineoplásicos/farmacocinética , Vias Biossintéticas/efeitos dos fármacos , Células CHO , Linhagem Celular Tumoral , Cricetulus , Receptor 1 de Folato/metabolismo , Antagonistas do Ácido Fólico/farmacocinética , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Nucleotídeos de Purina/metabolismo , Piridinas/farmacocinética , Pirróis/farmacocinética
11.
J Mater Chem B ; 7(39): 5983-5991, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31532444

RESUMO

Drug-loaded nanoparticles can be specifically uptaken by tumor cells to realize active targeting due to the conjugated ligands or antibodies on their surface. However, some non-cancerous cells express non-specific receptors or antigens on their surface, which can react with the ligands or antibodies conjugated on the nanoparticle surface and then result in non-specific uptake of the nanoparticles by non-cancerous cells. In order to reduce the non-specific uptake of nanoparticles by non-cancerous cells, in this study, we proposed a pH-sensitive polymer based precise tumor targeting strategy and synthesized superparamagnetic iron oxide nanoparticle (SPION) encapsulated albumin nanoparticles (AN) with conjugation of folic acid (FA) and mPEG-DCA (SPION-AN-FA@mPEG), in which mPEG can shield FA, avoiding the non-specific recognition by normal cells under physiological conditions, and can be shed to expose FA in tumor microenvironments. The pH-sensitivity of mPEG-DCA was verified by HPLC characterization and 1H-NMR spectroscopy. The graft density and length of mPEG-DCA were optimized via the cellular uptake of SPION-AN-FA@mPEG measured by flow cytometry analysis. The r2 value and r2/r1 ratio of the optimized SPION-AN-FA@mPEG (i.e., SPION-AN-FA@mPEG4) are 168.6 mM-1 s-1 and 42.8, respectively, which are both much higher than that of the commercial contrast agent Resovist®. The in vitro T2-weighted MR images and in vivo MRI performance demonstrate that our SPION-AN-FA@mPEG4 nanoparticles can be used as an effective T2-weighted MRI contrast agent.


Assuntos
Terapia de Alvo Molecular , Nanopartículas/química , Nanopartículas/metabolismo , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Transporte Biológico , Compostos Férricos/química , Receptor 1 de Folato/metabolismo , Ácido Fólico/química , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7
12.
Mol Pharm ; 16(9): 3996-4006, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31369274

RESUMO

Folate receptor α (FRα) is a well-studied tumor biomarker highly expressed in many epithelial tumors such as breast, ovarian, and lung cancers. Mirvetuximab soravtansine (IMGN853) is the antibody-drug conjugate of FRα-binding humanized monoclonal antibody M9346A and cytotoxic maytansinoid drug DM4. IMGN853 is currently being evaluated in multiple clinical trials, in which the immunohistochemical evaluation of an archival tumor or biopsy specimen is used for patient screening. However, limited tissue collection may lead to inaccurate diagnosis due to tumor heterogeneity. Herein, we developed a zirconium-89 (89Zr)-radiolabeled M9346A (89Zr-M9346A) as an immuno-positron emission tomography (immuno-PET) radiotracer to evaluate FRα expression in triple-negative breast cancer (TNBC) patients, providing a novel means to guide intervention with therapeutic IMGN853. In this study, we verified the binding specificity and immunoreactivity of 89Zr-M9346A by in vitro studies in FRαhigh cells (HeLa) and FRαlow cells (OVCAR-3). In vivo PET/computed tomography (PET/CT) imaging in HeLa xenografts and TNBC patient-derived xenograft (PDX) mouse models with various levels of FRα expression demonstrated its targeting specificity and sensitivity. Following PET imaging, the treatment efficiencies of IMGN853, pemetrexed, IMGN853 + pemetrexed, paclitaxel, and saline were assessed in FRαhigh and FRαlow TNBC PDX models. The correlation between 89Zr-M9346A tumor uptake and treatment response using IMGN853 in FRαhigh TNBC PDX model suggested the potential of 89Zr-M9346A PET as a noninvasive tool to prescreen patients based on the in vivo PET imaging for IMGN853-targeted treatment.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Receptor 1 de Folato/imunologia , Receptor 1 de Folato/metabolismo , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Maitansina/análogos & derivados , Radioisótopos/farmacocinética , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Zircônio/farmacocinética , Animais , Anticorpos Monoclonais Humanizados/química , Antineoplásicos Fitogênicos/química , Quimioterapia Combinada , Feminino , Células HeLa , Humanos , Imunoconjugados/química , Masculino , Maitansina/química , Maitansina/farmacocinética , Maitansina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Terapia de Alvo Molecular/métodos , Paclitaxel/uso terapêutico , Pemetrexede/uso terapêutico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Radioisótopos/química , Distribuição Tecidual , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Zircônio/química
13.
Stem Cells ; 37(11): 1441-1454, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31381815

