The Role of Cyclodextrins in COVID-19 Therapy-A Literature Review.

Coronavirus disease-19 (COVID-19) emerged in December 2019 and quickly spread, giving rise to a pandemic crisis. Therefore, it triggered tireless efforts to identify the mechanisms of the disease, how to prevent and treat it, and to limit and hamper its global dissemination. Considering the above, the search for prophylactic approaches has led to a revolution in the reglementary pharmaceutical pipeline, with the approval of vaccines against COVID-19 in an unprecedented way. Moreover, a drug repurposing scheme using regulatory-approved antiretroviral agents is also being pursued. However, their physicochemical characteristics or reported adverse events have sometimes limited their use. Hence, nanotechnology has been employed to potentially overcome some of these challenges, particularly cyclodextrins. Cyclodextrins are cyclic oligosaccharides that present hydrophobic cavities suitable for complexing several drugs. This review, besides presenting studies on the inclusion of antiviral drugs in cyclodextrins, aims to summarize some currently available prophylactic and therapeutic schemes against COVID-19, highlighting those that already make use of cyclodextrins for their complexation. In addition, some new therapeutic approaches are underscored, and the potential application of cyclodextrins to increase their promising application against COVID-19 will be addressed. This review describes the instances in which the use of cyclodextrins promotes increased bioavailability, antiviral action, and the solubility of the drugs under analysis. The potential use of cyclodextrins as an active ingredient is also covered. Finally, toxicity and regulatory issues as well as future perspectives regarding the use of cyclodextrins in COVID-19 therapy will be provided.

A Ruler for Abdominoplasty Preoperative Markings: The Potential of Best Scar Symmetry.

Background. Scar appearance is an important outcome in abdominoplasty surgery, and its asymmetry can have a significant impact on patient and surgeon satisfaction. Here, we compared the scar symmetry reached with a ruler specially designed for the preoperative marking in abdominoplasty to the classic preoperative incision marking. Methods. In this randomized, uni-blind study, 42 patients were allocated to 2 different groups. Group 1 patients had their preoperative marking made by a group of surgeons that used the classic technique as described by Baroudi (n = 21), and Group 2 patients received their preoperative marking by another group of surgeons, using a ruler specially designed to fit the abdominal contour (n = 21). Patients were evaluated using a standard questionnaire that collected information about general patient's characteristics. On the follow-up period, we evaluated the presence of late surgical complications, need for revision surgery, patient's satisfaction concerning the postoperative scar, and 4 distances were measured in both groups to assess symmetry. Statistical analysis was made. Results. A total of 42 patients underwent abdominoplasty and were evaluated on the follow-up period (mean time: 4 months). The mean difference of corresponding measures on each side (A-B vs. A-B' and A-C vs. A-C') was higher in Group 1 comparing to Group 2. The level of correlation between corresponding measurements was higher in Group 2. Better satisfaction regarding the scar symmetry was achieved in Group 2, being this result statistically significant (P = .004). Conclusions. The use of the specialized ruler may help surgeons achieve a better scar symmetry with higher patient satisfaction.

Nanofiber Carriers of Therapeutic Load: Current Trends.

The fast advancement in nanotechnology has prompted the improvement of numerous methods for the creation of various nanoscale composites of which nanofibers have gotten extensive consideration. Nanofibers are polymeric/composite fibers which have a nanoscale diameter. They vary in porous structure and have an extensive area. Material choice is of crucial importance for the assembly of nanofibers and their function as efficient drug and biomedicine carriers. A broad scope of active pharmaceutical ingredients can be incorporated within the nanofibers or bound to their surface. The ability to deliver small molecular drugs such as antibiotics or anticancer medications, proteins, peptides, cells, DNA and RNAs has led to the biomedical application in disease therapy and tissue engineering. Although nanofibers have shown incredible potential for drug and biomedicine applications, there are still difficulties which should be resolved before they can be utilized in clinical practice. This review intends to give an outline of the recent advances in nanofibers, contemplating the preparation methods, the therapeutic loading and release and the various therapeutic applications.

Nanotheranostic Pluronic-Like Polymeric Micelles: Shedding Light into the Dark Shadows of Tumors.

