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1.
J Pharm Biomed Anal ; 205: 114288, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34371449

RESUMO

Prostate cancer (PCa) is associated with cellular metabolism alterations leading to changes of the metabolome. So far, studies investigating these alterations mainly focused on comparisons of metabolite profiles of PCa patients and healthy controls. In the present study we compared for the first time metabolite profiles in a significant number of paired urine samples collected before and eight weeks after radical prostatectomy (rPX) in 34 patients with PCa. Our comprehensive non-targeted liquid chromatographic-mass spectrometric metabolomics approach covered > 3000 metabolite ion masses. We annotated 23 metabolites showing significant changes eight weeks after rPX. While the levels of uridine and six acylcarnitines in urine were increased before surgery, lower levels were detected for 16 metabolites, like e.g. citrate, phenyl-lactic acid, choline, myo-inositol, emphasizing a relevant pathophysiological role of these biomarkers and the associated metabolic pathways. These results have important implications for potential use of metabolome analyses for detection of prostate cancer and related pathologic and molecular features.


Assuntos
Metaboloma , Neoplasias da Próstata , Humanos , Masculino , Metabolômica , Prostatectomia , Neoplasias da Próstata/cirurgia
2.
Nat Commun ; 12(1): 184, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420073

RESUMO

Molecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.


Assuntos
DNA Tumoral Circulante/sangue , Genômica , Plasma , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma de Células de Transição/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Receptor ErbB-2/genética , Estudos Retrospectivos , Análise de Sobrevida , Bexiga Urinária , Proteína Grupo D do Xeroderma Pigmentoso/genética
3.
Expert Opin Biol Ther ; 21(7): 801-809, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33325754

RESUMO

Introduction: The therapeutic landscape of metastatic urothelial carcinoma (mUC) becomes increasingly dense: standard therapy remains cisplatin-based chemotherapy, followed by immunotherapy with checkpoint inhibitors as maintenance or second-line. New directions include erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor in patients with corresponding mutations in FGFR2/3 receptor. Enfortumab vedotin (EV) is an antibody-drug conjugate targeting nectin-4 and is conjugated with monomethyl auristatin E (MMAE). It received FDA approval based on phase I/II data recently and thus represents an alternative to established third-line chemotherapies with vinflunine, paclitaxel, or docetaxel.Areas covered: The aim of this review was to evaluate the added value of Enfortumab vedotin in the therapeutic landscape of mUC. Current therapeutic options and alternatives for the affected patients are described, followed by a detailed description of the characteristics and available results of EV. Ongoing studies are explained, the present significance of the substance is assessed and its further future potential is outlined.Expert opinion Enfortumab vedotin has shown encouraging efficacy and a good tolerability in phase I/II trials, especially in heavily pretreated patients and patients with liver metastases. It appears to outperform third-line chemotherapies; ongoing studies will show the future potential of EV in treatment sequence.

4.
Urol Oncol ; 38(12): 935.e17-935.e28, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32773234

RESUMO

INTRODUCTION AND OBJECTIVES: Somatostatin receptors (SSTR) recently have been identified as potential targets for treatment of solid tumors. Furthermore, they have been shown to be of high relevance for tumor biology and prognosis in various types of cancer. However, there is a lack of clinical data for SSTR in bladder cancer (BC). Aim of this study was to determine the expression of all relevant somatostatin receptor subtypes in benign urothelium and tumor tissue of patients with muscle invasive BC. Furthermore, their potential role as prognostic factor for cancer-specific survival (CSS) and overall survival (OS) was evaluated. METHODS: The collective included BC and benign urothelium tissue of 103 patients (Median age 69; range 32-84, 79 male, 24 female) who underwent a radical cystectomy. A tissue microarray with subsequent immunohistochemical staining was used to assess membranous expression of SSTR1-5. Results were correlated to clinical and histopathological data as well as CSS and OS. RESULTS: Expressions of SSTR1-4 were significantly decreased in BC compared to benign urothelium (P < 0.002 each), whereas SSTR5 expression was increased (P = 0.0017). Expression of SSTR1 was associated with organ-confined disease (≤pT2) (P = 0.0477). No correlation between SSTR1-5 expression and N- and M-stage was observed. Univariate analyses showed a significantly longer CSS and OS in patients with high expression of SSTR3 (P = 0.0316 and 0.0044). Multivariate analyses confirmed SSTR3 expression as independent marker of improved CSS and OS (P = 0.0324 and 0.0076). CONCLUSIONS: The majority of somatostatin receptor subtypes exhibit decreased expression in BC compared to benign bladder tissue. Expression of SSTR3 is an indicator for favorable prognosis in patients with muscle-invasive BC. These results support preclinical investigations using somatostatin receptor analogues such as octreotide to influence BC growth.