RESUMO

In a previous study, we showed that folate receptor-α (FRα) translocates to the nucleus where it acts as a transcription factor and upregulates Hes1, Oct4, Sox2, and Klf4 genes responsible for pluripotency. Here, we show that acetylation and phosphorylation of FRα favor its nuclear translocation in the presence of folate and can cause a phenotypic switch from differentiated glial cells to dedifferentiated cells. shRNA-FRα mediated knockdown of FRα was used to confirm the role of FRα in dedifferentiation. Ocimum sanctum hydrophilic fraction-1 treatment not only blocks the folate mediated dedifferentiation of glial cells but also promotes redifferentiation of dedifferentiated glial cells, possibly by reducing the nuclear translocation of ~38 kDa FRα and subsequent interaction with chromatin assembly factor-1. Stem Cells 2019;37:1441-1454.


Assuntos
Receptor 1 de Folato/metabolismo , Crista Neural/efeitos dos fármacos , Crista Neural/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Desdiferenciação Celular/efeitos dos fármacos , Desdiferenciação Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Receptor 1 de Folato/genética , Ácido Fólico/análogos & derivados , Ácido Fólico/farmacologia , Humanos , Técnicas de Transferência Nuclear , Ocimum sanctum/química , Fator 3 de Transcrição de Octâmero/metabolismo , RNA Interferente Pequeno/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
14.
Theranostics ; 9(18): 5282-5297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410215

RESUMO

Purpose: Methotrexate (MTX) is a first-line drug for rheumatoid arthritis (RA)therapy. However, MTX monotherapy often results in irreversible joint damage due to its slow onset of action and long duration. microRNA-124 (miR-124) has shown direct bone protection activity against RA. A co-delivery system for MTX and microRNA combination may provide therapeutic synergy. Methods: Methotrexate-conjugated polymer hybrid micelles (M-PHMs) were prepared by self-assembly of two functional amphiphilic polymers (MTX-PEI-LA and mPEG-LA) at an optimized weight ratio. Incorporation of microRNA was achieved through electrostatic interactions between microRNA and cationic polymer MTX-PEI-LA. Cellular uptake, endosome escape, biodistribution, and therapeutic efficacy of M-PHMs/miR-124 complexes were investigated and evaluated in RAW264.7 cells and a rat adjuvant-induced arthritis (AIA) model. Results: M-PHMs/miR-124 complexes exhibited folate receptor-mediated uptake in activated RAW264.7 cells. miR-124 was able to escape from the endosome and down-regulate nuclear factor of activated T cells cytoplasmic1 (NFATc1). M-PHMs/miR-124 complexes accumulated in inflamed joints of AIA rats and showed superior therapeutic efficacy through both anti-inflammatory effect and direct bone protective effect. Combination of miR-124 and MTX in these micelles induced disease remission. Conclusions: M-PHMs/miR-124 was highly effective against RA through therapeutic synergy. Additional studies are warranted to further investigate its therapeutic potential and delineate its mechanisms of action.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Micelas , MicroRNAs/metabolismo , Polímeros/química , Animais , Artrite Reumatoide/sangue , Morte Celular/efeitos dos fármacos , Citocinas/sangue , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Endossomos/metabolismo , Receptor 1 de Folato/metabolismo , Hemólise/efeitos dos fármacos , Mediadores da Inflamação/sangue , Articulações/patologia , Ácido Linoleico/síntese química , Lipopolissacarídeos , Metotrexato/farmacologia , Camundongos , MicroRNAs/genética , Fatores de Transcrição NFATC/metabolismo , Polietilenoglicóis/síntese química , Polietilenoimina/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7 , Ratos , Distribuição Tecidual/efeitos dos fármacos
15.
Proc Natl Acad Sci U S A ; 116(35): 17531-17540, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31405972