Cancer is a leading cause of death worldwide. Despite the advances in prevention, detection, diagnosis, and treatment, many tumors relapse and become resistant to conventional treatments. Theranostics and real-time molecular imaging using nanoscale materials, such as polymeric micelles, are being widely explored as promising gold standard approaches in a personalized medicine perspective for cancer. Theranostics is intended for the three-in-one purpose of simultaneously diagnose, treat, and monitor tumor evolution. Compared to the conventional treatments, theranostic functional polymeric micelles have demonstrated great potential to improve and monitor the delivery of pharmacological agents following administration, which can enhance therapeutic efficacy and minimize off-target toxicity. This review provides an overview of the current state of the art related to the use of polymeric micelles as theranostic multicarriers targeting the cancer cells and tumor microenvironment. Some future directions toward the design of nanotheranostic platforms are also proposed. In particular, we focused our attention on Pluronics and Tetronics as they advantageously present sol-gel transition, which makes them smart nanosystems suitable for oral theranostic administration and sustained depots, increasing patient compliance.

Ice-sheet mass balance and climate change.

Since the 2007 Intergovernmental Panel on Climate Change Fourth Assessment Report, new observations of ice-sheet mass balance and improved computer simulations of ice-sheet response to continuing climate change have been published. Whereas Greenland is losing ice mass at an increasing pace, current Antarctic ice loss is likely to be less than some recently published estimates. It remains unclear whether East Antarctica has been gaining or losing ice mass over the past 20 years, and uncertainties in ice-mass change for West Antarctica and the Antarctic Peninsula remain large. We discuss the past six years of progress and examine the key problems that remain.

The role of immune system exhaustion on cancer cell escape and anti-tumor immune induction after irradiation.

Immune surveillance seems to represent an effective tumor suppressor mechanism. However, some cancer cells survive and become variants, being poorly immunogenic and able to enter a steady-state phase. These cells become functionally dormant or remain hidden clinically throughout. Neoplastic cells seem to be able to instruct immune cells to undergo changes promoting malignancy. Radiotherapy may act as a trigger of the immune response. After radiotherapy a sequence of reactions occurs, starting in the damage of oncogenic cells by multiple mechanisms, leading to the immune system positive feedback against the tumor. The link between radiotherapy and the immune system is evident. T cells, macrophages, Natural Killer cells and other immune cells seem to have a key role in controlling the tumor. T cells may be dysfunctional and remain in a state of T cell exhaustion, nonetheless, they often retain a high potential for successful defense against cancer, being able to be mobilized to become highly functional. The lack of clinical trials on a large scale makes data a little robust, in spite of promising information, there are still many variables in the studies relating to radiation and immune system. The clarification of the mechanisms underlying immune response to radiation exposure may contribute to treatment improvement, gain of life quality and span of patients.

The importance of radiotherapy on diffuse large B cell lymphoma treatment: a current review.

Diffuse large B cell lymphoma is recognized as a heterogeneous group of hematological malignancies; two main subtypes germinal center B and activated B cells are well defined although 15% of patients remain with unclassifiable disease. R-CHOP treatment has proven to provide very effective results in limited or advanced stage of the disease. However, treatment solely involving R-CHOP submits the patient to possible chemotherapy-induced toxicities, which may be avoided with the use of radiotherapy. Patients with early stage localized disease or who are particularly unresponsive to chemotherapy may be more suitable for mixed modality treatment with R-CHOP and consolidative radiotherapy. Although radiotherapy is being slowly phased out by other treatment strategies including chemotherapy and therapeutic drugs, it is still a highly important method of treatment. The different forms of radiotherapy can be used alongside these "new-age" treatment strategies to further improve prognostic outcomes and overall survival rates. The establishment of radiotherapy as a treatment strategy provides a highly beneficial prognostic advantage in early stage, localized disease.

Improved estimates of upper-ocean warming and multi-decadal sea-level rise.

