A bio-ionic liquid based self-healable and adhesive ionic hydrogel for the on-demand transdermal delivery of a chemotherapeutic drug.

The non-invasive nature and potential for sustained release make transdermal drug administration an appealing treatment option for cancer therapy. However, the strong barrier of the stratum corneum (SC) poses a challenge for the penetration of hydrophilic chemotherapy drugs such as 5-fluorouracil (5-FU). Due to its biocompatibility and capacity to increase drug solubility and permeability, especially when paired with chemical enhancers, such as oleic acid (OA), which is used in this work, choline glycinate ([Cho][Gly]) has emerged as a potential substance for transdermal drug delivery. In this work, we examined the possibility of transdermal delivery of 5-FU for the treatment of breast cancer using an ionic hydrogel formulation consisting of [Cho][Gly] with OA. Small angle neutron scattering, rheological analysis, field emission scanning electron microscopy, and dynamic light scattering analysis were used to characterize the ionic hydrogel. The non-covalent interactions present between [Cho][Gly] and OA were investigated by computational simulations and FTIR spectroscopy methods. When subjected to in vitro drug permeation using goat skin in a Franz diffusion cell, the hydrogel demonstrated sustained release of 5-FU and effective permeability in the order: [Cho][Gly]-OA gel > [Cho][Gly] > PBS (control). The hydrogel also demonstrated 92% cell viability after 48 hours for the human keratinocyte cell line (HaCaT cells) as well as the normal human cell line L-132. The breast cancer cell line MCF-7 and the cervical cancer cell line HeLa were used to study in vitro cytotoxicity that was considerably affected by the 5-FU-loaded hydrogel. These results indicate the potential of the hydrogel as a transdermal drug delivery vehicle for the treatment of breast cancer.

Multifunctional Ionic Hydrogel-Based Transdermal Delivery of 5-Fluorouracil for the Breast Cancer Treatment.

Transdermal drug delivery systems (TDDS) are a promising and innovative approach for breast cancer treatment, offering advantages such as noninvasiveness, potential for localized and prolonged drug delivery while minimizing systemic side effects through avoiding first-pass metabolism. Utilizing the distinctive characteristics of hydrogels, such as their biocompatibility, versatility, and higher drug loading capabilities, in the present work, we prepared ionic hydrogels through synergistic interaction between ionic liquids (ILs), choline alanine ([Cho][Ala]), and choline proline ([Cho][Pro]) with oleic acid (OA). ILs used in the study are biocompatible and enhance the solubility of 5-fluorouracil (5-FU), whereas OA is a known chemical penetration enhancer. The concentration-dependent (OA) change in morphological aggregates, that is, from cylindrical micelles to worm-like micelles to hydrogels was formed with both ILs and was characterized by SANS measurement, whereas the interactions involved were confirmed by FTIR spectroscopy. The hydrogels have excellent mechanical properties, which studied by rheology and their morphology through FE-SEM analysis. The in vitro skin permeation study revealed that both hydrogels penetrated 255 times ([Cho][Ala]) and 250 times ([Cho][Pro]) more as compared to PBS after 48 h. Those ionic hydrogels exhibited the capability to change the lipid and keratin arrangements within the skin layer, thereby enhancing the transdermal permeation of the 5-FU. Both ionic hydrogels exhibit excellent biocompatibility with normal cell lines (L-132 cells) as well as cancerous cell lines (MCF-7 cells), demonstrating over 92% cell viability after 48 h in both cell lines. In vitro, the cytotoxicity of the 5-FU-loaded hydrogels was evaluated on MCF-7 and HeLa cell lines. These results indicate that the investigated biocompatible and nontoxic ionic hydrogels enable the transdermal delivery of hydrophilic drugs, making them a viable option for effectively treating breast cancer.

Chain length impact on the retro Diels-Alder mediated release of gemcitabine from hybrid nanoparticles towards pancreatic cancer therapy.

