RESUMO
The survival of patients with glioblastoma multiforme (GBM), the most common and invasive form of malignant brain tumors, remains poor despite advances in current treatment methods including surgery, radiotherapy, and chemotherapy. Minocycline is a semi-synthetic tetracycline derivative that has been widely used as an antibiotic and more recently, it has been utilized as an antiangiogenic factor to inhibit tumorigenesis. The objective of this study was to investigate the utilization of electrospraying process to fabricate minocycline-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles with high drug loading and loading efficiency and to evaluate their ability to induce cell toxicity in human glioblastoma (i.e., U87-MG) cells. The results from this study demonstrated that solvent mixture of dicholoromethane (DCM) and methanol is the optimal solvent combination for minocycline and larger amount of methanol (i.e., 70:30) resulted in a higher drug loading. All three solvent ratios of DCM:methanol tested produced microparticles that were both spherical and smooth, all in the micron size range. The electrosprayed microparticles were able to elicit a cytotoxic response in U87-MG glioblastoma cells at a lower concentration of drug compared to the free drug. This work provides proof of concept to the hypothesis that electrosprayed minocycline-loaded PLGA microparticles can be a promising agent for the treatment of GBM and could have potential application for cancer therapies.
RESUMO
The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC) and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent mechanisms (including constitutively active AR splice variants) highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA-binding protein 2 (GATA2) as a regulator of AR signaling and an actionable therapeutic target in PC. We demonstrate that GATA2 directly promotes expression of both full-length and splice-variant AR, resulting in a strong positive correlation between GATA2 and AR expression in both PC cell lines and patient specimens. Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of both full-length and splice-variant AR. GATA2 colocalizes with AR and Forkhead box protein A1 on chromatin to enhance recruitment of steroid receptor coactivators and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of both full-length and splice-variant AR and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a first-in-field approach to target AR expression and function and improve outcomes in CRPC.
Assuntos
Fator de Transcrição GATA2/fisiologia , Coativadores de Receptor Nuclear/metabolismo , Receptores Androgênicos/metabolismo , Proliferação de Células , Cromatina/metabolismo , Elementos Facilitadores Genéticos , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Masculino , Prognóstico , Receptores Androgênicos/fisiologia , Transdução de Sinais , Transcrição Gênica/fisiologiaRESUMO
The p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2 [nuclear receptor coactivator (NCOA)2], and SRC-3 [amplified in breast cancer 1 (AIB1)/NCOA3] are key pleiotropic "master regulators" of transcription factor activity necessary for cancer cell proliferation, survival, metabolism, and metastasis. SRC overexpression and overactivation occur in numerous human cancers and are associated with poor clinical outcomes and resistance to therapy. In prostate cancer (PC), the p160 SRCs play critical roles in androgen receptor transcriptional activity, cell proliferation, and resistance to androgen deprivation therapy. We recently demonstrated that the E3 ubiquitin ligase adaptor speckle-type poxvirus and zinc finger (POZ) domain protein (SPOP) interacts directly with SRC-3 and promotes its cullin 3-dependent ubiquitination and proteolysis in breast cancer, thus functioning as a potential tumor suppressor. Interestingly, somatic heterozygous missense mutations in the SPOP substrate-binding cleft recently were identified in up to 15% of human PCs (making SPOP the gene most commonly affected by nonsynonymous point mutations in PC), but their contribution to PC pathophysiology remains unknown. We now report that PC-associated SPOP mutants cannot interact with SRC-3 protein or promote its ubiquitination and degradation. Our data suggest that wild-type SPOP plays a critical tumor suppressor role in PC cells, promoting the turnover of SRC-3 protein and suppressing androgen receptor transcriptional activity. This tumor suppressor effect is abrogated by the PC-associated SPOP mutations. These studies provide a possible explanation for the role of SPOP mutations in PC, and highlight the potential of SRC-3 as a therapeutic target in PC.
