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1.
Biomed Pharmacother ; 146: 112531, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34906771

RESUMO

Despite the promising medicinal properties, berberine (BBR), due to its relatively poor solubility in plasma, low bio-stability and limited bioavailability is not used broadly in clinical stages. Due to these drawbacks, drug delivery systems (DDSs) based on nanoscale natural polysaccharides, are applied to address these concerns. Natural polymers are biodegradable, non-immunogenic, biocompatible, and non-toxic agents that are capable of trapping large amounts of hydrophobic compounds in relatively small volumes. The use of nanoscale natural polysaccharide improves the stability and pharmacokinetics of the small molecules and, consequently, increases the therapeutic effects and reduces the side effects of the small molecules. Therefore, this paper presents an overview of the different methods used for increasing the BBR solubility and bioavailability. Afterwards, the pharmacodynamic and pharmacokinetic of BBR nanostructures were discussed followed by the introduction of natural polysaccharides of plant (cyclodextrines, glucomannan), the shells of crustaceans (chitosan), and the cell wall of brown marine algae (alginate)-based origins used to improve the dissolution rate of poorly soluble BBR and their anticancer and antibacterial properties. Finally, the anticancer and antibacterial mechanisms of free BBR and BBR nanostructures were surveyed. In conclusion, this review may pave the way for providing some useful data in the development of BBR-based platforms for clinical applications.

2.
Biomed Pharmacother ; 146: 112251, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34916087

RESUMO

Thyroid cancer (TC) is the most prevalent malignancy of the endocrine system. Although there are few treatment choices for individuals with TC, determining the underlying mechanisms is essential for treatment due to the complex carcinogenesis of this disease. Recent pieces of evidence suggest that non-coding RNAs (ncRNAs) play an important role in the progression of TC. Nevertheless, the role and function of the complex regulatory interactions between multiple types of ncRNAs in the growth of this malignancy remains unknown. Competing endogenous RNA (ceRNA) is a recently found mechanism that suggests regulatory interactions between various RNAs. It has been proposed that some ncRNAs, such as long noncoding RNAs (lncRNAs), pseudogenes and circular RNAs (circRNAs), can share microRNA (miRNA) response elements, which may influence miRNA interaction with target RNAs and by doing so modulate gene expression at the transcriptional level. According to the analysis of relevant literature, numerous ceRNA networks are deregulated during TC development, metastasis, migration, invasion, epithelial-mesenchymal transition (EMT), and drug resistance. As a result, learning more about these deregulations could lead to earlier diagnosis of TC patients and the discovery of effective therapeutic targets. In this review we outline the current body of information regarding the essential roles of ceRNA networks and highlight the emerging roles of some newfound ceRNA members in different TC hallmarks.

3.
Sci Rep ; 11(1): 20389, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34650162

RESUMO

Endothelial cells and pericytes are highly dynamic vascular cells and several subtypes, based on their spatiotemporal dynamics or molecular expression, are believed to exist. The interaction between endothelial cells and pericytes is of importance in many aspects ranging from basic development to diseases like cancer. Identification of spatiotemporal dynamics is particularly interesting and methods to studies these are in demand. Here we describe the technical details of a method combining the benefits of high resolution intravital imaging and whole-mount histology. With intravital imaging using an adapted light weight dorsal skinfold chamber we identified blood flow patterns and spatiotemporal subtypes of endothelial cells and pericytes in a 4D (XYZ, spatial+T, time dimension) manner as representative examples for this model. Thereafter the tissue was extracted and stained as a whole-mount, by which the position and volumetric space of endothelial cells as well as pericytes were maintained, to identify molecular subtypes. Integration of the two imaging methods enabled 4D dissection of endothelial cell-pericyte association at the molecular level.

