Technological challenges of biomembrane-coated top-down cancer nanotherapy

J.M.J.M.R., J.C. and A.C.P.S. acknowledge the financial support from the Fundacão para a Ciência e a Tecnologia I.P. (FCT)-Research and Development Project grant PTDC/BTMMAT/ 4738/2020. J.C. acknowledges financial support from the European Research Council-ERC Starting Grant 848325. The authorspublishersversionpublishe

Exploring biomedical applications in cancer diagnosis and therapy

The authors acknowledge the financial support from the grants 2021.05914.BD (given to D.P.) and PTDC/BTM-MAT/4738/2020 project (given to A.C.P.-S., J.C., and F.V.) from Fundacão para a Ciência e Tecnologia (FCT). J.C. acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325).Bio-mimicking principles have recently been proposed for the surface functionalization of nanoparticles (NPs). Such a strategy is based on camouflaging the NP surface with functional biomembranes to render superior biocompatibility, interfacial features, immune evasion, and active targeting properties to nanomaterials. In this area of research, cell membranes derived from a plethora of highly optimized cells, such as red blood cells, immune cells, platelets, stem cells, cancer cells, and others, have been the pioneers as coating materials. This biomimetic concept has then been applied to subcellular structures, namely extracellular vesicles and intracellular organelles. Exosomes are a nanosized extracellular vesicle subtype secreted by most cells. These phospholipid bilayer nanovesicles are surface enriched with proteins accounting for their dynamic and prominent roles in immune escape, cell-cell communication, and specific cell uptake. Their intrinsic stability, biocompatibility, reduced immunogenicity and toxicity, and specific cell-targeting features denote an optimal biological nanocarrier for biomedical applications. This review highlights the current clinical applications of exosome membrane-coated nanosystems in cancer diagnosis and therapy. These biomimetic nanosystems have emerged as a promising avenue to provide effective, highly specific, and safer cancer-targeted applications. Finally, challenges hindering their clinical application will be mentioned.publishersversionpublishe

neurodegenerative diseases, tissue engineering and regenerative medicine

Funding This work was supported by grants from Fundação para a Ciência e Tecnologia (FCT) (SFRH/BD/148771/2019, 2021.05914.BD, PTDC/BTM-MAT/4738/2020), and also from the European Research Council—ERC Starting Grant (848325).A bio-inspired strategy has recently been developed for camouflaging nanocarriers with biomembranes, such as natural cell membranes or subcellular structure-derived membranes. This strategy endows cloaked nanomaterials with improved interfacial properties, superior cell targeting, immune evasion potential, and prolonged duration of systemic circulation. Here, we summarize recent advances in the production and application of exosomal membrane-coated nanomaterials. The structure, properties, and manner in which exosomes communicate with cells are first reviewed. This is followed by a discussion of the types of exosomes and their fabrication methods. We then discuss the applications of biomimetic exosomes and membrane-cloaked nanocarriers in tissue engineering, regenerative medicine, imaging, and the treatment of neurodegenerative diseases. Finally, we appraise the current challenges associated with the clinical translation of biomimetic exosomal membrane-surface-engineered nanovehicles and evaluate the future of this technology.publishersversionpublishe