Assuntos
Regulação da Expressão Gênica/fisiologia , Proteínas Nucleares/genética , Coativador 3 de Receptor Nuclear/metabolismo , Neoplasias da Próstata/genética , Proteínas Repressoras/genética , Análise de Variância , Linhagem Celular Tumoral , Eletroforese em Gel de Poliacrilamida , Vetores Genéticos/genética , Células HEK293 , Humanos , Immunoblotting , Imunoprecipitação , Lentivirus , Masculino , Mutação de Sentido Incorreto/genética , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Receptores Androgênicos/metabolismo , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sais de Tetrazólio , TiazóisRESUMO
In this work, the effects of primary amines, ligand targeting, and overall charge on the effectiveness of branched poly(ethylenimine)-hyaluronic acid conjugate (bPEI-HA) zwitterionic gene delivery vectors are investigated. To elucidate the relative importance of each of these parameters, we explored the zeta potential, cytotoxicity, and transfection efficiency for a variety of formulations of bPEI-HA. It was found that the length of the hyaluronic acid (HA) oligosaccharide had the most significant effect on cytotoxicity and transfection efficiency with human mesenchymal stem cells. Test groups of bPEI incorporating HA with a length of 10 saccharides had significantly higher transfection efficiency (14.6 ± 2.0%) and lower cytotoxicity than other formulations tested, with the cytotoxicity of the group containing the greatest mass of 10 saccharide showing similar results as the positive controls at the highest polymer concentration (100 µg/mL). Additionally, molar incorporation of HA, as opposed to the saccharide length and HA mass incorporation, had the greatest effect on zeta potential but a minor effect on both cytotoxicity and transfection efficiency. This work demonstrates the relative importance of each of these tunable design criteria when creating a zwitterionic polymeric gene delivery vector and provides useful specific information regarding the design of bPEI-HA gene delivery vectors.
Assuntos
Portadores de Fármacos/química , Técnicas de Transferência de Genes , Ácido Hialurônico/química , Polietilenoimina/química , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/farmacologia , Humanos , Ácido Hialurônico/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Polietilenoimina/farmacologia , Relação Estrutura-AtividadeRESUMO
Although advances have been made in cancer therapy, cancer remains the second leading cause of death in the U.S. and Europe, and thus efforts to continue to study and discover better treatment methods are ongoing. Three-dimensional (3D) tumor models have shown advantages over bi-dimensional (2D) cultures in evaluating the efficacy of chemotherapy. This commentary aims to highlight the potential of combined application of biomaterials with patient-derived cancer cells as a 3D in vitro model for the study and treatment of cancer patients. Five studies were discussed which demonstrate and provided early evidence to create 3D models with accurate microenvironments that are comparable to in vivo tumors. To date, the use of patient-derived cells for a more personalized approach to healthcare in combination with biomaterials to create a 3D tumor is still relatively new and uncommon for application in clinics. Although highly promising, it is important to acknowledge the current limitations and challenges of developing these innovative in vitro models, including the need for biologists and laboratory technicians to become familiar with biomaterial scaffolds, and the effort for bioengineers to create easy-to-handle scaffolds for routine assessment.
RESUMO
Background: Combination antiretroviral therapy has significantly advanced HIV-1 infection treatment. However, HIV-1 remains persistent in the brain; the inaccessibility of the blood-brain barrier allows for persistent HIV-1 infections and neuroinflammation. Nanotechnology-based drug carriers such as nanodiscoidal bicelles can provide a solution to combat this challenge. Methods: This study investigated the safety and extended release of a combination antiretroviral therapy drug (tenofovir)-loaded nanodiscs for HIV-1 treatment in the brain both in vitro and in vivo. Result: The nanodiscs entrapped the drug in their interior hydrophobic core and released the payload at the desired location and in a controlled release pattern. The study also included a comparative pharmacokinetic analysis of nanodisc formulations in in vitro and in vivo models. Conclusion: The study provides potential applications of nanodiscs for HIV-1 therapy development.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Tenofovir , Preparações de Ação Retardada/farmacologia , Infecções por HIV/tratamento farmacológico , Portadores de Fármacos/química , Encéfalo , Lipídeos/uso terapêutico , Fármacos Anti-HIV/uso terapêuticoRESUMO
PURPOSE: As the next step in the development of an intra-articular controlled release system to treat painful temporomandibular joint (TMJ) inflammation, we developed several biodegradable poly(DL-lactic-co-glycolic acid) (PLGA)-based microparticle (MP) formulations encapsulating a model anti-inflammatory small interfering RNA (siRNA) together with branched poly(ethylenimine) (PEI) as a transfecting agent. The effect of siRNA loading and N:P ratio on the release kinetics of siRNA-PEI polyplexes was determined, and the size and N:P ratio of the polyplexes released over time was characterized. METHODS: Polyplex-loaded PLGA MPs were prepared using an established double emulsion technique. Increasing the pH of the release samples enabled siRNA-PEI dissociation and subsequent measurement of the release of each component over 28 days. Polyplex diameter was measured for all release samples and compared to freshly prepared siRNA-PEI under simulated physiologic conditions. RESULTS: Systematic variation of siRNA loading and N:P ratio resulted in distinct siRNA and PEI release profiles. Polyplex diameter remained constant despite large variations in the relative amounts of siRNA and PEI. Excess PEI was sequestered through complexation with 500-1,000 nm diameter PLGA MP-derived particles, including small MPs and PLGA degradation products. CONCLUSIONS: These PLGA MP formulations show exciting potential as the first intra-articular TMJ controlled release system.