Previously reported gold coated iron oxide nanoparticles (Au-IONP's) have demonstrated their effectiveness as drug delivery vehicles for gemcitabine conjugated to a thermally labile Diels-Alder linker containing a chain of 4 carbon atoms (TTLD4) for the treatment of pancreatic cancer. Heat generated via laser irradiation of Au-IONPs facilitated retro Diels-Alder mediated release in a burst release profile where approximately half of all total release over 180 min occurred within the first 5 min. Two analogues of TTLD4, which differ only in linker chain length (TTLD3 & TTLD6) were synthesised and conjugated to Au-IONP's. Heat-mediated release of gemcitabine at 45 °C over 180 min from these formulations was confirmed to be based on linker length, which was 94%, 76% and 45% for TTLD3, TTLD4 and TTLD6, respectively. Drug loading of the Diels-Alder linkers in a 5:1 Drug/Au-IONP w/w ratio appears to favour those containing an even number of carbons TTLD4 (76%) & TTLD6 (57%) over TTLD3 (25%), possibly due to the linker likely being positioned perpendicular to the Au-IONP surface because of the 120 °C-C bond.

Exploration of Nanosilver Calcium Alginate-Based Multifunctional Polymer Wafers for Wound Healing.

Wound care is an integral part of effective recovery. However, its associated financial burden on national health services globally is significant enough to warrant further research and development in this field. In this study, multifunctional polymer wafers were prepared, which provide antibacterial activity, high cell viability, high swelling capacity and a thermally stable medium which can be used to facilitate the delivery of therapeutic agents. The purpose of this polymer wafer is to facilitate wound healing, by creating nanosilver particles within the polymer matrix itself via a one-pot synthesis method. This study compares the use of two synthetic agents in tandem, detailing the effects on the morphology and size of nanosilver particles. Two synthetic methods with varying parameters were tested, with one method using silver nitrate, calcium chloride and sodium alginate, whilst the other included aloe vera gel as an extra component, which serves as another reductant for nanosilver synthesis. Both methods generated thermally stable alginate matrices with high degrees of swelling capacities (400-900%) coupled with interstitially formed nanosilver of varying shapes and sizes. These matrices exhibited controlled nanosilver release rates which were able to elicit antibacterial activity against MRSA, whilst maintaining an average cell viability value of above 90%. Based on the results of this study, the multifunctional polymer wafers that were created set the standard for future polymeric devices for wound healing. These polymer wafers can then be further modified to suit specific types of wounds, thereby allowing this multifunctional polymer wafer to be applied to different wounding scenarios.

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. STATEMENT OF SIGNIFICANCE: Considering that conventional treatments for pancreatic cancer are highly associated with sub-optimal performance and systemic toxicity, the development of novel therapeutic strategies holds outmost relevance for pancreatic cancer management. Liposomes are being increasingly considered as promising nanocarriers for providing not only an early diagnosis but also effective, highly specific, and safer treatment, improving overall patient outcome. This manuscript is the first in the last 10 years that revises the advances in the application of liposome-based formulations in bioimaging, chemotherapy, phototherapy, immunotherapy, combination therapies, and emergent therapies for pancreatic cancer management. Prospective insights are provided regarding several advantages resulting from the use of liposome technology in precision strategies, fostering new ideas for next-generation diagnosis and targeted therapies of pancreatic cancer.

Exploration of Dual Ionic Cross-Linked Alginate Hydrogels Via Cations of Varying Valences towards Wound Healing.

This study explored the synergistic effects of simultaneously using calcium and gallium cations in the cross-linking of alginate, detailing its effects on the characteristics of alginate compared to its single cation counterparts. The primary goal is to determine if there are any synergistic effects associated with the utilisation of multiple multivalent cations in polymer cross-linking and whether or not it could therefore be used in pharmaceutical applications such as wound healing. Given the fact divalent and trivalent cations have never been utilised together for cross-linking, an explanation for the mode of binding that occurs between the alginate and the cations during the cross-linking process and how it may affect the future applications of the polymer has been investigated. The calcium gallium alginate polymers were able to retain the antibacterial effects of gallium within the confines of the polymer matrix, possessing superior rheological properties, 6 times that of pure calcium and pure gallium, coupled with an improved swelling capacity that is 4 times higher than that of gallium alginate.

3D printed biodegradable multifunctional implants for effective breast cancer treatment.