4.
Cancers (Basel) ; 13(20)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34680296

RESUMO

This paper presents three devices suitable for the preclinical application of hyperthermia via the simultaneous high-resolution imaging of intratumoral events. (Pre)clinical studies have confirmed that the tumor micro-environment is sensitive to the application of local mild hyperthermia. Therefore, heating is a promising adjuvant to aid the efficacy of radiotherapy or chemotherapy. More so, the application of mild hyperthermia is a useful stimulus for triggered drug release from heat-sensitive nanocarriers. The response of thermosensitive nanoparticles to hyperthermia and ensuing intratumoral kinetics are considerably complex in both space and time. To obtain better insight into intratumoral processes, longitudinal imaging (preferable in high spatial and temporal resolution) is highly informative. Our devices are based on (i) an external electric heating adaptor for the dorsal skinfold model, (ii) targeted radiofrequency application, and (iii) a microwave antenna for heating of internal tumors. These models, while of some technical complexity, significantly add to the understanding of effects of mild hyperthermia warranting implementation in research on hyperthermia.

5.
Cancers (Basel) ; 13(18)2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34572855

RESUMO

Preclinical studies have shown that application of mild hyperthermia (40-43 °C) is a promising adjuvant to solid tumor treatment. To improve preclinical testing, enhance reproducibility, and allow comparison of the obtained results, it is crucial to have standardization of the available methods. Reproducibility of methods in and between research groups on the same techniques is crucial to have a better prediction of the clinical outcome and to improve new treatment strategies (for instance with heat-sensitive nanoparticles). Here we provide a preclinically oriented review on the use and applicability of basic hyperthermia systems available for solid tumor thermal treatment in small animals. The complexity of these techniques ranges from a simple, low-cost water bath approach, irradiation with light or lasers, to advanced ultrasound and capacitive heating devices.

6.
J Control Release ; 338: 341-357, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-34428480

RESUMO

Microneedle arrays have recently received much attention as cancer detection and treatment platforms, because invasive injections and detection of the biopsy are not needed, and drug metabolism by the liver, as well as adverse effects of systemic drug administration, are diminished. Microneedles have been used for diagnosis, vaccination, and in targeted drug delivery of breast cancer. In this review, we summarize the recent progress in diagnosis and targeted drug delivery for breast cancer treatment, using microneedle arrays to deliver active molecules through the skin. The results not only suggest that health and well-being of patients are improved, but also that microneedle arrays can deliver anticancer compounds in a relatively noninvasive manner, based on body weight, breast tumor size, and circulation time of the drug. Moreover, microneedles could allow simultaneous loading of multiple drugs and enable controlled release, thus effectively optimizing or preventing drug-drug interactions. This review is designed to encourage the use of microneedles for diagnosis and treatment of breast cancer, by describing general properties of microneedles, materials used for construction, mechanism of action, and principal benefits. Ongoing challenges and future perspectives for the application of microneedle array systems in breast cancer detection and treatment are highlighted.


Assuntos
Neoplasias da Mama , Administração Cutânea , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Microinjeções , Agulhas , Pele/metabolismo
7.
Commun Biol ; 4(1): 920, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321602

RESUMO

Intravascular triggered drug delivery systems (IV-DDS) for local drug delivery include various stimuli-responsive nanoparticles that release the associated agent in response to internal (e.g., pH, enzymes) or external stimuli (e.g., temperature, light, ultrasound, electromagnetic fields, X-rays). We developed a computational model to simulate IV-DDS drug delivery, for which we quantified all model parameters in vivo in rodent tumors. The model was validated via quantitative intravital microscopy studies with unencapsulated fluorescent dye, and with two formulations of temperature-sensitive liposomes (slow, and fast release) encapsulating a fluorescent dye as example IV-DDS. Tumor intra- and extravascular dye concentration dynamics were extracted from the intravital microscopy data by quantitative image processing, and were compared to computer model results. Via this computer model we explain IV-DDS delivery kinetics and identify parameters of IV-DDS, of drug, and of target tissue for optimal delivery. Two parameter ratios were identified that exclusively dictate how much drug can be delivered with IV-DDS, indicating the importance of IV-DDS with fast drug release (~sec) and choice of a drug with rapid tissue uptake (i.e., high first-pass extraction fraction). The computational model thus enables engineering of improved future IV-DDS based on tissue parameters that can be quantified by imaging.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Corantes Fluorescentes/química , Cinética , Lipossomos/química , Nanopartículas/metabolismo , Temperatura
8.
Hum Mol Genet ; 30(23): 2286-2299, 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34244757