Changes in the climate system's energy budget are predominantly revealed in ocean temperatures and the associated thermal expansion contribution to sea-level rise. Climate models, however, do not reproduce the large decadal variability in globally averaged ocean heat content inferred from the sparse observational database, even when volcanic and other variable climate forcings are included. The sum of the observed contributions has also not adequately explained the overall multi-decadal rise. Here we report improved estimates of near-global ocean heat content and thermal expansion for the upper 300 m and 700 m of the ocean for 1950-2003, using statistical techniques that allow for sparse data coverage and applying recent corrections to reduce systematic biases in the most common ocean temperature observations. Our ocean warming and thermal expansion trends for 1961-2003 are about 50 per cent larger than earlier estimates but about 40 per cent smaller for 1993-2003, which is consistent with the recognition that previously estimated rates for the 1990s had a positive bias as a result of instrumental errors. On average, the decadal variability of the climate models with volcanic forcing now agrees approximately with the observations, but the modelled multi-decadal trends are smaller than observed. We add our observational estimate of upper-ocean thermal expansion to other contributions to sea-level rise and find that the sum of contributions from 1961 to 2003 is about 1.5 +/- 0.4 mm yr(-1), in good agreement with our updated estimate of near-global mean sea-level rise (using techniques established in earlier studies) of 1.6 +/- 0.2 mm yr(-1).

Polymersomes as the Next Attractive Generation of Drug Delivery Systems: Definition, Synthesis and Applications.

Polymersomes are artificial nanoparticles formed by the self-assembly process of amphiphilic block copolymers composed of hydrophobic and hydrophilic blocks. They can encapsulate hydrophilic molecules in the aqueous core and hydrophobic molecules within the membrane. The composition of block copolymers can be tuned, enabling control of characteristics and properties of formed polymersomes and, thus, their application in areas such as drug delivery, diagnostics, or bioimaging. The preparation methods of polymersomes can also impact their characteristics and the preservation of the encapsulated drugs. Many methods have been described, including direct hydration, thin film hydration, electroporation, the pH-switch method, solvent shift method, single and double emulsion method, flash nanoprecipitation, and microfluidic synthesis. Considering polymersome structure and composition, there are several types of polymersomes including theranostic polymersomes, polymersomes decorated with targeting ligands for selective delivery, stimuli-responsive polymersomes, or porous polymersomes with multiple promising applications. Due to the shortcomings related to the stability, efficacy, and safety of some therapeutics in the human body, polymersomes as drug delivery systems have been good candidates to improve the quality of therapies against a wide range of diseases, including cancer. Chemotherapy and immunotherapy can be improved by using polymersomes to deliver the drugs, protecting and directing them to the exact site of action. Moreover, this approach is also promising for targeted delivery of biologics since they represent a class of drugs with poor stability and high susceptibility to in vivo clearance. However, the lack of a well-defined regulatory plan for polymersome formulations has hampered their follow-up to clinical trials and subsequent market entry.

Analytical methods for amatoxins: A comprehensive review.

Amatoxins are toxic bicyclic octapeptides found in certain wild mushroom species, particularly Amanita phalloides. These mushrooms contain predominantly α- and ß-amanitin, which can lead to severe health risks for humans and animals if ingested. Rapid and accurate identification of these toxins in mushroom and biological samples is crucial for diagnosing and treating mushroom poisoning. Analytical methods for the determination of amatoxins are critical to ensure food safety and prompt medical treatment. This review provides a comprehensive overview of the research literature on the determination of amatoxins in clinical specimens, biological and mushroom samples. We discuss the physicochemical properties of toxins, highlighting their influence on the choice of the analytical method and the importance of sample preparation, particularly solid-phase extraction with cartridges. Chromatographic methods are emphasised with a focus on liquid chromatography coupled to mass spectrometry as one of the most relevant analytical method for the determination of amatoxins in complex matrices. Furthermore, current trends and future perspectives in amatoxin detection are also suggested.

The Debate between the Human Microbiota and Immune System in Treating Aerodigestive and Digestive Tract Cancers: A Review.