Assuntos
Iminas/química , Ácido Láctico/química , Microesferas , Osteíte/terapia , Polietilenos/química , Ácido Poliglicólico/química , RNA Interferente Pequeno/química , Implantes Absorvíveis , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Química Farmacêutica/métodos , Preparações de Ação Retardada , Emulsões , Concentração de Íons de Hidrogênio , Iminas/administração & dosagem , Injeções Intra-Articulares , Cinética , Ácido Láctico/administração & dosagem , Osteíte/genética , Tamanho da Partícula , Polietilenos/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , RNA Interferente Pequeno/administração & dosagem , Articulação TemporomandibularRESUMO
Glioblastoma multiforme (GBM) is the most prevalent and aggressive form of glioma, with poor prognosis and high mortality rates. As GBM is a highly vascularized cancer, antiangiogenic therapies to halt or minimize the rate of tumor growth are critical to improving treatment. In this review, antiangiogenic therapies, including small-molecule drugs, nucleic acids and proteins and peptides, are discussed. The authors further explore biomaterials that have been utilized to increase the bioavailability and bioactivity of antiangiogenic factors for better antitumor responses in GBM. Finally, the authors summarize the current status of biomaterial-based targeting moieties that target endothelial cells in GBM to more efficiently deliver therapeutics to these cells and avoid off-target cell or organ side effects.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Materiais Biocompatíveis/química , Materiais Biocompatíveis/uso terapêutico , Terapia Combinada , Docetaxel/química , Docetaxel/uso terapêutico , Humanos , Minociclina/química , Minociclina/uso terapêutico , Ácidos Nucleicos/química , Ácidos Nucleicos/uso terapêutico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêuticoRESUMO
Background: The utilization of iron oxide nanoparticles (Fe3O4 NPs) to control minocycline release rates from poly(lactic-co-glycolic acid) scaffolds fabricated from an easy/economical technique is presented. Results & methodology: A larger change in temperature and amount of minocycline released was observed for scaffolds with higher amounts of Fe3O4 NPs, demonstrating that nanoparticle concentration can control heat generation and minocycline release. Temperatures near a polymer's glass transition temperature can result in the polymer's chain becoming more mobile and thus increasing drug diffusion out of the scaffold. Elevated temperature and minocycline released from the scaffold can work synergistically to enhance glioblastoma cell death. Conclusion: This study suggests that Fe3O4 NPs are promising materials for controlling minocycline release from polymeric scaffolds by magnetic hyperthermia for the treatment of glioblastoma.