By carefully controlling the dose administered and the drug release rate from drug-eluting implants, safety and efficacy of the therapeutic agent dispensed can be improved. The present work focuses on the promising advantages of 3D Bioprinting process in developing two layers' implantable scaffolds. The two layers have different functions, in order to ensure a more effective and synergistic breast cancer therapy. First layer involves use of polymers such as Poly- ε-Caprolactone (PCL) and Chitosan (CS), and incorporation of 5-Fluorouracil (5-FU). The aim of the first layer is releasing the drug within 4 weeks, obtaining a prolonged and modified release. According to in vitro drug release tests performed, ∼32 % of 5-FU was released after one month, after an initial burst effect of 17.22 %. The sudden release of the drug into the body would quickly reach an effective therapeutic concentration, while the drug sustained release maintains an effective therapeutic concentration range during the administration time. The second layer is made exclusively from PCL as polymeric matrix, into which Gold Nanoparticles (AuNPs) were subsequently loaded, and its main purpose is to be radiation enhancement. The long biodegradation time of PCL would make the non-soluble scaffold an alternative to conventional chemotherapy, optimizing drug release to the specific needs of the patients.

Electrocatalytic enhancement of [Ru(bpy)3]2+ electrochemiluminescence for gemcitabine detection toward precision measurement via gold nanoparticle addition.

With a rise in the development and subsequent employment of precision medicine, their lies an immediate necessity for the development of technology to enable the implementation of such treatment plans into the healthcare environment. Electrochemistry stands to offer one of the most viable techniques for such technologies given its success within current medical devices. One electrochemical technique, electrochemiluminescence (ECL), warrants investigation. Previously we have determined the inability to reliably detect cancer therapy gemcitabine via traditional ruthenium based ECL. Here we demonstrate how the addition of gold nanoparticles into the ECL film can promote GMB detection via enhanced electrocatalytic oxidation, generating the required ECL radicals. Via this approach we have been able to improve the ECL signal intensity 60-fold and achieve detection down to 6.25 µM across a linear range of 6.25-50 µM. Which lies within the therapeutically relevant range. This approach has successfully addressed the prior limitations encountered for the employment of traditional ruthenium based ECL for substance identification, where species exhibit limited electro-activity and suffer from electrochemically induced side reactions.

Current and future strategies against cutaneous parasites.

Cutaneous parasites are identified by their specific cutaneous symptoms which are elicited based on the parasite's interactions with the host. Standard anti-parasitic treatments primarily focus on the use of specific drugs to disrupt the regular function of the target parasite. In cases where secondary infections are induced by the parasite itself, antibiotics may also be used in tandem with the primary treatment to deal with the infection. Whilst drug-based treatments are highly effective, the development of resistance by bacteria and parasites, is increasingly prevalent in the modern day, thus requiring the development of non-drug based anti-parasitic strategies. Cutaneous parasites vary significantly in terms of the non-systemic methods that are required to deal with them. The main factors that need to be considered are the specifically elicited cutaneous symptoms and the relative cutaneous depth in which the parasites typically reside in. Due to the various differences in their migratory nature, certain cutaneous strategies are only viable for specific parasites, which then leads to the idea of developing an all-encompassing anti-parasitic strategy that works specifically against cutaneous parasites. The main benefit of this would be the overall time saved in regards to the period that is needed for accurate diagnosis of parasite, coupled with the prescription and application of the appropriate treatment based on the diagnosis. This review will assess the currently identified cutaneous parasites, detailing their life cycles which will allow for the identification of certain areas that could be exploited for the facilitation of cutaneous anti-parasitic treatment.

Investigation into the Use of Microfluidics in the Manufacture of Metallic Gold-Coated Iron Oxide Hybrid Nanoparticles.

Hybrid iron oxide-gold nanoparticles are of increasing interest for applications in nanomedicine, photonics, energy storage, etc. However, they are often difficult to synthesise without experience or 'know-how'. Additionally, standard protocols do not allow for scale up, and this is significantly hindering their future potential. In this study, we seek to determine whether microfluidics could be used as a new manufacturing process to reliably produce hybrid nanoparticles with the line of sight to their continuous manufacture and scaleup. Using a Precision Nano NanoAssemblr Benchtop® system, we were able to perform the intermediate coating steps required in order to construct hybrid nanoparticles around 60 nm in size with similar chemical and physical properties to those synthesised in the laboratory using standard processes, with Fe/Au ratios of 1:0.6 (standard) and 1:0.7 (microfluidics), indicating that the process was suitable for their manufacture with optimisation required in order to configure a continuous manufacturing plant.

Potential use of the Diels-Alder reaction in biomedical and nanomedicine applications.