Assuntos
Receptores de Somatostatina/biossíntese , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/patologia
5.
Expert Opin Biol Ther ; 20(9): 971-979, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32407144

RESUMO

INTRODUCTION: The immune checkpoint inhibitors (ICI) programmed cell death protein and ligands 1 (PD1- and PD-L1) as well as cytotoxic T-lymphocyte-associated protein 4 have demonstrated clinical efficacy in genitourinary cancer. While different ICI exist, focus of the current study work was to evaluate the PD-L1 antibody avelumab within this framework of ICI. AREAS COVERED: The manuscript reviews the pharmacological characteristics and preclinical and clinical data of avelumab in the treatment for advanced or metastatic genitourinary cancers. It highlights its respective clinical relevance and special features in the context of the other available ICI. EXPERT OPINION: Avelumab has shown promising antitumor activity and a manageable safety profile in patients with mRCC and mUC as mono- and combination therapy. The approach of an avelumab maintenance therapy in mUC is promising and could become part of future clinical practice. Results of ICI used in the neoadjuvant or adjuvant setting are eagerly awaited. Avelumab's uniqueness is its capacity to enhance antibody-dependent cell-mediated cytotoxicity. Because of this, currently ongoing clinical trials investigate the combination of avelumab with other immune modulating agents like IL-12 and IL-15. Thereby, it can be assumed that avelumab will have an ongoing role in the treatment of patients with genitourinary tumors.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Urogenitais/tratamento farmacológico , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/metabolismo , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/metabolismo , Antígeno B7-H1/imunologia , Ensaios Clínicos como Assunto , Meia-Vida , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Resultado do Tratamento , Neoplasias Urogenitais/patologia
6.
Blood Cancer J ; 10(2): 24, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111817

RESUMO

The B-cell maturation antigen (BCMA) is currently being evaluated as promising tumor-associated surface antigen for T-cell-based immunotherapy approaches, such as CAR T cells and bispecific antibodies, in multiple myeloma (MM). Cytotoxic T cells bearing BCMA-specific T-cell receptors might further allow targeting HLA-presented antigens derived from the intracellular domain of BCMA. By analyzing a mass spectrometry-acquired immunopeptidome dataset of primary MM samples and MM cell lines for BCMA-derived HLA ligands, we identified the naturally presented HLA-B*18-restricted ligand P(BCMA)B*18. Additionally, P(BCMA)B*18 was identified on primary CLL samples, thereby expanding the range for possible applications. P(BCMA)B*18 induced multifunctional BCMA-specific cells de novo from naïve CD8+ T cells of healthy volunteers. These T cells exhibited antigen-specific lysis of autologous peptide-loaded cells. Even in the immunosuppressive context of MM, we detected spontaneous memory T-cell responses against P(BCMA)B*18 in patients. By applying CTLA-4 and PD-1 inhibition in vitro we induced multifunctional P(BCMA)B*18-specific CD8+ T cells in MM patients lacking preexisting BCMA-directed immune responses. Finally, we could show antigen-specific lysis of autologous peptide-loaded target cells and even MM.1S cells naturally presenting P(BCMA)B*18 using patient-derived P(BCMA)B*18-specific T cells. Hence, this BCMA-derived T-cell epitope represents a promising target for T-cell-based immunotherapy and monitoring following immunotherapy in B-cell malignancy patients.