Práticas e desafios da regulação do Sistema Único de Saúde

OBJECTIVE: To analyze the obstacles and challenges faced by managers and coordination professionals in their practices in municipal coordinating centers. METHODS: An exploratory descriptive study with a qualitative focus, applied in 40 managers and coordination professionals, from September 2017 to November 2018, with semi-structured interviews, resulting in two categories of analysis: limiting factors and factors that facilitate the management and operationalization of the Brazilian Unified Health System (SUS) coordinating sector. RESULTS: Analyzing the statements, we found evidence of the following limiting factors: failure in the criteria of referral, unavailability of beds, high demand, systemic difficulties in relation to the coordinating system, procedures of difficult scheduling and execution, increased repressed demand for elective procedures and difficulties in the flow of information between primary care and coordination. In the category of facilitating factors, the most significant possibilities were: expansion of the capability to know the user’s reality, improvement in primary care and increase in health financial resources, health training and education and restructuring, in addition to reorganizing internal coordinating procedures. CONCLUSION: The limiting factors of coordination show the need to promote actions that offer all SUS users full access to health services.OBJETIVO: Analisar os entraves e desafios enfrentados pelos gestores e profissionais de regulação em suas práticas nas centrais reguladoras municipais. MÉTODOS: Estudo descritivo exploratório com enfoque qualitativo, aplicado em quarenta gestores e profissionais de regulação, no período de setembro de 2017 e novembro de 2018, por meio de entrevista semiestruturada, resultando em duas categorias de análise: fatores limitantes e fatores facilitadores da gestão e operacionalização do setor de regulação do SUS. RESULTADOS: Na análise dos enunciados, foram encontradas evidências dos seguintes fatores limitantes: falha nos critérios de encaminhamento, indisponibilidade de leitos, grande demanda, dificuldades sistêmicas em relação ao sistema de regulação, procedimentos de difícil agendamento e execução, aumento da demanda reprimida de procedimentos eletivos e dificuldades no fluxo de informações entre a atenção primária e a regulação. Na categoria de fatores facilitadores, as possibilidades mais significativas foram: ampliação da capacidade de conhecer a realidade do usuário, melhoria na atenção primária e incrementos de recursos financeiros para a saúde, capacitação e formação em saúde e reestruturação, além de reorganização dos procedimentos internos de regulação. CONCLUSÃO: Os fatores limitantes da regulação demonstram a necessidade de fomentar ações que ofereçam a todos os usuários do SUS o acesso pleno aos serviços de saúde

Chronic inflammation's transformation to cancer : a nanotherapeutic paradigm

The body’s normal immune response against any invading pathogen that causes infection in the body results in inflammation. The sudden transformation in inflammation leads to the rise of inflammatory diseases such as chronic inflammatory bowel disease, autoimmune disorders, and colorectal cancer (different types of cancer develop at the site of chronic infection and inflammation). Inflammation results in two ways: short-term inflammation i.e., non-specific, involves the action of various immune cells; the other results in long-term reactions lasting for months or years. It is specific and causes angiogenesis, fibrosis, tissue destruction, and cancer progression at the site of inflammation. Cancer progression relies on the interaction between the host microenvironment and tumor cells along with the inflammatory responses, fibroblast, and vascular cells. The two pathways that have been identified connecting inflammation and cancer are the extrinsic and intrinsic pathways. Both have their own specific role in linking inflammation to cancer, involving various transcription factors such as Nuclear factor kappa B, Activator of transcription, Single transducer, and Hypoxia-inducible factor, which in turn regulates the inflammatory responses via Soluble mediators cytokines (such as Interleukin-6, Hematopoietin-1/Erythropoietin, and tumor necrosis factor), chemokines (such as Cyclooxygenase-2, C-X-C Motif chemokines ligand-8, and IL-8), inflammatory cells, cellular components (such as suppressor cells derived from myeloid, tumor-associated macrophage, and acidophils), and promotes tumorigenesis. The treatment of these chronic inflammatory diseases is challenging and needs early detection and diagnosis. Nanotechnology is a booming field nowadays for its rapid action and easy penetration inside the infected destined cells. Nanoparticles are widely classified into different categories based on their different factors and properties such as size, shape, cytotoxicity, and others. Nanoparticles emerged as excellent with highly progressive medical inventions to cure diseases such as cancer, inflammatory diseases, and others. Nanoparticles have shown higher binding capacity with the biomolecules in inflammation reduction and lowers the oxidative stress inside tissue/cells. In this review, we have overall discussed inflammatory pathways that link inflammation to cancer, major inflammatory diseases, and the potent action of nanoparticles in chronic inflammation-related diseases

pH-Sensitive Peptide Hydrogels as a Combination Drug Delivery System for Cancer Treatment