The Diels-Alder reaction and its retro breakdown has garnered increasing research focus due to several of its advantageous properties including, atomic conservation, reversibility, and substituent retention. This is especially true in biomedical application and nanomedicine development which display a preference for rapid, efficient, and clean "click" chemistry reactions allowing for delivery of active ingredients and subsequent release upon temperature elevation. There are multiple variations on the Diels-Alder reaction based around substitution position and materials being coupled which can affect the temperature threshold for and rate of the retro reaction reversal. Hence, the Diels-Alder reaction offers a simple coupling reaction for active ingredients with tailorable release. In this review the incorporation of the Diels-Alder chemistries and linkers within the biomedical and nanomedicine field will be discussed, as well as its use in future potential technologies.

Unleashing the potential of cell membrane-based nanoparticles for COVID-19 treatment and vaccination.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a particular coronavirus strain responsible for the coronavirus disease 2019 (COVID-19), accounting for more than 3.1 million deaths worldwide. Several health-related strategies have been successfully developed to contain the rapidly-spreading virus across the globe, toward reduction of both disease burden and infection rates. Particularly, attention has been focused on either the development of novel drugs and vaccines, or by adapting already-existing drugs for COVID-19 treatment, mobilizing huge efforts to block disease progression and to overcome the shortage of effective measures available at this point.Areas covered: This perspective covers the breakthrough of multifunctional biomimetic cell membrane-based nanoparticles as next-generation nanosystems for cutting-edge COVID-19 therapeutics and vaccination, specifically cell membrane-derived nanovesicles and cell membrane-coated nanoparticles, both tailorable cell membrane-based nanosystems enriched with the surface repertoire of native cell membranes, toward maximized biointerfacing, immune evasion, cell targeting and cell-mimicking properties.Expert opinion: Nano-based approaches have received widespread interest regarding enhanced antigen delivery, prolonged blood circulation half-life and controlled release of drugs. Cell membrane-based nanoparticles comprise interesting antiviral multifunctional nanoplatforms for blocking SARS-CoV-2 binding to host cells, reducing inflammation through cytokine neutralization and improving drug delivery toward COVID-19 treatment.

Thermally reactive N-(2-hydroxypropyl)methacrylamide (HPMA) amphiphiles for drug solubilisation.

Thermally active polymers, can respond structurally to temperature changes, making them interesting as potential drug delivery vehicles. Polymers of N-(3-aminopropyl) methacrylamide hydrochloride (APMA) are cationic with primary amine groups in their structure, which have been explored in biomedical applications via post-polymerisation modifications. In this work, we synthesised amphiphilic APMA monomers using hydrophobic pendant groups via conjugation onto their primary amine group. The pendant groups chosen in this study were palmitoyl, dansyl and cholesteryl moieties. The amphiphilic monomers were subsequently copolymerized with N-(2-hydroxypropyl)methacrylamide (HPMA) using varied monomer feed ratios resulting in a thermo-responsive system. The ability of the resultant aggregates in aqueous solution to encapsulate and liberate model drugs (e.g., propofol, griseofulvin and prednisolone) was then determined. Our data showed that the HPMA based formulations were capable of loading the model drug molecules inside their lipophilic core; HPMA-co-(APMA-Dansyl 2%) exhibited the largest drug encapsulation ability. Subsequently, poly(ethylene glycol) (PEG) was incorporated into the intrinsic polymer structure. This resulted in a more rapid drug release profile, whereby 100% of griseofulvin and prednisolone were liberated after only 4 h, which was only 5% and 10% before the PEG inclusion, respectively. Similarly, propofol showed 70% liberation from the polymer aggregate after 24 h, compared with only 30% liberation pre-PEGylation. These studies give an insight into the potential of the HMPA based amphiphiles as thermally responsive cargo carrier/release systems which could be exploited in the delivery of poorly soluble drugs.

Using circular economy principles to recycle materials in guiding the design of a wet scrubber-reactor for indoor air disinfection from coronavirus and other pathogens.

An arduous need exists to discover rapid solutions to avoid the accelerated spread of coronavirus especially through the indoor environments like offices, hospitals, and airports. One such measure could be to disinfect the air, especially in indoor environments. The goal of this work is to propose a novel design of a wet scrubber-reactor to deactivate airborne microbes using circular economy principles. Based on Fenton's reaction mechanism, the system proposed here will deactivate airborne microbes (bioaerosols) such as SARS-CoV-2. The proposed design relies on using a highly porous clay-glass open-cell structure as an easily reproducible and cheap material. The principle behind this technique is an in-situ decomposition of hydrogen peroxide into highly reactive oxygen species and free radicals. The high porosity of a tailored ceramic structure provides a high contact area between atomized oxygen, free radicals and supplied polluted air. The design is shown to comply with the needs of achieving sustainable development goals.

