Recent Progress in Lipid Nanoparticles for Cancer Theranostics: Opportunity and Challenges

Cancer is one of the major leading causes of mortality in the world. The implication of nanotherapeutics in cancer has garnered splendid attention owing to their capability to efficiently address various difficulties associated with conventional drug delivery systems such as non-specific biodistribution, poor efficacy, and the possibility of occurrence of multi-drug resistance. Amongst a plethora of nanocarriers for drugs, this review emphasized lipidic nanocarrier systems for delivering anticancer therapeutics because of their biocompatibility, safety, high drug loading and capability to simultaneously carrying imaging agent and ligands as well. Furthermore, to date, the lack of interaction between diagnosis and treatment has hampered the efforts of the nanotherapeutic approach alone to deal with cancer effectively. Therefore, a novel paradigm with concomitant imaging (with contrasting agents), targeting (with biomarkers), and anticancer agent being delivered in one lipidic nanocarrier system (as cancer theranostics) seems to be very promising in overcoming various hurdles in effective cancer treatment. The major obstacles that are supposed to be addressed by employing lipidic theranostic nanomedicine include nanomedicine reach to tumor cells, drug internalization in cancer cells for therapeutic intervention, off-site drug distribution, and uptake via the host immune system. A comprehensive account of recent research updates in the field of lipidic nanocarrier loaded with therapeutic and diagnostic agents is covered in the present article. Nevertheless, there are notable hurdles in the clinical translation of the lipidic theranostic nanomedicines, which are also highlighted in the present review along with plausible countermeasures.Peer reviewedFinal Published versio

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Corneal Epithelial Hyperplasia after 5-Fluorouracil Injection

Background: 5-Fluorouracil (5-FU) is a pyrimidine analogue which selectively inhibits DNA synthesis, RNA synthesis, and VEGF antibodies. 5-FU is widely used in ophthalmology for inhibition of postoperative corneal scarring and scleral bleb fibrosis. Case Presentation: In this case report, we describe an unusual case of a 65-year-old male who presented to the clinic with progressive decrease of vision after he underwent a revision of scleral bleb with the administration of 0.05 mL 5-FU (2.5 mg) injection and was diagnosed with corneal epithelial hyperplasia. The patient had a history of glaucoma managed by deep sclerotomy and phacoemulsification with intraocular lens implantation. Conclusion: Our case demonstrates an unusual consequence of corneal epithelial hyperplasia developed after 5-FU injection

Application of Green Nanoemulsion for Elimination of Rifampicin from a Bulk Aqueous Solution

The study aimed to prepare green nanoemulsion (GNE) multi-components ((water/dimethyl sulfoxide–transcutol/isopropyl alcohol/capmul MCM C8 (CMC8)) to remove rifampicin (RIF) from a contaminated aqueous bulk solution. Pseudo ternary phase diagrams dictated several batches of GNE prepared following the reported method. Selected nanoemulsions (NF1–NF5) were characterized for morphology, globular size, size distribution (polydispersity index, PDI), viscosity, zeta potential, refractive index (RI), and free-thaw kinetic stability. They were investigated for percent removal efficiency (%RE) of RIF from the bulk aqueous solution for varied time intervals (10–60 min). Finally, scanning electron microscopy–energy dispersive x-ray (SEM–EDX) and inductive coupled plasma–optical emission system (ICP–OE) were used to confirm the extraction of trace content of dimethyl sulfoxide (DMSO) and others in the treated water. Considering the data obtained for globule size, PDI, viscosity, zeta potential, freeze–thaw stability, and refractive index, NF5 was the most suitable for RIF removal. The largest %RE value (91.7%) was related to NF5, which may be prudent to correlate with the lowest value (~39 nm) of size (maximum surface area available for contact adsorption), PDI (0.112), and viscosity (82 cP). Moreover, %RE was profoundly influenced by the content of CMC8 and the aqueous phase. These two phases had immense impact on the viscosity, size, and RI. The percent content of water, Smix, and CMC8 were 15% w/w), 60% w/w, and 25% w/w, respectively in NF5. SEM–EDX and ICP–OE confirmed the absence of DMSO and other hydrophilic components in the treated water. Thus, efficient NF5 could be a promising option to the conventional method to decontaminate the polluted aqueous system