Conventional antitumor chemotherapeutics generally have shortcomings in terms of dissolubility, selectivity and drug action time, and it has been difficult to achieve high antitumor efficacy with single-drug therapy. At present, combination therapy with two or more drugs is widely used in the treatment of cancer, but a shortcoming is that the drugs do not reach the target at the same time, resulting in a reduction in efficacy. Therefore, it is necessary to design a carrier that can release two drugs at the same site. We designed an injectable pH-responsive OE peptide hydrogel as a carrier material for the antitumor drugs gemcitabine (GEM) and paclitaxel (PTX) that can release drugs at the tumor site simultaneously to achieve the antitumor effect. After determining the optimal gelation concentration of the OE polypeptide, we conducted an in vitro release study to prove its pH sensitivity. The release of PTX from the OE hydrogel in the medium at pH 5.8 and pH 7.4 was 96.90% and 38.98% in 7 days. The release of GEM from the OE hydrogel in media with pH of 5.8 and 7.4 was 99.99% and 99.63% in 3 days. Transmission electron microscopy (TEM) and circular dichroism (CD) experiments were used to observe the microstructure of the peptides. The circular dichroism of OE showed a single negative peak shape when under neutral conditions, indicating a β-folded structure, while under acidic conditions, it presented characteristics of a random coil. Rheological experiments were used to investigate the mechanical strength of this peptide hydrogel. Furthermore, the treatment effect of the drug-loaded peptide hydrogel was demonstrated through in vitro and in vivo experiments. The results show that the peptide hydrogels have different structures at different pH values and are highly sensitive to pH. They can reach the tumor site by injection and are induced by the tumor microenvironment to release antitumor drugs slowly and continuously. This biologically functional material has a promising future in drug delivery for combination drugs

A Brazilian cohort of patients with immuno-mediated chronic inflammatory diseases infected by SARS-CoV-2 (ReumaCoV-Brasil Registry) : protocol for a prospective, observational study

Background: Patients with immune-mediated rheumatic diseases (IMRD) are at increased risk of infections, including significant morbidity and high mortality. Considering the potential for unfavorable outcomes of SARS-CoV-2 infection in patients with IMRD, several questions were raised regarding the impact of COVID-19 at the start of the pandemic. Objective: This paper presents the protocol of a study that aims to prospectively evaluate patients with IMRD and a confirmed COVID-19 diagnosis (using criteria provided by the Brazilian Ministry of Health). Methods: The study comprised a prospective, observational cohort (patients with IMRD and COVID-19) and a comparison group (patients with only IMRD), with a follow-up time of 6 months to evaluate differences in health outcomes. The primary outcomes will be changes in IMRD disease activity after SARS-CoV-2 infection at 4 time points: (1) at baseline, (2) within 4-6 weeks after infection, (3) at 3 months after the second assessment (±15 days), and (4) at 6 months (±15 days). The secondary outcomes will be the progression rate to moderate or severe forms of COVID-19, need for intensive care unit admission and mechanical ventilation, death, and therapeutic changes related to IMRD. Two outcomes—pulmonary and thromboembolic events in patients with both IMRD and SARS-CoV-2 infection—are of particular interest and will be monitored with close attention (clinical, laboratory, and function tests as well as imaging). Results: Recruitment opened in May 2020, with 1300 participants recruited from 43 sites as of November 2020. Patient recruitment will conclude by the end of December 2020, with follow-up occurring until April 2021. Data analysis is scheduled to start after all inclusion data have been collected, with an aim to publish a peer-reviewed paper in December 2020. Conclusions: We believe this study will provide clinically relevant data on the general impact of COVID-19 on patients with IMRD

Liposome-based diagnostic and therapeutic applications for pancreatic cancer

Pancreatic cancer is one of the harshest and most challenging cancers to treat, often labeled as incurable. Chemotherapy continues to be the most popular treatment yet yields a very poor prognosis. The main barriers such as inefficient drug penetration and drug resistance, have led to the development of drug carrier systems. The benefits, ease of fabrication and modification of liposomes render them as ideal future drug delivery systems. This review delves into the versatility of liposomes to achieve various mechanisms of treatment for pancreatic cancer. Not only are there benefits of loading chemotherapy drugs and targeting agents onto liposomes, as well as mRNA combined therapy, but liposomes have also been exploited for immunotherapy and can be programmed to respond to photothermal therapy. Multifunctional liposomal formulations have demonstrated significant pre-clinical success. Functionalising drug-encapsulated liposomes has resulted in triggered drug release, specific targeting, and remodeling of the tumor environment. Suppressing tumor progression has been achieved, due to their ability to more efficiently and precisely deliver chemotherapy. Currently, no multifunctional surface-modified liposomes are clinically approved for pancreatic cancer thus we aim to shed light on the trials and tribulations and progress so far, with the hope for liposomal therapy in the future and improved patient outcomes