RESUMO

Folates are critical for central nervous system function. Folate transport is mediated by 3 major pathways, reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor alpha (FRα/Folr1), known to be regulated by ligand-activated nuclear receptors. Cerebral folate delivery primarily occurs at the choroid plexus through FRα and PCFT; inactivation of these transport systems can result in very low folate levels in the cerebrospinal fluid causing childhood neurodegenerative disorders. These disorders have devastating effects in young children, and current therapeutic approaches are not sufficiently effective. Our group has previously reported in vitro that functional expression of RFC at the blood-brain barrier (BBB) and its upregulation by the vitamin D nuclear receptor (VDR) could provide an alternative route for brain folate uptake. In this study, we further demonstrated in vivo, using Folr1 knockout (KO) mice, that loss of FRα led to a substantial decrease of folate delivery to the brain and that pretreatment of Folr1 KO mice with the VDR activating ligand, calcitriol (1,25-dihydroxyvitamin D3), resulted in over a 6-fold increase in [13C5]-5-formyltetrahydrofolate ([13C5]-5-formylTHF) concentration in brain tissues, with levels comparable to wild-type animals. Brain-to-plasma concentration ratio of [13C5]-5-formylTHF was also significantly higher in calcitriol-treated Folr1 KO mice (15-fold), indicating a remarkable enhancement in brain folate delivery. These findings demonstrate that augmenting RFC functional expression at the BBB could effectively compensate for the loss of Folr1-mediated folate uptake at the choroid plexus, providing a therapeutic approach for neurometabolic disorders caused by defective brain folate transport.


Assuntos
Encéfalo/metabolismo , Receptor 1 de Folato/metabolismo , Ácido Fólico/metabolismo , Proteína Carregadora de Folato Reduzido/metabolismo , Vitamina D/metabolismo , Animais , Transporte Biológico , Biomarcadores , Barreira Hematoencefálica/metabolismo , Cromatografia Líquida , Feminino , Receptor 1 de Folato/genética , Expressão Gênica , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Espectrometria de Massas em Tandem
16.
Mol Pharm ; 16(9): 3985-3995, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31356752

RESUMO

Folate-based small molecule drug conjugates (SMDCs) are currently under development and have shown promising preclinical and clinical results against various cancers and polycystic kidney disease. Two requisites for response to a folate-based SMDC are (i) folate receptor alpha (FRα) protein is expressed in the diseased tissues, and (ii) FRα in those tissues is accessible and functionally competent to bind systemically administered SMDCs. Here we report on the development of a small molecule reporter conjugate (SMRC), called EC2220, which is composed of a folate ligand for FRα binding, a multilysine containing linker that can cross-link to FRα in the presence of formaldehyde fixation, and a small hapten (fluorescein) used for immunohistochemical detection. Data show that EC2220 produces a far greater IHC signal in FRα-positive tissues over that produced with EC17, a folate-fluorescein SMRC that is released from the formaldehyde-denatured FRα protein. Furthermore, the extent of the EC2220 IHC signal was proportional to the level of FRα expression. This EC2220-based assay was qualified both in vitro and in vivo using normal tissue, cancer tissue, and polycystic kidneys. Overall, EC2220 is a sensitive and effective reagent for evaluating functional and accessible receptor expression in vitro and in vivo.


Assuntos
Receptor 1 de Folato/metabolismo , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Doenças Renais Policísticas/tratamento farmacológico , Células A549 , Animais , Doxiciclina/farmacologia , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/metabolismo , Receptor 1 de Folato/análise , Ácido Fólico/análogos & derivados , Ácido Fólico/química , Ácido Fólico/metabolismo , Células HeLa , Humanos , Lisina/análogos & derivados , Lisina/química , Lisina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos Transgênicos , Neoplasias/metabolismo , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Doenças Renais Policísticas/induzido quimicamente , Doenças Renais Policísticas/metabolismo , Proteína Quinase C/genética , Distribuição Tecidual , Compostos de Tritil/química , Compostos de Tritil/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Anal Chem ; 91(15): 9580-9589, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31264409