Co-Delivery of Letrozole and Cyclophosphamide via Folic Acid-Decorated Nanoniosomes for Breast Cancer Therapy: Synergic Effect, Augmentation of Cytotoxicity, and Apoptosis Gene Expression.

Breast cancer is one of the most prevalent causes of cancer mortality in women. In order to increase patient prognosis and survival rates, new technologies are urgently required to deliver therapeutics in a more effective and efficient manner. Niosome nanoparticles have been recently employed as therapeutic platforms capable of loading and carrying drugs within their core for both mono and combination therapy. Here, niosome-based nanoscale carriers were investigated as a targeted delivery system for breast cancer therapy. The platform developed consists of niosomes loaded with letrozole and cyclophosphamide (NLC) and surface-functionalized with a folic-acid-targeting moiety (NLCPFA). Drug release from the formulated particles exhibited pH-sensitive properties in which the niosome showed low and high release in physiological and cancerous conditions, respectively. The results revealed a synergic effect in cytotoxicity by co-loading letrozole and cyclophosphamide with an efficacy increment in NLCPFA use in comparison with NLC. The NLCPFA resulted in the greatest drug internalization compared to the non-targeted formulation and the free drug. Additionally, downregulation of cyclin-D, cyclin-E, MMP-2, and MMP-9 and upregulating the expression of caspase-3 and caspase-9 genes were observed more prominently in the nanoformulation (particularly for NLCPFA) compared to the free drug. This exciting data indicated that niosome-based nanocarriers containing letrozole and cyclophosphamide with controlled release could be a promising platform for drug delivery with potential in breast cancer therapy.

Cancer Nanomedicine.

This Special Issue on Cancer Nanomedicine within Cancers brings together 46 cutting-edge papers covering research within the field along with insightful reviews and opinions reflecting our community [...].

Resilient and agile engineering solutions to address societal challenges such as coronavirus pandemic.

The world is witnessing tumultuous times as major economic powers including the US, UK, Russia, India, and most of Europe continue to be in a state of lockdown. The worst-hit sectors due to this lockdown are sales, production (manufacturing), transport (aerospace and automotive) and tourism. Lockdowns became necessary as a preventive measure to avoid the spread of the contagious and infectious "Coronavirus Disease 2019" (COVID-19). This newly identified disease is caused by a new strain of the virus being referred to as Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS CoV-2; formerly called 2019-nCoV). We review the current medical and manufacturing response to COVID-19, including advances in instrumentation, sensing, use of lasers, fumigation chambers and development of novel tools such as lab-on-the-chip using combinatorial additive and subtractive manufacturing techniques and use of molecular modelling and molecular docking in drug and vaccine discovery. We also offer perspectives on future considerations on climate change, outsourced versus indigenous manufacturing, automation, and antimicrobial resistance. Overall, this paper attempts to identify key areas where manufacturing can be employed to address societal challenges such as COVID-19.

The regulation of nanomaterials and nanomedicines for clinical application: current and future perspectives.

The use of nanomaterials in biomedicine has increased over the past 10 years, with many different nanoparticle systems being utilised within the clinical setting. With limited emerging success in clinical trials, polymeric, metallic, and lipid based nanoparticles have all found a place in medicine, with these generally providing enhanced drug efficacy or therapeutic effect compared to the standard drug treatments. Although there is great anticipation surrounding the field of nanomedicine and its influence on the pharmaceutical industry, there is currently very little regulatory guidance in this area, despite repeated calls from the research community, something that is critical to provide legal certainty to manufacturers, policymakers, healthcare providers and the general public. This is reflected in the lack of an international definition of what these materials are, with several bodies, including the National Institute of Health, USA, the European Science Foundation and the European Technology Platform, having differing definitions, and the FDA having no clear definition at all. The uncertainty created by the lack of consistency across the board may ultimately impact funding, research and development of such products negatively thus destroying public acceptance and perception of nano-products. This review aims to discuss the use of nanomaterials within the clinical setting, why regulation of these materials is so important, and the challenges faced in regulating these materials generally, as well as the current regulation used in different nations.