Safety and efficacy of health supplement (Stevia rebaudiana)

Purpose: The aim of this review is to evaluate the safety and efficacy of a product containing Stevia rebaudiana and its related marketing restriction governed by laws. Methods: An electronic search was conducted through searching at Cochrane Library, EMBASE, PUBMED to assess the literature of Stevia rebaudiana. Results: Stevia was considered safe to be used as sugar substitution in patients with diabetes. No serious adverse events and health risk were reported. However, until now, most of the beneficial results were from the study conducted in short-term. Not many studies conducted to assess the health risk of consuming stevia for long-term effect. Therefore, consumers must be warned to used stevia product cautiously and not exceed the recommended dose as instructed. No definite findings yet regarding dose range, minimum and maximum, to achieve optimal outcome and avoid risk of hypoglycemia. Conclusion: Although some countries still banned the use of stevia since lack of toxicology profile, it was credited with the various health benefits. The Joint Expert Committee on Food Additives revealed that stevia extracts containing 95% steviol glycosides are safe for human use in the range of 4 mg/kg of body weight/day

Pattern Recognition of Phytoconstituents and Bioactivities of Date Pit Extracts from Different Cultivars Grown in the Qassim Area

A huge number of date varieties grow annually throughout the world. The genetic variation between different date varieties is reflected in their variable sensory characters and phytochemical contents. Date pits are considered a waste product of the date industry, despite their rich metabolic content. The present study attempts to generate visual clustering to clarify the diversity among fourteen date cultivars growing in the Qassim region, according to the phytochemical contents and biological potentials of their pits. The results indicated a wide variation in the total phenolic content (11.4–29.7 mg GAE/g), flavonoids content (21.9–37.1 mg RE/g), proanthocyanidine content (12.0–207.0 mg CE/g), and antioxidant potential (10.3–25.5 mg AEAC/g) among the tested cultivars. Screening the antimicrobial activity of extracts from the 14 tested cultivars indicated different activities against Listeria monocytogenes, Staphylococcus aureus, Escherichia coli, Salmonella enterica, and Candida albicans. Multivariate analysis of phytochemical content and biological activity, using different analytical models, allowed the classification of the 14 cultivars into four classes, Class-1: Barhi, Safawi, and Sukkari; Class-2: Khodry and Nabtat Ali; Class-3: Ruthana, Segae, Shaqra, and Sheishee; and Class-4: Hulwa Aljouf, Mabroom, Meneifi, Rushodia, and Wannana. These findings provide a scientific basis for the classification of date pits which facilitates the future selection of promising candidates for more phytochemical and biological exploration

Safety and efficacy of sea cucumber containing products

Purpose: The aim of this study is to assess the therapeutic effect of sea cucumber. It is a traditional medicine used for centuries as a general tonic to improve the health of the body and to boost the energy levels. Methodology: An electronic search on PubMed, MEDLINE and Cochrane Library with keywords “sea cucumber”, “gamat”, “effectiveness OR efficacy”,“safety OR adverse reaction OR side effects” was carried out. The literatures are summarized in the evidence tables. Findings and conclusions: Most sea cucumbers species have been validated through scientific and ethnopharmacological research and have shown to have medicinal value such as anti-angiogenic, anticancer, anticoagulant antihypertension, anti-inflammatory, antimicrobial, antifungal, antioxidant, antithrombotic, and antitumor. The discovery of bioactive compounds and therapeutic properties isolated from sea cucumber such as chondroitin sulfate, triterpene glycosides (saponins), lectins, heparin, cerebrosides, gangliosides, bioactive peptides, sterols, and omega-6 and omega-3 fatty acids leads to potential drug development in various pharmaceuticals, agrochemicals, functional foods, and nutraceuticals industries. However, further clinical trials are still needed which could transform the bioactive compound from sea cucumber extraction into a drug that could be a cure for certain disease