Assuntos
Antineoplásicos/farmacologia , Glioblastoma/tratamento farmacológico , Nanopartículas Magnéticas de Óxido de Ferro/química , Minociclina/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/patologia , Humanos , Minociclina/químicaRESUMO
In this work, biodegradable branched polycationic polymers were synthesized by Michael addition polymerization from different amine monomers and the triacrylate monomer trimethylolpropane triacrylate. The polymers varied in the number of amines that dissociate in different pH ranges, which are considered to be beneficial to different parts of the gene delivery process. P-DED, a polymer synthesized from trimethylolpropane triacrylate and dimethylethylenediamine, had the highest number of protonated amines that are available for plasmid DNA (pDNA) complexation at pH 7.4 of all polymers synthesized. P-DED formed a positive polyplex (13.9 +/- 0.5 mV) at a polymer/pDNA weight ratio of 10:1 in contrast with the other polymers synthesized, which formed positive polyplexes only at higher weight ratios. Polyplexes formed with the synthesized polymers at the highest polymer/pDNA weight ratio tested (300:1) resulted in higher transfection with enhanced green fluorescent protein reporter gene (5.3 +/- 1.0 to 30.6 +/- 6.6%) compared with naked pDNA (0.8 +/- 0.4%), as quantified by flow cytometry. Polyplexes formed with P-DED (weight ratio of 300:1) also showed higher transfection (30.6 +/- 6.6%) as compared with polyplexes formed with branched polyethylenimine (weight ratio of 2:1, 25.5 +/- 2.7%). The results from this study demonstrated that polymers with amines that dissociate above pH 7.4, which are available as positively charged groups for pDNA complexation at pH 7.4, can be synthesized to produce stable polyplexes with increased zeta potential and decreased hydrodynamic size that efficiently transfect cells. This work indicated that polymers containing varying amine functionalities with different buffering capabilities can be synthesized by using different amine monomers and used as effective gene delivery vectors.
Assuntos
Aminas/química , Técnicas de Transferência de Genes , Animais , Cromatografia em Gel , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Peso Molecular , RatosRESUMO
Angiogenesis is an important process in tissue repair and regeneration as blood vessels are integral to supply nutrients to a functioning tissue. In this review, the application of microRNAs (miRNAs) or anti-miRNAs that can induce angiogenesis to aid in blood vessel formation for vascular tissue engineering in ischemic diseases such as peripheral arterial disease and stroke, cardiac diseases, and skin and bone tissue engineering is discussed. Endothelial cells (ECs) form the endothelium of the blood vessel and are recognized as the primary cell type that drives angiogenesis and studied in the applications that were reviewed. Besides ECs, mesenchymal stem cells can also play a pivotal role in these applications, specifically, by secreting growth factors or cytokines for paracrine signaling and/or as constituent cells in the new blood vessel formed. In addition to delivering miRNAs or cells transfected/transduced with miRNAs for angiogenesis and vascular tissue engineering, the utilization of extracellular vesicles (EVs), such as exosomes, microvesicles, and EVs collectively, has been more recently explored. Proangiogenic miRNAs and anti-miRNAs contribute to angiogenesis by targeting the 3'-untranslated region of targets to upregulate proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and hypoxia-inducible factor-1 and increase the transduction of VEGF signaling through the PI3K/AKT and Ras/Raf/MEK/ERK signaling pathways such as phosphatase and tensin homolog or regulating the signaling of other pathways important for angiogenesis such as the Notch signaling pathway and the pathway to produce nitric oxide. In conclusion, angiogenesis-inducing miRNAs and anti-miRNAs are promising tools for vascular tissue engineering for several applications; however, future work should emphasize optimizing the delivery and usage of these therapies as miRNAs can also be associated with the negative implications of cancer.
Assuntos
Endotélio Vascular , MicroRNAs , Neovascularização Fisiológica , Engenharia Tecidual , Proliferação de Células , Células Endoteliais , Humanos , MicroRNAs/genética , Transdução de SinaisRESUMO
Biodegradable branched polycationic polymers with varying hydrophilic spacer lengths were synthesized from different triacrylate monomers and the amine monomer 1-(2-aminoethyl)piperazine by Michael addition polymerization. The hydrophilic spacers were varied by the number of ethyleneoxy groups in the triacrylate monomer (E/M) that ranged from 0 to 14. The polymer degradation depended on the spacer length and pH; the amount of ester degraded as determined by (1)H NMR after 14 days was 43.4 +/- 2.1% (pH 5.0) and 89.7 +/- 1.3% (pH 7.4) for the polymer with 0 E/M compared to 55.7 +/- 2.6% (pH 5.0) and 98.5 +/- 1.6% (pH 7.4) for the polymer with 14 E/M. Cell viability of rat fibroblasts after exposure to polymer solutions of concentrations up to 1000 microg/mL remained high (above 66.9 +/- 12.1% compared to below 7.6 +/- 1.1% for polyethylenimine at a concentration of 50 microg/mL or higher) and increased with the spacer length. The polyplexes made with all the synthesized polymers showed higher transfection efficiency (4.5 +/- 1.7% to 9.4 +/- 2.0%, dependent on the polymer/pDNA weight ratio) with an enhanced green fluorescent protein reporter gene compared to naked pDNA (0.8 +/- 0.4%) as quantified by flow cytometry. This study demonstrates that hydrophilic spacers can be incorporated into polycationic polymers to reduce their cytotoxicity and enhance their degradability for nonviral gene delivery.