RESUMO

Aortic aneurysms (AAs) are pathological dilatations of the aorta. Pathogenic variants in genes encoding for proteins of the contractile machinery of vascular smooth muscle cells (VSMCs), genes encoding proteins of the transforming growth factor beta signaling pathway and extracellular matrix (ECM) homeostasis play a role in the weakening of the aortic wall. These variants affect the functioning of VSMC, the predominant cell type in the aorta. Many variants have unknown clinical significance, with unknown consequences on VSMC function and AA development. Our goal was to develop functional assays that show the effects of pathogenic variants in aneurysm-related genes. We used a previously developed fibroblast transdifferentiation protocol to induce VSMC-like cells, which are used for all assays. We compared transdifferentiated VSMC-like cells of patients with a pathogenic variant in genes encoding for components of VSMC contraction (ACTA2, MYH11), transforming growth factor beta (TGFß) signaling (SMAD3) and a dominant negative (DN) and two haploinsufficient variants in the ECM elastic laminae (FBN1) to those of healthy controls. The transdifferentiation efficiency, structural integrity of the cytoskeleton, TGFß signaling profile, migration velocity and maximum contraction were measured. Transdifferentiation efficiency was strongly reduced in SMAD3 and FBN1 DN patients. ACTA2 and FBN1 DN cells showed a decrease in SMAD2 phosphorylation. Migration velocity was impaired for ACTA2 and MYH11 cells. ACTA2 cells showed reduced contractility. In conclusion, these assays for showing effects of pathogenic variants may be promising tools to help reclassification of variants of unknown clinical significance in AA-related genes.

9.
J Nanobiotechnology ; 19(1): 102, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849551

RESUMO

BACKGROUND: The immunomodulation of the antitumor response driven by immunocheckpoint inhibitors (ICIs) such as PD-L1 (Programmed Death Ligand-1) monoclonal antibody (α-PD-L1) have shown relevant clinical outcomes in a subset of patients. This fact has led to the search for rational combinations with other therapeutic agents such as Doxorubicin (Dox), which cytotoxicity involves an immune activation that may enhance ICI response. Therefore, this study aims to evaluate the combination of chemotherapy and ICI by developing Dox Immunoliposomes functionalized with monovalent-variable fragments (Fab') of α-PD-L1. RESULTS: Immunoliposomes were assayed in vitro and in vivo in a B16 OVA melanoma murine cell line over-expressing PD-L1. Here, immune system activation in tumor, spleen and lymph nodes, together with the antitumor efficacy were evaluated. Results showed that immunoliposomes bound specifically to PD-L1+ cells, yielding higher cell interaction and Dox internalization, and decreasing up to 30-fold the IC50, compared to conventional liposomes. This mechanism supported a higher in vivo response. Indeed, immunoliposomes promoted full tumor regression in 20% of mice and increased in 1 month the survival rate. This formulation was the only treatment able to induce significant (p < 0.01) increase of activated tumor specific cytotoxic T lymphocytes at the tumor site. CONCLUSION: PD-L1 targeted liposomes encapsulating Dox have proved to be a rational combination able to enhance the modulation of the immune system by blocking PD-L1 and selectively internalizing Dox, thus successfully providing a dual activity offered by both, chemo and immune therapeutic strategies.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/metabolismo , Doxorrubicina/farmacologia , Imunidade/efeitos dos fármacos , Lipossomos/imunologia , Melanoma/tratamento farmacológico , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Tratamento Farmacológico , Feminino , Imunoterapia/métodos , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL
10.
Theranostics ; 11(12): 5700-5712, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897876