The human microbiota comprises a group of microorganisms co-existing in the human body. Unbalanced microbiota homeostasis may impact metabolic and immune system regulation, shrinking the edge between health and disease. Recently, the microbiota has been considered a prominent extrinsic/intrinsic element of cancer development and a promising milestone in the modulation of conventional cancer treatments. Particularly, the oral cavity represents a yin-and-yang target site for microorganisms that can promote human health or contribute to oral cancer development, such as Fusobacterium nucleatum. Moreover, Helicobacter pylori has also been implicated in esophageal and stomach cancers, and decreased butyrate-producing bacteria, such as Lachnospiraceae spp. and Ruminococcaceae, have demonstrated a protective role in the development of colorectal cancer. Interestingly, prebiotics, e.g., polyphenols, probiotics (Faecalibacterium, Bifidobacterium, Lactobacillus, and Burkholderia), postbiotics (inosine, butyrate, and propionate), and innovative nanomedicines can modulate antitumor immunity, circumventing resistance to conventional treatments and could complement existing therapies. Therefore, this manuscript delivers a holistic perspective on the interaction between human microbiota and cancer development and treatment, particularly in aerodigestive and digestive cancers, focusing on applying prebiotics, probiotics, and nanomedicines to overcome some challenges in treating cancer.

Pediatric Drug Development: Reviewing Challenges and Opportunities by Tracking Innovative Therapies.

The paradigm of pediatric drug development has been evolving in a "carrot-and-stick"-based tactic to address population-specific issues. However, the off-label prescription of adult medicines to pediatric patients remains a feature of clinical practice, which may compromise the age-appropriate evaluation of treatments. Therefore, the United States and the European Pediatric Formulation Initiative have recommended applying nanotechnology-based delivery systems to tackle some of these challenges, particularly applying inorganic, polymeric, and lipid-based nanoparticles. Connected with these, advanced therapy medicinal products (ATMPs) have also been highlighted, with optimistic perspectives for the pediatric population. Despite the results achieved using these innovative therapies, a workforce that congregates pediatric patients and/or caregivers, healthcare stakeholders, drug developers, and physicians continues to be of utmost relevance to promote standardized guidelines for pediatric drug development, enabling a fast lab-to-clinical translation. Therefore, taking into consideration the significance of this topic, this work aims to compile the current landscape of pediatric drug development by (1) outlining the historic regulatory panorama, (2) summarizing the challenges in the development of pediatric drug formulation, and (3) delineating the advantages/disadvantages of using innovative approaches, such as nanomedicines and ATMPs in pediatrics. Moreover, some attention will be given to the role of pharmaceutical technologists and developers in conceiving pediatric medicines.

Colorectal cancer cell exosome and cytoplasmic membrane for homotypic delivery of therapeutic molecules.

Colorectal cancer (CRC) is one of the most common causes of death in the world. The multi-drug resistance, especially in metastatic colorectal cancer, drives the development of new strategies that secure a positive outcome and reduce undesirable side effects. Nanotechnology has made an impact in addressing some pharmacokinetic and safety issues related to administration of free therapeutic agents. However, demands of managing complex biointerfacing require equally complex methods for introducing stimuli-responsive or targeting elements. In order to procure a more efficient solution to the overcoming of biological barriers, the physiological functions of cancer cell plasma and exosomal membranes provided the source of highly functionalized coatings. Biomimetic nanovehicles based on colorectal cancer (CRC) membranes imparted enhanced biological compatibility, immune escape and protection to diverse classes of therapeutic molecules. When loaded with therapeutic load or used as a coating for other therapeutic nanovehicles, they provide highly efficient and selective cell targeting and uptake. This review presents a detailed overview of the recent application of homotypic biomimetic nanovehicles in the management of CRC. We also address some of the current possibilities and challenges associated with the CRC membrane biomimetics.

Amanitins in Wild Mushrooms: The Development of HPLC-UV-EC and HPLC-DAD-MS Methods for Food Safety Purposes.