RESUMO

The invasiveness evaluation of nonfunctional pituitary adenoma (NFPAs) is crucial for the prediction of the malignant potential and for making surgical plans of NFPAs. Current invasiveness evaluation of NFPAs is based on neuroimaging, which can hardly predict the invasive potential and dynamically monitor disease progress. Here we used microbead-assisted flow cytometry to detect and analyze the serum extracellular vesicles (EVs) from 30 NFPAs patients (15 invasive and 15 noninvasive). Lower expressions of folate receptor 1 (FOLR1) and epithelial cell adhesion molecule (EpCAM) were found in serum EVs from the invasive NFPAs patients compared to the noninvasive ones [area under the curve (AUC) of 0.94 for FOLR1 and 0.88 for EpCAM]. Meanwhile, increased mRNA expression of vimentin and N-cadherin, two mesenchymal markers, was found in serum EVs from the invasive NFPAs patients compared to the noninvasive ones. Consistent results were observed in the tumor tissue that invasive NFPAs have lower expression of the epithelial markers while higher expression of the mesenchymal markers. These results suggested the possible role of epithelial-mesenchymal transition (EMT) in the invasiveness of NFPAs. Pituitary tumor transforming gene 1 (PTTG1) mRNA in serum EVs was also found to be an indicator for invasive NFPAs and is related with EMT. These results provide a method for the blood-based diagnosis and invasiveness evaluation of NFPAs and would be beneficial to the diagnosis, prognosis prediction, and surgical risk evaluation of NFPAs.


Assuntos
Vesículas Extracelulares/metabolismo , Invasividade Neoplásica , Neoplasias Hipofisárias/patologia , Animais , Biomarcadores Tumorais , Linhagem Celular , Molécula de Adesão da Célula Epitelial/metabolismo , Citometria de Fluxo , Receptor 1 de Folato/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Hipófise/citologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Securina/metabolismo
18.
Drug Metab Dispos ; 47(8): 890-898, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31167838

RESUMO

Preliminary analysis of ongoing birth surveillance study identified evidence of potential increased risk for neural tube defects (NTDs) in newborns associated with exposure to dolutegravir at the time of conception. Folate deficiency is a common cause of NTDs. Dolutegravir and other HIV integrase inhibitor drugs were evaluated in vitro for inhibition of folate transport pathways: proton-coupled folate transporter (PCFT), reduced folate carrier (RFC), and folate receptor α (FRα)-mediated endocytosis. Inhibition of folate transport was extrapolated to the clinic by using established approaches for transporters in intestine, distribution tissues, and basolateral and apical membranes of renal proximal tubules (2017 FDA Guidance). The positive controls, methotrexate and pemetrexed, demonstrated clinically relevant inhibition of PCFT, RFC, and FRα in folate absorption, distribution, and renal sparing. Valproic acid was used as a negative control that elicits folate-independent NTDs; valproic acid did not inhibit PCFT, RFC, or FRα At clinical doses and exposures, the observed in vitro inhibition of FRα by dolutegravir and cabotegravir was not flagged as clinically relevant; PCFT and RFC inhibition was not observed in vitro. Bictegravir inhibited both PCFT and FRα, but the observed inhibition did not reach the criteria for clinical relevance. Elvitegravir and raltegravir inhibited PCFT, but only raltegravir inhibition of intestinal PCFT was flagged as potentially clinically relevant at the highest 1.2-g dose (not the 400-mg dose). These studies showed that dolutegravir is not a clinical inhibitor of folate transport pathways, and it is not predicted to elicit clinical decreases in maternal and fetal folate levels. Clinically relevant HIV integrase inhibitor drug class effect on folate transport pathways was not observed. SIGNIFICANCE STATEMENT: Preliminary analysis of ongoing birth surveillance study identified evidence of potential increased risk for neural tube defects (NTDs) in newborns associated with exposure to the HIV integrase inhibitor dolutegravir at the time of conception; folate deficiency is a common cause of NTDs. Dolutegravir and other HIV integrase inhibitor drugs were evaluated in vitro for inhibition of the major folate transport pathways: proton-coupled folate transporter, reduced folate carrier, and folate receptor α-mediated endocytosis. The present studies showed that dolutegravir is not a clinical inhibitor of folate transport pathways, and it is not predicted to elicit clinical decreases in maternal and fetal folate levels. Furthermore, clinically relevant HIV integrase inhibitor drug class effect on folate transport pathways was not observed.