Assuntos
Técnicas de Transferência de Genes , Polímeros/síntese química , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Fibroblastos/citologia , Poliaminas/síntese química , Poliaminas/química , Poliaminas/farmacologia , Polieletrólitos , Polímeros/química , Polímeros/farmacologia , Ratos , Eletricidade EstáticaRESUMO
More than 70 % of women with ovarian cancer are diagnosed with advanced-stage disease, which is initially treated with cytoreductive surgery, and combination chemotherapy with platinum-based compounds. Most patients initially respond to platinum-based therapy, but eventually up to 80 % of this responsive cohort becomes refractory due to the development of platinum resistance. This review discusses current and potential therapeutic approaches that exploit biomaterial-based applications to combat platinum resistance either by enhancing the delivery of platinum-based drugs or prodrugs, delivering other toxic non-platinum-based bioactive factors (by themselves or in combination with platinum-based drugs) or by delivering other bioactive factors that re-sensitize resistant ovarian cancer cells to these drugs. The types of materials that are used, the bioactive factors applied (i.e., drug or gene delivery), and the specific agents that are employed to target these types of cancer cells are discussed. We conclude that the unique attributes of biomaterial-based applications can be further explored toward overcoming platinum-resistant ovarian cancer as monotherapy, or in combination with other treatment strategies.
Assuntos
Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/química , Materiais Biocompatíveis/química , Reparo do DNA , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Feminino , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Compostos Organoplatínicos/química , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/metabolismoRESUMO
Glioblastoma multiforme (GBM) is the most common and invasive form of malignant brain tumors and despite advances in surgery, radiotherapy, and chemotherapy, the survival of patients with GBM still remains poor. Temozolomide (TMZ) is the chemotherapy drug that is most commonly given orally after surgical resection of these tumors. In this study, the effects of solvents (i.e., dichloromethane and acetonitrile) used for the fabrication of electrosprayed TMZ-loaded poly(lactic-co-glycolic acid) (PLGA) on drug loading, loading efficiency, drug release kinetics, surface morphology, and particle size were investigated. The results from this study demonstrated that by using a larger volume of a solvent with higher polarity (i.e., acetonitrile) which allows for a higher amount of hydrophilic TMZ to dissolve into the polymer solution, higher drug loading could be achieved. However, the particles fabricated with high amount of acetonitrile, which has a lower vapor pressure, had large pores and a smaller diameter which led to an initial burst release and high cumulative release at the end of the study. An optimal combination of the two solvents is needed to result in particles with a good amount of loading and minimal initial burst release. The electrosprayed microparticles were able to illicit a cytotoxic response in U-87 MG glioblastoma cells at a lower concentration of drug compared to the free drug. This work indicated that electrospraying is a promising method for the fabrication of TMZ-loaded PLGA microparticles for the treatment of GBM and solvent composition can be altered to control drug loading and release kinetics. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2317-2324, 2019.