Mushroom poisoning remains a serious food safety and health concern in some parts of the world due to its morbidity and mortality. Identification of mushroom toxins at an early stage of suspected intoxication is crucial for a rapid therapeutic decision. In this study, a new extraction method was developed to determine α- and ß-amanitin in mushroom samples collected from central Portugal. High-performance liquid chromatography with in-line ultraviolet and electrochemical detection was implemented to improve the specificity of the method. The method was fully validated for linearity (0.5-20.0 µg·mL-1), sensitivity, recovery, and precision based on a matrix-matched calibration method. The limit of detection was 55 µg mL-1 (UV) and 62 µg mL-1 (EC) for α-amanitin and 64 µg mL-1 (UV) and 24 µg mL-1 (EC) for ß-amanitin. Intra- and inter-day precision differences were less than 13%, and the recovery ratios ranged from 89% to 117%. The developed method was successfully applied to fourteen Amanita species (A. sp.) and compared with five edible mushroom samples after extraction with Oasis® PRIME HLB cartridges without the conditioning and equilibration step. The results revealed that the A. phalloides mushrooms present the highest content of α- and ß-amanitin, which is in line with the HPLC-DAD-MS. In sum, the developed analytical method could benefit food safety assessment and contribute to food-health security, as it is rapid, simple, sensitive, accurate, and selectively detects α- and ß-amanitin in any mushroom samples.

Osteosarcoma from the unknown to the use of exosomes as a versatile and dynamic therapeutic approach.

The most common primary malignant tumor of bone in children is osteosarcoma (OS). Nowadays, the prognosis and the introduction of chemotherapy in OS have improved survival rates of patients. Nevertheless, the results are still unsatisfactory, especially, in patients with recurrent disease or metastatic. OS chemotherapy has two main challenges related to treatment toxicity and multiple drug resistance. In this way, nanotechnology has developed nanosystems capable of releasing the drug directly at the OS cells and decreasing the drug's toxicity. Exosomes (Exo), a cell-derived nano-sized and a phospholipid vehicle, have been recognized as important drug delivery systems in several cancers. They are involved in a variety of biological processes and are an important mediator of long-distance intercellular communication. Exo can reduce inflammation and show low toxicity in healthy cells. Furthermore, the incorporation of specific proteins or peptides on the Exo surface improves their targeting capability in several clinical applications. Due to their unique structure and relevant characteristics, Exo is a promising nanocarrier for OS treatment. This review intends to describe the properties that turn Exo into an efficient, as well as safe nanovesicle for drug delivery and treatment of OS.

Where Is Nano Today and Where Is It Headed? A Review of Nanomedicine and the Dilemma of Nanotoxicology.

Worldwide nanotechnology development and application have fueled many scientific advances, but technophilic expectations and technophobic demands must be counterbalanced in parallel. Some of the burning issues today are the following: (1) Where is nano today? (2) How good are the communication and investment networks between academia/research and governments? (3) Is there any spotlight application for nanotechnology? Nanomedicine is a particular arm of nanotechnology within the healthcare landscape, focused on diagnosis, treatment, and monitoring of emerging (such as coronavirus disease 2019, COVID-19) and contemporary (including diabetes, cardiovascular diseases, neurodegenerative disorders, and cancer) diseases. However, it may only represent the bright side of the coin. In fact, in the recent past, the concept of nanotoxicology has emerged to address the dark shadows of nanomedicine. The nanomedicine field requires more nanotoxicological studies to identify undesirable effects and guarantee safety. Here, we provide an overall perspective on nanomedicine and nanotoxicology as central pieces of the giant puzzle of nanotechnology. First, the impact of nanotechnology on education and research is highlighted, followed by market trends and scientific output tendencies. In the next section, the nanomedicine and nanotoxicology dilemma is addressed through the interplay of in silico, in vitro, and in vivo models with the support of omics and microfluidic approaches. Lastly, a reflection on the regulatory issues and clinical trials is provided. Finally, some conclusions and future perspectives are proposed for a clearer and safer translation of nanomedicines from the bench to the bedside.

Novel Non-Viral Vectors Based on Pluronic® F68PEI with Application in Oncology Field.