RESUMO

Rationale: Increasing the bioavailable drug level in a tumor is the key to enhance efficacy of chemotherapy. Thermosensitive smart drug delivery systems (SDDS) in combination with local hyperthermia facilitate high local drug levels, thus improving uptake in the tumor. However, inability to rapidly and efficiently absorb the locally released drug results in reduced efficacy, as well as undesired redistribution of the drug away from the tumor to the system. Methods: Based on this paradigm we propose a novel approach in which we replaced doxorubicin (DXR), one of the classic drugs for nanocarrier-based delivery, with idarubicin (IDA), a hydrophobic anthracycline used solely in the free form for treatment hematologic cancers. We established a series of in vitro and in vivo experiments to in depth study the kinetics of SDDS-based delivery, drug release, intratumor biodistribution and subsequent cell uptake. Results: We demonstrate that IDA is taken up over 10 times more rapidly by cancer cells than DXR in vitro. Similar trend is observed in in vivo online imaging and less drug redistribution is shown for IDA, together resulting in 4-times higher whole tumor drug uptake for IDA vs. DXR. Together his yielded an improved intratumoral drug distribution for IDA-SDDS, translating into superior tumor response compared to DXR-SDDS treatment at the same dose. Thus, IDA - a drug that is not used for treatment of solid cancers - shows superior therapeutic index and better outcome when administered in externally triggered SDDS. Conclusions: We show that a shift in selection of chemotherapeutics is urgently needed, away from the classic drugs towards selection based on properties of a chemotherapeutic in context of the nanoparticle and delivery mode, to maximize the therapeutic efficacy.


Assuntos
Idarubicina/farmacologia , Idarubicina/farmacocinética , Neoplasias/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Hipertermia Induzida/métodos , Cinética , Camundongos , Nanopartículas/química , Neoplasias/metabolismo , Distribuição Tecidual/efeitos dos fármacos
11.
Pharmaceutics ; 14(1)2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-35056922

RESUMO

Cancer immunotherapy, a promising and widely applied mode of oncotherapy, makes use of immune stimulants and modulators to overcome the immune dysregulation present in cancer, and leverage the host's immune capacity to eliminate tumors. Although some success has been seen in this field, toxicity and weak immune induction remain challenges. Liposomal nanosystems, previously used as targeting agents, are increasingly functioning as immunotherapeutic vehicles, with potential for delivery of contents, immune induction, and synergistic drug packaging. These systems are tailorable, multifunctional, and smart. Liposomes may deliver various immune reagents including cytokines, specific T-cell receptors, antibody fragments, and immune checkpoint inhibitors, and also present a promising platform upon which personalized medicine approaches can be built, especially with preclinical and clinical potentials of liposomes often being frustrated by inter- and intrapatient variation. In this review, we show the potential of liposomes in cancer immunotherapy, as well as the methods for synthesis and in vivo progression thereof. Both preclinical and clinical studies are included to comprehensively illuminate prospects and challenges for future research and application.

12.
Pharmaceutics ; 12(11)2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33105816

RESUMO

Nanotechnology has great capability in formulation, reduction of side effects, and enhancing pharmacokinetics of chemotherapeutics by designing stable or long circulating nano-carriers. However, effective drug delivery at the cellular level by means of such carriers is still unsatisfactory. One promising approach is using spatiotemporal drug release by means of nanoparticles with the capacity for content release triggered by internal or external stimuli. Among different stimuli, interests for application of external heat, hyperthermia, is growing. Advanced technology, ease of application and most importantly high level of control over applied heat, and as a result triggered release, and the adjuvant effect of hyperthermia in enhancing therapeutic response of chemotherapeutics, i.e., thermochemotherapy, make hyperthermia a great stimulus for triggered drug release. Therefore, a variety of temperature sensitive nano-carriers, lipid or/and polymeric based, have been fabricated and studied. Importantly, in order to achieve an efficient therapeutic outcome, and taking the advantages of thermochemotherapy into consideration, release characteristics from nano-carriers should fit with applicable clinical thermal setting. Here we introduce and discuss the application of the three most studied temperature sensitive nanoparticles with emphasis on release behavior and its importance regarding applicability and therapeutic potentials.