Assuntos
Antígeno de Maturação de Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Espectrometria de Massas/métodos , Mieloma Múltiplo/imunologia , Linfócitos T Citotóxicos/imunologia , Anticorpos Monoclonais/imunologia , Estudos de Casos e Controles , Estudos de Viabilidade , Voluntários Saudáveis , Humanos , Imunoterapia/métodos , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/terapia , Proteínas de Neoplasias/imunologia
7.
World J Mens Health ; 38(2): 151-163, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31081297

RESUMO

Bone health in prostate cancer patients represents a prerequisite for acceptable quality of life and optimal outcome of this disease. The major threat for bone health in prostate cancer displays cancer treatment induced bone loss as well as the development of bone metastases. In recent years, several new pharmaceuticals targeting bone metabolism such as denosumab or androgen pathway targeting drugs (abiraterone acetate and enzalutamide) have been approved for the treatment of progressive disease aiming to interrupt the vicious circle of bone metastasis and aberrant bone resorption. This development raised the awareness of the pivotal role of bone health in prostate cancer and introduced (symptomatic) skeletal related events as an important end point in recent clinical trials. Bone targeted drugs have become standard of care in patients with metastatic castration resistant prostate cancer, their role in metastatic hormone sensitive prostate cancer has been discussed controversely. In oligometastatic prostate cancer patients several promising approaches in metastasis directed therapy, including conventional surgery, stereotactic ablative radiation and image-guided single-fraction robotic stereotactic radiosurgery (CyberKnife®) were launched but are not in routine clinical use until now caused by sparse clinical evidence.

8.
Expert Rev Mol Diagn ; 18(5): 443-455, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29707982

RESUMO

INTRODUCTION: Diagnosis and surveillance of non-muscle invasive bladder cancer (NMIBC) is mainly based on endoscopic bladder evaluation and urine cytology. Several assays for determining additional molecular markers (urine-, tissue- or blood-based) have been developed in recent years but have not been included in clinical guidelines so far. Areas covered: This review gives an update on different molecular markers in the urine and evaluates their role in patients with NMIBC in disease detection and surveillance. Moreover, the potential of recent approaches such as DNA methylation assays, multi-panel RNA gene expression assays and cell-free DNA analysis is assessed. Expert commentary: Most studies on various molecular urine markers have mainly focused on a potential replacement of cystoscopy. New developments in high throughput technologies and urine markers may offer further advantages as they may represent a non-invasive approach for molecular characterization of the disease. This opens new options for individualized surveillance strategies and may help to choose the best therapeutic option. The implementation of these technologies in well-designed clinical trials is essential to further promote the use of urine diagnostics in the management of patients with NMIBC.


Assuntos
Biomarcadores Tumorais , Técnicas de Diagnóstico Molecular , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Ácidos Nucleicos Livres , DNA de Neoplasias , Detecção Precoce de Câncer , Seguimentos , Marcadores Genéticos , Humanos , Invasividade Neoplásica , Estadiamento de Neoplasias , Proteoma , Proteômica/métodos , Neoplasias da Bexiga Urinária/urina
9.
Dis Markers ; 2018: 5823870, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29651327

RESUMO

Objectives: To assess the performance of urine markers determined in urine samples from the bladder compared to samples collected from the upper urinary tract (UUT) for diagnosis of UUT urothelial carcinoma (UC). Patients and Methods: The study comprised 758 urine samples either collected from the bladder (n = 373) or UUT (n = 385). All patients underwent urethrocystoscopy and UUT imaging or ureterorenoscopy. Cytology, fluorescence in situ hybridization (FISH), immunocytology (uCyt+), and nuclear matrix protein 22 (NMP22) were performed. Results: UUT UC was diagnosed in 59 patients (19.1%) (UUT urine) and 27 patients (7.2%) (bladder-derived urine). For UUT-derived samples, sensitivities for cytology, FISH, NMP22, and uCyt+ were 74.6, 79.0, 100.0, and 100.0, while specificities were 66.6, 50.7, 5.9, and 66.7%, respectively. In bladder-derived samples, sensitivities were 59.3, 52.9, 62.5, and 50.0% whereas specificities were 82.9, 85.0, 31.3, and 69.8%. In UUT-derived samples, concomitant bladder cancer led to increased false-positive rates of cytology and FISH. Conclusions: Urine markers determined in urine collected from the UUT exhibit better sensitivity but lower specificity compared to markers determined in bladder-derived urine. Concomitant or recent diagnosis of UC of the bladder can further influence markers determined in UUT urine.