Assuntos
Glioblastoma/tratamento farmacológico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Temozolomida , Linhagem Celular Tumoral , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Temozolomida/química , Temozolomida/farmacocinética , Temozolomida/farmacologiaRESUMO
In recent years, the application of microRNAs (miRNAs) or anti-microRNAs (anti-miRNAs) that can induce expression of the runt-related transcription factor 2 (RUNX2), a master regulator of osteogenesis, has been investigated as a promising alternative bone tissue engineering strategy. In this review, biomaterial scaffold-based applications that have been used to deliver cells expressing miRNAs or anti-miRNAs that induce expression of RUNX2 for bone tissue engineering are discussed. An overview of the components of the scaffold-based therapies including the miRNAs/anti-miRNAs, cell types, gene delivery vectors, and scaffolds that have been applied are provided. To date, there have been nine miRNAs/anti-miRNAs (i.e., miRNA-26a, anti-miRNA-31, anti-miRNA-34a, miRNA-135, anti-miRNA-138, anti-miRNA-146a, miRNA-148b, anti-miRNA-221, and anti-miRNA-335) that have been incorporated into scaffold-based bone tissue engineering applications and investigated in an in vivo bone critical-sized defect model. For all of the biomaterial scaffold-based miRNA therapies that have been developed thus far, cells that are transfected or transduced with the miRNA/anti-miRNA are loaded into the scaffolds and implanted at the site of interest instead of locally delivering the miRNA/anti-miRNAs directly from the scaffolds. Thus, future work may focus on developing biomaterial scaffolds to deliver miRNAs or anti-miRNAs into cells in vivo.
Assuntos
Osso e Ossos/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , MicroRNAs/genética , Animais , Transplante Ósseo , Humanos , Engenharia Tecidual , Alicerces Teciduais , Via de Sinalização WntRESUMO
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer diagnosed and the second leading cause of death worldwide. Despite advancement in current treatments for HCC, the prognosis for this cancer is still unfavorable. This comprehensive review article focuses on all the current technology that applies biomaterials to treat and study liver cancer, thus showing the versatility of biomaterials to be used as smart tools in this complex pathologic scenario. Specifically, after introducing the liver anatomy and pathology by focusing on the available treatments for HCC, this review summarizes the current biomaterial-based approaches for systemic delivery and implantable tools for locally administrating bioactive factors and provides a comprehensive discussion of the specific therapies and targeting agents to efficiently deliver those factors. This review also highlights the novel application of biomaterials to study HCC, which includes hydrogels and scaffolds to tissue engineer 3D in vitro models representative of the tumor environment. Such models will serve to better understand the tumor biology and investigate new therapies for HCC. Special focus is given to innovative approaches, e.g., combined delivery therapies, and to alternative approaches-e.g., cell capture-as promising future trends in the application of biomaterials to treat HCC.
RESUMO
This review article focuses on the current local therapies mediated by implanted macroscaled biomaterials available or proposed for fighting cancer and also highlights the upcoming research in this field. Several authoritative review articles have collected and discussed the state-of-the-art as well as the advancements in using biomaterial-based micro- and nano-particle systems for drug delivery in cancer therapy. On the other hand, implantable biomaterial devices are emerging as highly versatile therapeutic platforms, which deserve an increased attention by the healthcare scientific community, as they are able to offer innovative, more effective and creative strategies against tumors. This review summarizes the current approaches which exploit biomaterial-based devices as implantable tools for locally administrating drugs and describes their specific medical applications, which mainly target resected brain tumors or brain metastases for the inaccessibility of conventional chemotherapies. Moreover, a special focus in this review is given to innovative approaches, such as combined delivery therapies, as well as to alternative approaches, such as scaffolds for gene therapy, cancer immunotherapy and metastatic cell capture, the later as promising future trends in implantable biomaterials for cancer applications.
Assuntos
Materiais Biocompatíveis , Terapia Genética/métodos , Imunoterapia/métodos , Implantes Experimentais , Neoplasias/terapia , Animais , Implantes de Medicamento , HumanosRESUMO
In this work, PLGA scaffolds with different architectures were fabricated to investigate the effects of surface area to volume ratio (SVR) (which resulted from the different architectures) on scaffold degradation characteristics and drug release kinetics with minocycline as the model drug. It was hypothesized that the thin strand scaffolds, which had the highest SVR, would degrade faster than the thick strand and globular scaffolds as the increase in surface area will allow more contact between water molecules and degradable ester groups in the polymer. However, it was found that globular scaffolds, which had the lowest SVR, resulted in the fastest degradation which demonstrated that the amount of degradation of the scaffolds does not only depend on the SVR but also on other factors such as the retention of acidic degradation byproducts in the scaffold and scaffold porosity. PLGA 50 : 50 globular scaffolds resulted in a biphasic release profile, with a burst release in the beginning and the middle of the release study which may be beneficial for some drug delivery applications. A clear correlation between SVR and release rates was not observed, indicating that besides the availability of more surface area for drug to diffuse out of the polymer matrix, other factors such as amount of scaffold degradation and scaffold porosity may play a role in determining drug release kinetics. Further studies, such as scanning electron microscopy, need to be performed in the future to further evaluate the porosity, morphology and structure of the scaffolds.