13.
Nanoscale ; 12(32): 16967-16979, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32780078

RESUMO

Nanoparticles such as liposomes are able to overcome cancer treatment challenges such as multidrug resistance by increasing the bioavailability of the encapsulated drug, bypassing drug pumps or through targeting resistant cells. Here, we merge enhanced drug delivery by nanotechnology with tumor cell membrane modulation combined in a single formulation. This is achieved through the incorporation of Short chain sphingolipids (SCSs) in the liposomal composition, which permeabilizes cell membranes to amphiphilic drugs such as Doxorubicin (Dxr). To study the mechanism and capability of SCS-containing nanodevices to overcome Dxr resistance, a sensitive uterine sarcoma cell line, MES-SA, and a resistant derived cell line, MES-SA/MX2, were used. The mechanism of resistance was explored by lipidomics and flow cytometry, revealing significant differences in lipid composition and in P glycoprotein (Pgp) expression. In vitro assays show that SCS liposomes were able to reverse cell resistance, and importantly, display a higher net effect on resistant than sensitive cells. SCS lipids modulated the cell membrane of MES-SA/MX2 drug resistant cells, while Pgp expression was not affected. Furthermore, SCS-modified liposomes were evaluated in a sarcoma xenograft model on drug accumulation, pharmacokinetics and efficacy. SCS liposomes improved Dxr levels in tumor nuclei of MES-SA/MX2 tumor cells, which was accompanied by a delay in tumor growth of the resistant model. Here we show that Dxr accumulation in tumor cells by SCS-modified liposomes was especially improved in Dxr resistant cells, rendering Dxr as effective as in sensitive cells. Moreover, this phenomenon translated to improved efficacy when Dxr liposomes where modified with SCSs in the drug resistant tumor model, while no benefit was seen in the sensitive tumors.


Assuntos
Nanopartículas , Sarcoma , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Lipossomos , Sarcoma/tratamento farmacológico , Esfingolipídeos
14.
J Control Release ; 324: 669-678, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32512013

RESUMO

Thermosensitive liposomes, as one of the stimuli-responsive drug delivery systems, receive growing attention, due to their ability to generate rapid and massive drug release in the heated area, and marginal release of contents in non-heated parts of the body. This typical triggered release behavior cannot be fitted adequately by most of the current mathematical kinetic models. The aim of this study was to establish the proper kinetic equation to describe the rapid release of drugs from trigger-sensitive drug delivery systems. We summarized all commonly used kinetic models mentioned in the literature and fitted the release data with these models, finding that only the Korsmeyer-Peppas and the Weibull models show acceptable fitting results. To better describe the release from thermosensitive liposomes with a size below 100 nm, we took Laplace pressure as a release-driving force and proposed a new equation that demonstrates improved fitting in liposomes ranging down to a size of 70 nm. Our new kinetic model shows desirable fitting, not only at the optimal temperature but also of releases within the whole release-temperature range, providing a useful kinetic model to describe release profiles of smaller nano-sized stimuli-responsive drug delivery systems.


Assuntos
Sistemas de Liberação de Medicamentos , Lipossomos , Liberação Controlada de Fármacos , Cinética , Temperatura
15.
Cancers (Basel) ; 12(5)2020 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-32429338

RESUMO

Antibodies-recognising peptides bound to the major histocompatibility complex (pMHC) represent potentially valuable and promising targets for chimeric antigen receptor (CAR) T cells to treat patients with cancer. Here, a human phage-Fab library has been selected using HLA-A2 complexed with a heteroclitic peptide variant from an epitope shared among multiple melanoma-associated antigens (MAGEs). DNA restriction analyses and phage ELISAs confirmed selection of unique antibody clones that specifically bind to HLA-A2 complexes or HLA-A2-positive target cells loaded with native or heteroclitic peptide. Antibodies selected against heteroclitic peptide, in contrast to native peptide, demonstrated significantly lower to even negligible binding towards native peptide or tumour cells that naturally expressed peptides. The binding to native peptide was not rescued by phage panning with antigen-positive tumour cells. Importantly, when antibodies directed against heteroclitic peptides were engineered into CARs and expressed by T cells, binding to native peptides and tumour cells was minimal to absent. In short, TCR-like antibodies, when isolated from a human Fab phage library using heteroclitic peptide, fail to recognise its native peptide. We therefore argue that peptide modifications to improve antibody selections should be performed with caution as resulting antibodies, either used directly or as CARs, may lose activity towards endogenously presented tumour epitopes.

16.
Biochim Biophys Acta Mol Basis Dis ; 1866(8): 165776, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32222541

RESUMO

HOXA13 overexpression has been detected in human ESCC tissue and high HOXA13 protein expression is correlated with a shorter median survival time in ESCC patients. Although aberrant expression of HOXA13 in ESCC has thus been established, little is known regarding the functional consequences thereof. The present study aimed to examine to what extent aberrant HOXA13 might drive carcinogenesis in esophageal keratinocytes. To this end, we overexpressed HOXA13 in a non-transformed human esophageal cell line EPC2-hTERT, performed gene expression profiling to identify key processes and functions, and performed functional experiments. We found that HOXA13 expression confers oncogenic hallmarks to esophageal keratinocytes. It provides proliferation advantage to keratinocytes, reduces sensitivity to chemical agents, regulates MHC class I expression and differentiation status and promotes cellular migration. Our data indicate a crucial role of HOXA13 at early stages of esophageal carcinogenesis.


Assuntos
Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Neoplasias/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Adesão Celular , Diferenciação Celular , Linhagem Celular Transformada , Movimento Celular , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Esôfago/metabolismo , Esôfago/patologia , Perfilação da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Queratina-19/genética , Queratina-19/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Proteínas de Neoplasias/classificação , Proteínas de Neoplasias/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Transdução de Sinais , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Análise de Sobrevida
17.
Photochem Photobiol ; 96(3): 708-717, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32222965

RESUMO

Targeted photodynamic therapy (PDT) in head/neck cancer patients with a conjugate of the anti-epidermal growth factor receptor (EGFR) antibody, Cetuximab and a phthalocyanine photosensitizer IR700DX is under way, but the exact mechanisms of action are still not fully understood. In this study, the EGFR-overexpressing human head/neck OSC-19-luc2-cGFP tumor with transfected GFP gene was used in a skin-fold window chamber model in BALB/c nude mice. The uptake and localization of the conjugate in the tumor and its surrounding normal tissues were studied by an intravital confocal laser scanning microscopy with image analyses. The tumor was also irradiated with 690 nm laser light 24 h after conjugate administration. The vascular and tumor responses were examined by morphological evaluation and immunohistochemistry (IHC). The amount of conjugate in the tumor peaked at 24-48 h after injection. Image analyses of colocalization correlation parameters demonstrated a high fraction of the conjugate IR700DX colocalized in the GFP-expressing tumor cells. PDT-treated tumors showed extensive necrotic/apoptotic destruction with little vascular damage, while IHC showed no HIF-1α expression and decreased EGFR and Ki67 expression with activated caspase-3 overexpression, indicating a direct killing of tumor cells through both necrotic and apoptotic cell death.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Cetuximab/farmacologia , Humanos , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Adv Colloid Interface Sci ; 277: 102121, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32092487