Assuntos
Ácido Fólico/metabolismo , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Animais , Cães , Endocitose/efeitos dos fármacos , Ensaios Enzimáticos , Feminino , Receptor 1 de Folato/metabolismo , Ácido Fólico/sangue , Deficiência de Ácido Fólico/induzido quimicamente , Deficiência de Ácido Fólico/complicações , Deficiência de Ácido Fólico/epidemiologia , Infecções por HIV/tratamento farmacológico , Humanos , Incidência , Recém-Nascido , Células Madin Darby de Rim Canino , Exposição Materna/efeitos adversos , Troca Materno-Fetal , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/etiologia , Oxazinas , Piperazinas , Gravidez , Transportador de Folato Acoplado a Próton/metabolismo , Piridonas , Proteína Carregadora de Folato Reduzido/metabolismo , Medição de Risco
19.
J Biomater Sci Polym Ed ; 30(11): 983-993, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31064276

RESUMO

We report here a folate-modified membrane anchor for cell surface modification to induce cell adhesion to target cells. The membrane anchor region, which was consisted of cationic lysine residues and palmitoyl group-modified residues, was modified with folate through an oligoethlene glycol linker. The peptide anchor was modified on to the cell membrane by using ß-cyclodextrin as a solubilizer of the peptide anchor. After modification, the peptide anchor disappeared from the cell membrane via endocytotic uptake or dissociation from the cell membrane. However, the endocytosed peptide was represented on the cell surface via recycling endosome pathway. The obtained folate-modified cells successfully adhered on to target cells which expressed folate receptor α via ligand-receptor specific interaction and adhesion continued at least 4 hours.


Assuntos
Membrana Celular/química , Receptor 1 de Folato/metabolismo , Ácido Fólico/química , Peptídeos/química , Transporte Biológico , Adesão Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Humanos , Hidrocarbonetos/química , Células K562 , Cetonas/química , Ligantes , Lisina/química , Membranas Artificiais , Peptídeos/metabolismo , Propriedades de Superfície , beta-Ciclodextrinas/química
20.
Anal Cell Pathol (Amst) ; 2019: 1438628, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049278

RESUMO

This study was to validate changes in the levels of folate receptor-α (FOLR1), dihydrofolate reductase (DHFR), and methionine synthase reductase (MTRR) in the tissue of OC patients. The expression of FOLR1, DHFR, and MTRR was evaluated in 80 cases of primary OC, 50 cases of benign ovarian tumors, and 30 normal ovarian tissues. Associations between protein expression and clinicopathological characters were assessed, and diagnostic and prognostic evaluation of FOLR1, DHFR, and MTRR was performed. Results showed that upregulated FOLR1 and MTRR and downregulated DHFR were detected in OC. Patients with abnormality of FOLR1, DHFR, and MTRR tend to have a higher percentage of platinum resistance. Moreover, the areas under receiver operating characteristic curves (AUCs-ROC) for FOLR1, DHFR, and MTRR were 0.723, 0.717, and 0.714, respectively. The combination of FOLR1, DHFR, and MTRR could produce an area of 0.864 under the receiver-operating characteristic curve in distinguishing platinum-resistant patients from platinum-sensitive patients (P < 0.0001). Correlations were present between the expression of FOLR1, DHFR, and MTRR. Furthermore, Kaplan-Meier curves indicated that the patients with overexpressed MTRR had a poorer overall survival time compared to those with low expression (P < 0.05). Thus, folate metabolic enzymes could provide a potential promising biomarker for diagnosis platinum-resistant in OC.


Assuntos
Carcinoma Epitelial do Ovário/metabolismo , Ferredoxina-NADP Redutase/metabolismo , Receptor 1 de Folato/metabolismo , Neoplasias Ovarianas/metabolismo , Tetra-Hidrofolato Desidrogenase/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Western Blotting , Criança , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Adulto Jovem
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