Assuntos
Materiais Biocompatíveis/química , Sistemas de Liberação de Medicamentos/métodos , Ácido Láctico/química , Ácido Poliglicólico/química , Alicerces Teciduais/química , Liberação Controlada de Fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , PorosidadeRESUMO
The p160 family of steroid receptor coactivators (SRCs) are pleiotropic transcription factor coactivators and "master regulators" of gene expression that promote cancer cell proliferation, survival, metabolism, migration, invasion, and metastasis. Cancers with high p160 SRC expression exhibit poor clinical outcomes and resistance to therapy, highlighting the SRCs as critical oncogenic drivers and, thus, therapeutic targets. microRNAs are important epigenetic regulators of protein expression. To examine the regulation of p160 SRCs by microRNAs, we used and combined 4 prediction algorithms to identify microRNAs that could target SRC1, SRC2, and SRC3 expression. For validation of these predictions, we assessed p160 SRC protein expression and cell viability after transfection of corresponding microRNA mimetics in breast cancer, uveal melanoma, and prostate cancer (PC) cell lines. Transfection of selected microRNA mimetics into breast cancer, uveal melanoma, and PC cells depleted SRC protein expression levels and exerted potent antiproliferative activity in these cell types. In particular, microRNA-137 (miR-137) depleted expression of SRC1, SRC2, and very potently, SRC3. The latter effect can be attributed to the presence of 3 miR-137 recognition sequences within the SRC3 3'-untranslated region. Using reverse phase protein array analysis, we identified a network of proteins, in addition to SRC3, that were modulated by miR-137 in PC cells. We also found that miR-137 and its host gene are epigenetically silenced in human cancer specimens and cell lines. These results support the development and testing of microRNA-based therapies (in particular based on restoring miR-137 levels) for targeting the oncogenic family of p160 SRCs in cancer.
Assuntos
Proliferação de Células , MicroRNAs/metabolismo , Coativador 1 de Receptor Nuclear/metabolismo , Coativador 2 de Receptor Nuclear/metabolismo , Coativador 3 de Receptor Nuclear/metabolismo , Linhagem Celular Tumoral , Biologia Computacional , Metilação de DNA , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Células HEK293 , Histonas/química , Humanos , Células MCF-7 , Masculino , Mutação , Proteômica , Ativação TranscricionalRESUMO
PURPOSE: Uveal melanoma (UM) tumors require large doses of radiation therapy (RT) to achieve tumor ablation, which frequently results in damage to adjacent normal tissues, leading to vision-threatening complications. Approximately 50% of UM patients present with activating somatic mutations in the gene encoding for G protein αq-subunit (GNAQ), which lead to constitutive activation of downstream pathways, including protein kinase C (PKC). In this study, we investigated the impact of small-molecule PKC inhibitors bisindolylmaleimide I (BIM) and sotrastaurin (AEB071), combined with ionizing radiation (IR), on survival in melanoma cell lines. METHODS: Cellular radiosensitivity was determined by using a combination of proliferation, viability, and clonogenic assays. Cell-cycle effects were measured by flow cytometry. Transcriptomic and proteomic profiling were performed by quantitative real-time PCR, reverse-phase protein array analysis, and immunofluorescence. RESULTS: We found that the PKC inhibitors combined with IR significantly decreased the viability, proliferation, and clonogenic potential of GNAQ(mt), but not GNAQ(wt)/BRAF(mt) cells, compared with IR alone. Combined treatment increased the antiproliferative and proapoptotic effects of IR in GNAQ(mt) cells through delayed DNA-damage resolution and enhanced induction of proteins involved in cell-cycle arrest, cell-growth arrest, and apoptosis. CONCLUSIONS: Our preclinical results suggest that combined modality treatment may allow for reductions in the total RT dose and/or fraction size, which may lead to better functional organ preservation in the treatment of primary GNAQ(mt) UM. These findings suggest future clinical trials combining PKC inhibitors with RT in GNAQ(mt) UM warrant consideration.