Assuntos
Biomarcadores Tumorais/urina , Carcinoma de Células de Transição/diagnóstico , Detecção Precoce de Câncer/métodos , Neoplasias Urológicas/diagnóstico , Carcinoma de Células de Transição/metabolismo , Carcinoma de Células de Transição/urina , Cistoscopia , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Proteínas Nucleares/metabolismo , Estudos Retrospectivos , Sensibilidade e Especificidade , Ureteroscopia , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/urina
10.
BJU Int ; 122(1): 152-159, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29542849

RESUMO

OBJECTIVE: To evaluate the presence of circulating tumour cells (CTCs) at different stages of prostate cancer using the AdnaTest® ProstateCancerDetect kit (Qiagen). Moreover, we aimed to assess the expression of transcripts that are specific for cancer stem cells (AdnaTest StemCell) and epithelial-mesenchymal transition (EMT) in CTCs (AdnaTest EMT), as well as additional genes that are known to promote prostate cancer progression. PATIENTS AND METHODS: In this prospective study, we included 81 patients who underwent treatment for prostate cancer between 07/2014 and 02/2015, including: Group A, 18 patients (22.2%) with low-risk clinically localised prostate cancer; Group B, 25 patients (30.9%) with high-risk clinically localised prostate cancer; Group C, 11 patients (13.6%) with metastatic castration-sensitive prostate cancer (mCSPC); and Group D, 27 patients (33.3%) with metastatic castration-resistant prostate cancer (mCRPC). AdnaTest ProstateCancer and AdnaTest StemCell/EMT were performed in all cases. In addition, expression of the androgen receptor (AR), c-met, c-kit and thymidylate synthase (TYMS) in CTCs was assessed using specific polymerase chain reaction assays. RESULTS: A positive AdnaTest ProstateCancer was present in three (16.7%), two (8.0%), six (54.5%) and 19 (70.5%) patients in groups A, B, C and D, respectively (P < 0.01, chi-squared test). The AdnaTest EMT and AdnaTest StemCell were positive in zero (0.0%), zero (0.0%), one (9.1%), and two (7.4%); and in five (27.8%), four (16.0%), three (27.3%), and 11 (40.7%) patients in groups A, B, C and D, respectively, with no significant differences noted between groups. CTCs expressing TYMS (44.4% and 50.0% vs 13.9%) or AR (18.2% and 25.9% vs 0.0%) were seen more commonly in patients in groups C and D vs patients with non-metastatic disease (all P < 0.05). Expression of c-kit and c-met were rare events, with only two patients positive for either marker. CONCLUSIONS: AdnaTest ProstateCancerDetect exhibits positive results mainly in patients with metastatic disease. Expression of AR and TYMS are frequent events in CTCs of patients with advanced disease, whereas c-met and c-kit gene expression is seen in only a small proportion of patients. The implications of these results for the use of CTC analysis as a decision factor for personalised treatment strategies in advanced prostate cancer remain to be determined.


Assuntos
Genes Neoplásicos/fisiologia , Células Neoplásicas Circulantes , Neoplasias de Próstata Resistentes à Castração/genética , Idoso , Idoso de 80 Anos ou mais , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo
11.
Asian J Androl ; 2017 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-29286005

RESUMO

Bone metastases have a major impact on quality of life and survival of patients with advanced prostate cancer. In the last decade, the development and approval of substances inhibiting the vicious cycle of bone metastases have enabled the reduction of complications caused by bone metastases in patients with castration-resistant prostate cancer. These drugs have raised awareness of the importance of skeletal-related events which in the meantime represent an important end point also in trials using agents not specifically designed for bone lesions. Second-generation antihormonal drugs such as enzalutamide or abiraterone have been shown to have a positive impact on the incidence of skeletal complications and therefore provide an important tool in the armamentarium used for treating bone metastases. Radiopharmaceuticals such as radium-223 dichloride ([223Ra]) have been demonstrated not only to reduce skeletal-related events and bone-related pain, but also to prolong overall survival, thereby being the first bone-targeting agent showing a survival benefit. As previous studies have not provided an obvious benefit of bone-targeted lesions in castration-sensitive disease, the use of these agents is not recommended. In oligometastatic prostate cancer, the role of local treatment of metastases using stereotactic radiation or radiosurgery is a matter of intense debates and may play an increasing role in the future.