Microcephaly prevalence after the 2015 to 2016 Zika outbreak in Tangará da Serra, Brazil: a population-based study

Objective: Prenatal infection with the Zika virus (ZIKV) can lead to congenital Zika syndrome (CZS), characterized by microcephaly and brain injury. However, there are questions regarding the prevalence of microcephaly/CZS after the ZIKV outbreak in defined geographic areas. This study aimed to identify adverse outcomes in live births of fetuses exposed in utero to the ZIKV, compared to unexposed births, as well as maternal sociodemographic, delivery, and birth characteristics. Methods: Here, we conducted a cross-sectional observational study to investigate the characteristics of all live births in the city of Tangará da Serra, Mato Grosso, Brazil, in 2016, after the outbreak of ZIKV infection in late 2015. All live births of children to women residing in the municipality of Tangará da Serra between January 1 and December 31, 2016, were evaluated, and head circumference was measured at birth and after 24 hours. Children born with microcephaly or a maternal history of confirmed or suspected prenatal ZIKV infection were evaluated by a multidisciplinary team. The outcomes of the exposed and non-exposed children were compared. Prevalence ratios and their respective 95% confidence intervals were calculated for sociodemographic, delivery, and live birth characteristics. Results: Of 1,441 live births, 106 (7.3%) were from mothers with confirmed or highly probable exposure to ZIKV. The prevalence of severe congenital microcephaly (41.7/10,000) in Tangará da Serra in 2016 was ten-fold higher than that in Latin America before 2015. Conclusion: This study may serve as a model to investigate possible outbreaks of infections in a defined geographical space in the future

Topical delivery of nanoemulsions for skin cancer treatment

Skin cancer chemotherapeutics often lead to the development of severe cytotoxicity, compelling the development of novel delivery systems to not only enhance therapeutic efficacy but also minimize side effects and improve patient compliance. In recent years, topical nanoemulsions have emerged as powerful tools in the field of skin cancer therapeutic management. This review delves into the potential of these innovative formulations to revolutionize the treatment of skin malignancies, due to their unique properties, having relevant advantages, such as allowing high drug strength, skin drug permeation and retention enhancement, biocompatibility, and controlled release capacity. Despite the skin's formidable permeability challenges, it remains an accessible interface for the delivery of therapeutic carriers such as nanoemulsions both locally (topical and dermal) and systemically (transdermal). Nanoemulsions, once associated primarily with cosmetic applications, are now gaining prominence as essential components of skin cancer treatment strategies. This review explores the potential of topical nanoemulsions, shedding light on their ability to efficiently deliver a wide range of molecules, overcoming lipophilic barriers inherent to skin. In this comprehensive analysis of several distinct studies investigating NEs for skin cancer treatment, a diverse array of formulations and components were explored, revealing a spectrum of characteristics. The PDI spans from a minimum of 0.105 nm to a maximum of 0.421 nm, reflecting variations in droplet size distribution. Droplet sizes exhibit considerable diversity, ranging from a small 16 nm to a larger 200 nm, signifying varied potential for skin penetration. ZP values further contribute to this diversity, ranging from highly favorable (-66.6 mV) to less advantageous or near zero values, indicative of distinct surface charge characteristics. As healthcare costs continue to escalate, this nuanced overview of nanoemulsion characteristics provides valuable insights into their potential applications in the targeted treatment of melanoma and, to a lesser extent, non-melanoma skin cancers. The value of such innovative and safer drug delivery systems becomes increasingly evident. Here, we focus exclusively on the role of topical nanoemulsions in advancing skin cancer therapy