RESUMO

Liposomes, lipid-based vesicular systems, have attracted major interest as a means to improve drug delivery to various organs and tissues in the human body. Recent literature highlights the benefits of liposomes for use as drug delivery systems, including encapsulating of both hydrophobic and hydrophilic cargos, passive and active targeting, enhanced drug bioavailability and therapeutic effects, reduced systemic side effects, improved cargo penetration into the target tissue and triggered contents release. Pioneering work of liposomes researchers led to introduction of long-circulating, ligand-targeted and triggered release liposomes, as well as, liposomes containing nucleic acids and vesicles containing combination of cargos. Altogether, these findings have led to widespread application of liposomes in a plethora of areas from cancer to conditions such as cardiovascular, neurologic, respiratory, skin, autoimmune and eye disorders. There are numerous review articles on the application of liposomes in treatment of cancer, which seems the primary focus, whereas other diseases also benefit from liposome-mediated treatments. Therefore, this article provides an illustrated detailed overview of liposomal formulations, in vitro characterization and their applications in different disorders other than cancer. Challenges and future directions, which must be considered to obtain the most benefit from applications of liposomes in these disorders, are discussed.


Assuntos
Nanoestruturas/química , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Oftalmopatias/tratamento farmacológico , Humanos , Lipossomos/química , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças Respiratórias/tratamento farmacológico , Dermatopatias/tratamento farmacológico
19.
Biol Proced Online ; 22: 3, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021568

RESUMO

Background: Cell invasion through extracellular matrix (ECM) is a critical step in tumor metastasis. To study cell invasion in vitro, the internal microenvironment can be simulated via the application of 3D models. Results: This study presents a method for 3D invasion examination using microcarrier-based spheroids. Cell invasiveness can be evaluated by quantifying cell dispersion in matrices or tracking cell movement through time-lapse imaging. It allows measuring of cell invasion and monitoring of dynamic cell behavior in three dimensions. Here we show different invasive capacities of several cell types using this method. The content and concentration of matrices can influence cell invasion, which should be optimized before large scale experiments. We also introduce further analysis methods of this 3D invasion assay, including manual measurements and homemade semi-automatic quantification. Finally, our results indicate that the position of spheroids in a matrix has a strong impact on cell moving paths, which may be easily overlooked by researchers and may generate false invasion results. Conclusions: In all, the microcarrier-based spheroids 3D model allows exploration of adherent cell invasion in a fast and highly reproducible way, and provides informative results on dynamic cell behavior in vitro.

20.
Cancers (Basel) ; 12(1)2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31940973

RESUMO

Targeted photodynamic therapy (PDT) has the potential to improve the therapeutic effect of PDT due to significantly better tumor responses and less normal tissue damage. Here we investigated if the efficacy of epidermal growth factor receptor (EGFR) targeted PDT using cetuximab-IRDye700DX is fluence rate dependent. Cell survival after treatment with different fluence rates was investigated in three cell lines. Singlet oxygen formation was investigated using the singlet oxygen quencher sodium azide and singlet oxygen sensor green (SOSG). The long-term response (to 90 days) of solid OSC-19-luc2-cGFP tumors in mice was determined after illumination with 20, 50, or 150 mW·cm-2. Reflectance and fluorescence spectroscopy were used to monitor therapy. Singlet oxygen was formed during illumination as shown by the increase in SOSG fluorescence and the decreased response in the presence of sodium azide. Significantly more cell death and more cures were observed after reducing the fluence rate from 150 mW·cm-2 to 20 mW·cm-2 both in-vitro and in-vivo. Photobleaching of IRDye700DX increased with lower fluence rates and correlated with efficacy. The response in EGFR targeted PDT is strongly dependent on fluence rate used. The effectiveness of targeted PDT is, like PDT, dependent on the generation of singlet oxygen and thus the availability of intracellular oxygen.

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