12.
Oncotarget ; 8(27): 43915-43924, 2017 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-28159928

RESUMO

Hematological malignancies (HM) are highly amenable targets for immunotherapeutic intervention and may be effectively treated by antigen-specific T-cell based treatment. Recent studies demonstrate that physiologically occurring anti-cancer T-cell responses in certain HM entities target broadly presented non-mutated epitopes. HLA ligands are thus implied as prime targets for broadly applicable and antigen-specific off-the-shelf compounds. With the aim of assessing the presence of common targets shared among different HM which may enable addressing a larger patient collective we conducted a meta-analysis of 83 mass spectrometry-based HLA peptidome datasets (comprising 40,361 unique peptide identifications) across four major HM (19 AML, 16 CML, 35 CLL, and 13 MM/MCL samples) and investigated similarities and differences within the HLA presented antigenic landscape. We found the cancer HLA peptidome datasets to cluster specifically along entity and lineage lines, suggesting that the immunopeptidome directly reflects the differences in the underlying (tumor-)biology. In line with these findings, we only detected a small set of entity-spanning antigens, which were predominantly characterized by low presentation frequencies within the different patient cohorts. These findings suggest that design of T-cell immunotherapies for the treatment of HM should ideally be conducted in an entity-specific fashion.


Assuntos
Mapeamento de Epitopos , Epitopos/imunologia , Antígenos HLA/imunologia , Peptídeos/imunologia , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Análise por Conglomerados , Mapeamento de Epitopos/métodos , Epitopos/química , Epitopos/metabolismo , Antígenos HLA/química , Antígenos HLA/metabolismo , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/terapia , Humanos , Imunoterapia , Leucemia/imunologia , Leucemia/metabolismo , Leucemia/terapia , Ligantes , Peptídeos/química , Peptídeos/metabolismo
13.
Blood ; 126(10): 1203-13, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26138685

RESUMO

Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8(+) T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell-based immunotherapy of MM.


Assuntos
Epitopos de Linfócito T/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Ativação Linfocitária/imunologia , Mieloma Múltiplo/imunologia , Adulto , Idoso , Apresentação do Antígeno/imunologia , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem
14.
Acta Biomater ; 10(2): 688-700, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24148751

RESUMO

Despite the development of new coronary stent technologies, in-stent restenosis and stent thrombosis are still clinically relevant. Interactions of blood and tissue cells with the implanted material may represent an important cause of these side effects. We hypothesize material-dependent interaction of blood and tissue cells. The aim of this study is accordingly to investigate the impact of vascular endothelial cells, smooth muscle cells and platelets with various biodegradable polymers to identify a stent coating or platform material that demonstrates excellent endothelial-cell-supportive and non-thrombogenic properties. Human umbilical venous endothelial cells, human coronary arterial endothelial cells and human coronary arterial smooth muscle cells were cultivated on the surfaces of two established biostable polymers used for drug-eluting stents, namely poly(ethylene-co-vinylacetate) (PEVA) and poly(butyl methacrylate) (PBMA). We compared these polymers to new biodegradable polyesters poly(l-lactide) (PLLA), poly(3-hydroxybutyrate) (P(3HB)), poly(4-hydroxybutyrate) (P(4HB)) and a polymeric blend of PLLA/P(4HB) in a ratio of 78/22% (w/w). Biocompatibility tests were performed under static and dynamic conditions. Measurement of cell proliferation, viability, glycocalix width, eNOS and PECAM-1 mRNA expression revealed strong material dependency among the six polymer samples investigated. Only the polymeric blend of PLLA/P(4HB) achieved excellent endothelial markers of biocompatibility. Data show that PLLA and P(4HB) tend to a more thrombotic response, whereas the polymer blend is characterized by a lower thrombotic potential. These data demonstrate material-dependent endothelialization, smooth muscle cell growth and thrombogenicity. Although polymers such as PEVA and PBMA are already commonly used for vascular implants, they did not sufficiently meet the criteria for biocompatibility. The investigated biodegradable polymeric blend PLLA/P(4HB) evidently represents a promising material for vascular stents and stent coatings.


Assuntos
Plaquetas/citologia , Comunicação Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Miócitos de Músculo Liso/citologia , Polímeros/farmacologia , Stents , Biomarcadores/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Plaquetas/ultraestrutura , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/farmacologia , Glicocálix/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Selectina-P/metabolismo , Adesividade Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Reologia/efeitos dos fármacos , Estresse Mecânico , Propriedades de Superfície
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