Copolymers composed of low-molecular-weight polyethylenimine (PEI) and amphiphilic Pluronics® are safe and efficient non-viral vectors for pDNA transfection. A variety of Pluronic® properties provides a base for tailoring transfection efficacy in combination with the unique biological activity of this polymer group. In this study, we describe the preparation of new copolymers based on hydrophilic Pluronic® F68 and PEI (F68PEI). F68PEI polyplexes obtained by doping with free F68 (1:2 and 1:5 w/w) allowed for fine-tuning of physicochemical properties and transfection activity, demonstrating improved in vitro transfection of the human bone osteosarcoma epithelial (U2OS) and oral squamous cell carcinoma (SCC-9) cells when compared to the parent formulation, F68PEI. Although all tested systems condensed pDNA at varying polymer/DNA charge ratios (N/P, 5/1−100/1), the addition of free F68 (1:5 w/w) resulted in the formation of smaller polyplexes (<200 nm). Analysis of polyplex properties by transmission electron microscopy and dynamic light scattering revealed varied polyplex morphology. Transfection potential was also found to be cell-dependent and significantly higher in SCC-9 cells compared to the control bPEI25k cells, as especially evident at higher N/P ratios (>25). The observed selectivity towards transfection of SSC-9 cells might represent a base for further optimization of a cell-specific transfection vehicle.

New Advances in Biomedical Application of Polymeric Micelles.

In the last decade, nanomedicine has arisen as an emergent area of medicine, which studies nanometric systems, namely polymeric micelles (PMs), that increase the solubility and the stability of the encapsulated drugs. Furthermore, their application in dermal drug delivery is also relevant. PMs present unique characteristics because of their unique core-shell architecture. They are colloidal dispersions of amphiphilic compounds, which self-assemble in an aqueous medium, giving a structure-type core-shell, with a hydrophobic core (that can encapsulate hydrophobic drugs), and a hydrophilic shell, which works as a stabilizing agent. These features offer PMs adequate steric protection and determine their hydrophilicity, charge, length, and surface density properties. Furthermore, due to their small size, PMs can be absorbed by the intestinal mucosa with the drug, and they transport the drug in the bloodstream until the therapeutic target. Moreover, PMs improve the pharmacokinetic profile of the encapsulated drug, present high load capacity, and are synthesized by a reproducible, easy, and low-cost method. In silico approaches have been explored to improve the physicochemical properties of PMs. Based on this, a computer-aided strategy was developed and validated to enable the delivery of poorly soluble drugs and established critical physicochemical parameters to maximize drug loading, formulation stability, and tumor exposure. Poly(2-oxazoline) (POx)-based PMs display unprecedented high loading concerning water-insoluble drugs and over 60 drugs have been incorporated in POx PMs. Among various stimuli, pH and temperature are the most widely studied for enhanced drug release at the site of action. Researchers are focusing on dual (pH and temperature) responsive PMs for controlled and improved drug release at the site of action. These dual responsive systems are mainly evaluated for cancer therapy as certain malignancies can cause a slight increase in temperature and a decrease in the extracellular pH around the tumor site. This review is a compilation of updated therapeutic applications of PMs, such as PMs that are based on Pluronics®, micelleplexes and Pox-based PMs in several biomedical applications.

Recent advances in peptide-targeted micelleplexes: Current developments and future perspectives.

The decoding of the human genome revolutionized the understanding of how genetics influence the interplay between health and disease, in a multidisciplinary perspective. Thus, the development of exogenous nucleic acids-based therapies has increased to overcome hereditary or acquired genetic-associated diseases. Gene drug delivery using non-viral systems, for instance micelleplexes, have been recognized as promising options for gene-target therapies. Micelleplexes are core-shell structures, at a nanometric scale, designed using amphiphilic block copolymers. These can self-assemble in an aqueous medium, leading to the formation of a hydrophilic and positively charged corona - that can transport nucleic acids, - and a hydrophobic core - which can transport poor water-soluble drugs. However, the performance of these types of carriers usually is hindered by several in vivo barriers. Fortunately, due to a significant amount of research, strategies to overcome these shortcomings emerged. With a wide range of structural features, good stability against proteolytic degradation, affordable characteristic, easy synthesis, low immunogenicity, among other advantages, peptides have increasingly gained popularity as target ligands for non-viral carriers. Hence, this review addresses the use of peptides with micelleplexes illustrating, through the analysis of in vitro and in vivo studies, the potential and future perspectives of this combination.