Lipid nanocarriers loaded with natural compounds: Potential new therapies for age related neurodegenerative diseases?

Article in pressAge related neurodegenerative disorders (ARND) are presented as the most debilitating and challenging diseases associated with the central nervous system. Despite the advent of active molecules with a positive role on neurodegenerative mechanisms, many of the current therapeutic strategies remain ineffective in treating or preventing ARND. Lipid nanocarriers have emerged as efficient delivery systems with the capability to cross biological barriers, especially the blood brain barrier (BBB). Also, when associated to natural compounds, lipid nanocarriers have demonstrated to be an interesting alternative to ARND therapies with multiple beneficial effects. This comprehensive review focus on state-of-the-art lipid based nanocarriers for the delivery of natural compounds targeting neurodegeneration. A critical analysis of published reports will be also provided giving indications to researchers about the most promising ARND nanotherapy strategies.Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UID/FIS/04650/2013. Marlene Lúcio acknowledges the exploratory project funded by FCT with the reference IF/00498/2012. Telma Soares acknowledges COMPETE 2020 “Programa Operacional Competitividade e internacionalização”info:eu-repo/semantics/publishedVersio

Nanocarriers development for encapsulation of neuroprotective agents

Dissertação de mestrado em Biofísica e BionanossistemasA curcumina, o pó de ouro com fraca biodisponibilidade, também conhecida pelas suas propriedades anti-inflamatórias e antioxidantes, tem sido alvo de grande atenção em várias áreas da medicina, nomeadamente no tratamento de doenças neurodegenerativas. Neste âmbito, foram identificados vários alvos farmacológicos da curcumina capazes de promover a diminuição da agregação peptídica, do stress oxidativo e da neuroinflamação. Nesta investigação, tendo em conta que a proporção de curcuminóides é um fator crítico para a atividade biomédica, foi feita uma previsão e distinção das propriedades farmacocinéticas de C.longa, a maior fonte de curcuminóides, de C.aromatica, conhecida pela sua importância na medicina, e da curcumina comercial, cuja constituição é conhecida. Nesta previsão, resultados como baixa biodisponibilidade e solubilidade, rápida metabolização, bioacumulação, elevada afinidade relativa à HSA e propensão para promover alterações da física membranar salientaram a necessidade de encapsulamento da curcumina em nanotransportadores. Assim sendo, e de forma a otimizar a utilização destes compostos no tratamento de doenças neurodegenerativas, surge como objetivo primordial deste projeto o encapsulamento da curcumina e dos extratos de C.longa e C.aromatica em lipossomas de DODAB:MO (1:2). Os nanotransportadores desenvolvidos pelo método de injeção etanólica mostraram-se eficientes para encapsular a curcumina e os extratos, apresentando uma eficiência de encapsulamento de aproximadamente 100%. Adicionalmente, demonstraram possuir muitas outras propriedades atrativas para aplicações biomédicas, como: tamanho inferior a 200 nm, estabilidade em condições de armazenamento superior a 4 meses e carga superficial positiva. Foi também verificada uma elevada afinidade da curcumina e dos extratos para os lipossomas desenvolvidos bem como provada a prevenção da ligação a proteínas plasmáticas após a peguilação. Por último, as formulações desenvolvidas comprovaram a atividade antioxidante dos compostos naturais encapsulados.Curcumin, the golden powder with weak bioavailability, also known for its anti-inflammatory and antioxidant properties, has been a target of great heed in various medical fields, namely in the treatment of neurodegenerative diseases. In this particular field, multiple pharmacological targets, capable of promoting a decrease in peptidic aggregation, oxidative stress and neuroinflammation have been identified. Considering that the level of biomedical activity is highly dependent on the proportion of curcuminoids, a prior study of the prevision and distinction of pharmacokinetic properties of C.longa, the biggest source of curcuminoids, of C. aromática, known for its medical relevance, and commercial curcumin, whose chemical constitution is known, was conducted. This initial study revealed low bioavailability, low solubility, fast breakdown, bioaccumulation, and high affinity of curcuminoids to HSA and their tendency to alter physical characteristics of membranes, highlighted the need of encapsulating curcumin using nanocarriers. Following this rationale, and in order to optimize the use of such compounds in the treatment of neurodegenerative diseases, this project focused on encapsulating curcumin and both the C. longa and C. aromática extracts, in DODAB:MO (1:2) liposomes. The nanocarriers obtained by ethanolic injection showed an encapsulation efficiency of approximately 100%, being, thereby, highly efficient at encapsulating curcumin and extracts. Additionally, the same nanocarriers exhibited sizes inferior to 200 nm, high stability when stored up to 4 months and a positive superficial charge, increasing their attractiveness as biomedical applications. A high affinity of curcumin and the studied extracts to the liposomes, as well as the ability to prevent interactions with plasma proteins, after successful pegylation, was also confirmed. As final remark, the formulations here developed confirmed the antioxidant activity of the encapsulated natural compounds

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AimThe SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery.MethodsThis was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin.ResultsOverall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P ConclusionOne in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research

Núcleos de Ensino da Unesp: artigos 2008

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq