Simultaneous Light-Triggered Release of Nitric Oxide and Carbon Monoxide from a Lipid-Coated Upconversion Nanosystem Inhibits Colon Tumor Growth.

Gas therapy has gained noteworthy attention in biomedical research, with the rise of gas-releasing molecules enhancing their therapeutic potential, especially when integrated into nano-based drug delivery systems. Herein, we present a lipid-coated gas delivery system to simultaneously shuttle two gas-releasing molecules carrying nitric oxide (NO) and carbon monoxide (CO), respectively. Upconversion nanoparticles (UCNPs) are designed to generate photons at 360 nm upon 808 nm of near-infrared (NIR) irradiation. These in situ-generated UV photons trigger simultaneous NO and CO release from S-nitrosoglutathione (GSNO) and the CO-releasing molecule (CORM), respectively, which are coloaded into lipid-coated UCNP/GSNO/CORM/FA nanoparticles (LUGCF). LUGCF with a GSNO/CORM mass ratio of 2:1 is determined to be optimal in terms of synergistically instigating apoptosis in HCT116 and CT26 colon cancer cells, where both NO/CO are released and subsequent production of ROS are detected. This CO/NO combination nanoplatform exhibits a very effective inhibition of colon tumor growth in vivo at relatively low doses upon a mild 808 nm irradiation. Overall, we effectively integrated two therapeutic gas-releasing molecules in one NIR-responsive nanosystem, presenting a promising therapeutic strategy for future biomedical applications in dual-gas cancer therapy.

Targeting endothelial vascular cell adhesion molecule-1 in atherosclerosis: drug discovery and development of vascular cell adhesion molecule-1-directed novel therapeutics.

Vascular cell adhesion molecule-1 (VCAM-1) has been well established as a critical contributor to atherosclerosis and consequently as an attractive therapeutic target for anti-atherosclerotic drug candidates. Many publications have demonstrated that disrupting the VCAM-1 function blocks monocyte infiltration into the sub-endothelial space, which effectively prevents macrophage maturation and foam cell transformation necessary for atherosclerotic lesion formation. Currently, most VCAM-1-inhibiting drug candidates in pre-clinical and clinical testing do not directly target VCAM-1 itself but rather down-regulate its expression by inhibiting upstream cytokines and transcriptional regulators. However, the pleiotropic nature of these regulators within innate immunity means that optimizing dosage to a level that suppresses pathological activity while preserving normal physiological function is extremely challenging and oftentimes infeasible. In recent years, highly specific pharmacological strategies that selectively inhibit VCAM-1 function have emerged, particularly peptide- and antibody-based novel therapeutics. Studies in such VCAM-1-directed therapies so far remain scarce and are limited by the constraints of current experimental atherosclerosis models in accurately representing the complex pathophysiology of the disease. This has prompted the need for a comprehensive review that recounts the evolution of VCAM-1-directed pharmaceuticals and addresses the current challenges in novel anti-atherosclerotic drug development.

Nanoceria: an innovative strategy for cancer treatment.

Nanoceria or cerium oxide nanoparticles characterised by the co-existing of Ce3+ and Ce4+ that allows self-regenerative, redox-responsive dual-catalytic activities, have attracted interest as an innovative approach to treating cancer. Depending on surface characteristics and immediate environment, nanoceria exerts either anti- or pro-oxidative effects which regulate reactive oxygen species (ROS) levels in biological systems. Nanoceria mimics ROS-related enzymes that protect normal cells at physiological pH from oxidative stress and induce ROS production in the slightly acidic tumour microenvironment to trigger cancer cell death. Nanoceria as nanozymes also generates molecular oxygen that relieves tumour hypoxia, leading to tumour cell sensitisation to improve therapeutic outcomes of photodynamic (PDT), photothermal (PTT) and radiation (RT), targeted and chemotherapies. Nanoceria has been engineered as a nanocarrier to improve drug delivery or in combination with other drugs to produce synergistic anti-cancer effects. Despite reported preclinical successes, there are still knowledge gaps arising from the inadequate number of studies reporting findings based on physiologically relevant disease models that accurately represent the complexities of cancer. This review discusses the dual-catalytic activities of nanoceria responding to pH and oxygen tension gradient in tumour microenvironment, highlights the recent nanoceria-based platforms reported to be feasible direct and indirect anti-cancer agents with protective effects on healthy tissues, and finally addresses the challenges in clinical translation of nanoceria based therapeutics.

Protein Nanoparticles for Enhanced Oral Delivery of Coenzyme-Q10: in Vitro and in Silico Studies.

Coenzyme-Q10 (CoQ10) is a hydrophobic benzoquinone with antioxidant and anti-inflammatory properties. It is known to reduce oxidative stress in various health conditions. However, due to the low solubility, permeability, stability, and poor oral bioavailability, the oral dose of CoQ10 required for the desired therapeutic effect is very high. In the present study, CoQ10 is encapsulated into two milk derived proteins ß-lactoglobulin and lactoferrin (BLG and LF) to produce self-assembled nanostructures of around 100-300 nm with high encapsulation efficiency (5-10% w/w). Both CoQ10-BLG and CoQ10-LF nanoparticles (NPs) significantly improved the aqueous solubility of CoQ10 60-fold and 300-fold, compared to CoQ10 alone, which hardly dissolves in water. Insight into the difference in solubility enhancement between BLG and LF was obtained using in silico modeling, which predicted that LF possesses multiple prospective CoQ10 binding sites, potentially enabling greater loading of CoQ10 on LF compared to BLG, which was predicted to be less capable of binding CoQ10. At pH 7.4, CoQ10-LF NPs showed a burst release between 30 min and 2 h then plateaued at 12 h with 30% of the total drug released over 48 h. However, pure CoQ10-BLG and pure CoQ10 had a significantly lower release rate with less than 15% and 8% cumulative release in 48 h, respectively. Most importantly, both BLG and LF NPs significantly improved CoQ10 permeability compared to the pre-dissolved drug across the Caco-2 monolayer with up to 2.5-fold apparent permeability enhancement for CoQ10-LF─further confirming the utility of this nanoencapsulation approach. Finally, in murine macrophage cells (J774A.1), CoQ10-LF NPs displayed significantly higher anti-ROS properties compared to CoQ10 (predissolved in DMSO) without affecting the cell viability. This study paves the way in improving oral bioavailability of poorly soluble drugs and nutraceuticals using milk-based self-assembled nanoparticles.

Visions by WIMIN: Global Mentorship to Retain Underrepresented Trainees.

Mentorship is a fundamental aspect that contributes to the success of a career in science, technology, engineering, and mathematics (STEM), particularly in academia. Research suggests that underrepresented minorities (URMs) often experience less quality mentorship and face barriers to finding successful mentor-mentee relationships. URM trainees in STEM face challenges that are not encountered by their majority peers or mentors, adding another level of complexity to establishing important relationships. Mentors of URM trainees must therefore mentor beyond general scientific training and tailor their mentorship to be more culturally appropriate and inclusive, allowing URM trainees to bring their whole selves to the table and leading to their effective socialization. Herein, we present the perspectives of group leaders and trainees from around the globe to highlight key aspects of creating successful mentor-mentee relationships that are sustainable and productive for both parties.

Enhanced Blood Plasma Extraction Utilising Viscoelastic Effects in a Serpentine Microchannel.

Plasma extraction from blood is essential for diagnosis of many diseases. The critical process of plasma extraction requires removal of blood cells from whole blood. Fluid viscoelasticity promotes cell migration towards the central axis of flow due to differences in normal stress and physical properties of cells. We investigated the effects of altering fluid viscoelasticity on blood plasma extraction in a serpentine microchannel. Poly (ethylene oxide) (PEO) was dissolved into blood to increase its viscoelasticity. The influences of PEO concentration, blood dilution, and flow rate on the performance of cell focusing were examined. We found that focusing performance can be significantly enhanced by adding PEO into blood. The optimal PEO concentration ranged from 100 to 200 ppm with respect to effective blood cell focusing. An optimal flow rate from 1 to 15 µL/min was determined, at least for our experimental setup. Given less than 1% haemolysis was detected at the outlets in all experimental combinations, the proposed microfluidic methodology appears suitable for applications sensitive to haemocompatibility.

Therapeutic gas-releasing nanomedicines with controlled release: Advances and perspectives.

Nanoparticle-based drug delivery has become one of the most popular approaches for maximising drug therapeutic potentials. With the notable improvements, a greater challenge hinges on the formulation of gasotransmitters with unique challenges that are not met in liquid and solid active ingredients. Gas molecules upon release from formulations for therapeutic purposes have not really been discussed extensively. Herein, we take a critical look at four key gasotransmitters, that is, carbon monoxide (CO), nitric oxide (NO), hydrogen sulphide (H2S) and sulphur dioxide (SO2), their possible modification into prodrugs known as gas-releasing molecules (GRMs), and their release from GRMs. Different nanosystems and their mediatory roles for efficient shuttling, targeting and release of these therapeutic gases are also reviewed extensively. This review thoroughly looks at the diverse ways in which these GRM prodrugs in delivery nanosystems are designed to respond to intrinsic and extrinsic stimuli for sustained release. In this review, we seek to provide a succinct summary for the development of therapeutic gases into potent prodrugs that can be adapted in nanomedicine for potential clinical use.

Engineering chitosan nano-cocktail containing iron oxide and ceria: A two-in-one approach for treatment of inflammatory diseases and tracking of material delivery.

In this study, modular two-in-one nano-cocktails were synthesised to provide treatment of inflammatory diseases and also enable tracking of their delivery to the disease sites. Chitosan nano-cocktails loaded with treatment module (cerium oxide nanoparticles) and imaging module (iron oxide nanoparticles) were synthesised by electrostatic self-assembly (Chit-IOCO) and ionic gelation method (Chit-TPP-IOCO), respectively. Their MRI capability, anti-inflammatory and anti-fibrosis ability were investigated. Results demonstrated that Chit-IOCO significantly reduced the expression of TNF-α and COX-2, while Chit-TPP-IOCO reduced IL-6 in the LPS-stimulated macrophages RAW264.7. Cytotoxicity studies showed that the nano-cocktails inhibited the proliferation of macrophages. Additionally, Chit-IOCO exhibited higher in vitro MRI relaxivity than Chit-TPP-IOCO, indicating that Chit-IOCO is a better MRI contrast agent in macrophages. It was possible to track the delivery of Chit-IOCO to the inflamed livers of CCl4-treated C57BL/6 mice, demonstrated by a shortened T2⁎ relaxation time of the livers after injecting Chit-IOCO into mice. In vivo anti-inflammatory and blood tests demonstrated that Chit-IOCO reduced inflammation-related proteins (TNF-a, iNOS and Cox-2) and bilirubin in CCl4 treated C57BL/6. Histology images indicated that the nano-cocktails at the treatment doses did not affect the organs of the mice. Importantly, the nano-cocktail reduced fibrosis of CCl4-treated mouse liver. This is the first reported data on the anti-inflammation and anti-fibrosis efficacy of Chit-IOCO in C57BL/6 mouse liver inflammation model. Overall, Chit-IOCO nanoparticles have shown great potential in MR imaging/detecting and treating/therapeutic capabilities for inflammatory diseases.

Different approaches to synthesising cerium oxide nanoparticles and their corresponding physical characteristics, and ROS scavenging and anti-inflammatory capabilities.

The biological applications of cerium oxide nanoparticles (nanoceria) have received extensive attention in recent decades. The coexistence of trivalent cerium and tetravalent cerium on the surface of nanoceria allows the scavenging of reactive oxygen species (ROS). The regeneratable changes between Ce3+ and Ce4+ make nanoceria a suitable therapeutic agent for treating ROS-related diseases and inflammatory diseases. The size, morphology and Ce3+/Ce4+ state of cerium oxide nanoparticles are affected by the synthesis method. This review focuses on various synthesis methods of cerium oxide nanoparticles and discusses their corresponding physical characteristics, and anti-ROS and anti-inflammatory properties.

Vitamin E-facilitated carbon monoxide pro-drug nanomedicine for efficient light-responsive combination cancer therapy.

The quest to maximize therapeutic efficiency in cancer treatment requires innovative delivery nanoplatforms capable of employing different modules simultaneously. Combination therapy has proven to be one of the best anticancer strategies so far. Herein, we have developed a lipid-encapsulated nanoplatform that combines chemotherapy with photoresponsive gas therapy for colon cancer treatment. Carbon monoxide releasing molecules (CORMs) and vitamin E analogues (pure/pegylated α-tocopheryl succinate; α-TOS) were co-loaded into the lipid layer with core-shell upconversion nanoparticles (UCNPs), which converted 808 nm light to 360 nm photons to trigger CO release at the tumor site. This folic acid (FA)-targeting nanomedicine (Lipid/UCNP/CORM/α-TOS/FA: LUCTF) possessed a cancer-targeting ability and a light-triggered CO release ability for synergistic apoptosis of HCT116 cells via enhanced ROS generation and mitochondrial membrane breaking. In vivo data have confirmed the significantly enhanced therapeutic efficacy of LUCTF without any significant biosafety issues after intravenous administration. Thus, nanomedicine LUCTF represents a novel way for efficient cancer therapy via combining locally released CO and a compatible chemotherapeutic agent (e.g. α-TOS).

Recent Advances in the Development of Theranostic Nanoparticles for Cardiovascular Diseases.

Cardiovascular disease (CVD) is the leading cause of death worldwide. CVD includes a group of disorders of the heart and blood vessels such as myocardial infarction, ischemic heart, ischemic injury, injured arteries, thrombosis and atherosclerosis. Amongst these, atherosclerosis is the dominant cause of CVD and is an inflammatory disease of the blood vessel wall. Diagnosis and treatment of CVD remain the main challenge due to the complexity of their pathophysiology. To overcome the limitations of current treatment and diagnostic techniques, theranostic nanomaterials have emerged. The term "theranostic nanomaterials" refers to a multifunctional agent with both therapeutic and diagnostic abilities. Theranostic nanoparticles can provide imaging contrast for a diversity of techniques such as magnetic resonance imaging (MRI), positron emission tomography (PET) and computed tomography (CT). In addition, they can treat CVD using photothermal ablation and/or medication by the drugs in nanoparticles. This review discusses the latest advances in theranostic nanomaterials for the diagnosis and treatment of CVDs according to the order of disease development. MRI, CT, near-infrared spectroscopy (NIR), and fluorescence are the most widely used strategies on theranostics for CVDs detection. Different treatment methods for CVDs based on theranostic nanoparticles have also been discussed. Moreover, current problems of theranostic nanoparticles for CVDs detection and treatment and future research directions are proposed.

Investigation of viscoelastic focusing of particles and cells in a zigzag microchannel.

Microfluidic particle focusing has been a vital prerequisite step in sample preparation for downstream particle separation, counting, detection, or analysis, and has attracted broad applications in biomedical and chemical areas. Besides all the active and passive focusing methods in Newtonian fluids, particle focusing in viscoelastic fluids has been attracting increasing interest because of its advantages induced by intrinsic fluid property. However, to achieve a well-defined focusing position, there is a need to extend channel lengths when focusing micrometer-sized or sub-microsized particles, which would result in the size increase of the microfluidic devices. This work investigated the sheathless viscoelastic focusing of particles and cells in a zigzag microfluidic channel. Benefit from the zigzag structure of the channel, the channel length and the footprint of the device can be reduced without sacrificing the focusing performance. In this work, the viscoelastic focusing, including the focusing of 10 µm polystyrene particles, 5 µm polystyrene particles, 5 µm magnetic particles, white blood cells (WBCs), red blood cells (RBCs), and cancer cells, were all demonstrated. Moreover, magnetophoretic separation of magnetic and nonmagnetic particles after viscoelastic pre-focusing was shown. This focusing technique has the potential to be used in a range of biomedical applications.

Collagen and the effect of poly-l-lactic acid based materials on its synthesis.

Collagen is an important protein in various biological functions such as providing elasticity and waterproofing to the skin, structural stability to the cells in connective tissues (e.g. tendons, and bone) and stabilisation of atherosclerotic plaques. Collagen as a peptide with a peculiar triple helical structure is majorly composed of glycine and proline amino acids and is synthesised by fibroblasts via intracellular and extracellular mechanisms. Collagen plays an important role in wound healing, bone repair and plaque build-up during atherosclerosis. Various factors such as interleukins, insulin-like growth factor-I, nicotine, and glucose have been shown to influence collagen synthesis. This paper provides an overview of collagen structure, synthesis mechanisms, and the parameters that stimulate those mechanisms. Poly-l-lactic acid as a well-known biocompatible and biodegradable polymer has proved to stimulate collagen synthesis in various physical forms. As such, in this review special emphasis is laid on the effects of poly-l-lactic acid as well as its mechanism of action on collagen synthesis.

Poly(aspartic acid) in Biomedical Applications: From Polymerization, Modification, Properties, Degradation, and Biocompatibility to Applications.

Poly(aspartic acid) (PASP) is an anionic polypeptide that is a highly versatile, biocompatible, and biodegradable polymer that fulfils key requirements for use in a wide variety of biomedical applications. The derivatives of PASP can be readily tailored via the amine-reactive precursor, poly(succinimide) (PSI), which opens up a large window of opportunity for the design and development of novel biomaterials. PASP also has a strong affinity with calcium ions, resulting in complexation, which has been exploited for bone targeting and biomineralization. In addition, recent studies have further verified the biocompatibility and biodegradability of PASP-based polymers, which is attributed to their protein-like structure. In light of growing interest in PASP and its derivatives, this paper presents a comprehensive review on their synthesis, characterization, modification, biodegradation, biocompatibility, and applications in biomedical areas.

Targeted Molecular Imaging of Cardiovascular Diseases by Iron Oxide Nanoparticles.

Cardiovascular disease is one of the major contributors to global disease burden. Atherosclerosis is an inflammatory process that involves the accumulation of lipids and fibrous elements in the large arteries, forming an atherosclerotic plaque. Rupture of unstable plaques leads to thrombosis that triggers life-threatening complications such as myocardial infarction. Current diagnostic methods are invasive as they require insertion of a catheter into the coronary artery. Molecular imaging techniques, such as magnetic resonance imaging, have been developed to image atherosclerotic plaques and thrombosis due to its high spatial resolution and safety. The sensitivity of magnetic resonance imaging can be improved with contrast agents, such as iron oxide nanoparticles. This review presents the most recent advances in atherosclerosis, thrombosis, and myocardial infarction molecular imaging using iron oxide-based nanoparticles. While some studies have shown their effectiveness, many are yet to undertake comprehensive testing of biocompatibility. There are still potential hazards to address and complications to diagnosis, therefore strategies for overcoming these challenges are required.

Lipid-encapsulated upconversion nanoparticle for near-infrared light-mediated carbon monoxide release for cancer gas therapy.

Cancer gas therapy is just in an early stage of research and development. Several important gasotransmitters have proven their therapeutic potentials, but handling, delivery and controlled release of these gases remain very challenging for therapeutic purposes. This research develops a versatile nanosystem that is capable of delivering carbon monoxide (CO) gasotransmitter in the form of photo-responsive carbon monoxide-releasing molecule (CORM) for targeted cancer therapy. The core-shell upconversion nanoparticles (UCNPs) were designed to transfer bio-friendly low energy near infrared (NIR) light to ultraviolet (UV) light and trigger CO release from the loaded CORM. The synthesized delivery system demonstrated its ability to mediate the sustained release of CO upon 808 or 980 nm NIR light excitation. The optimized nanoformulation was efficiently taken up by HCT116 cancer cells and showed dose-dependent cytotoxicity to HCT116 and other cancer cells. Intracellular CO release and subsequent therapeutic action involving ROS production were found to significantly contribute to cell apoptosis. Therefore, the current research demonstrates the potency and efficiency of an NIR-mediated UCNP-based CORM prodrug delivery system for targeted cancer gas therapy.

Different Approaches to Develop Nanosensors for Diagnosis of Diseases.

The success of clinical treatments is highly dependent on early detection and much research has been conducted to develop fast, efficient, and precise methods for this reason. Conventional methods relying on nonspecific and targeting probes are being outpaced by so-called nanosensors. Over the last two decades a variety of activatable sensors have been engineered, with a great diversity concerning the operating principle. Therefore, this review delineates the achievements made in the development of nanosensors designed for diagnosis of diseases.

Surface Modification Techniques for Endothelial Cell Seeding in PDMS Microfluidic Devices.

Microfluidic lab-on-a-chip cell culture techniques have been gaining popularity by offering the possibility of reducing the amount of samples and reagents and greater control over cellular microenvironment. Polydimethylsiloxane (PDMS) is the commonly used polymer for microfluidic cell culture devices because of the cheap and easy fabrication techniques, non-toxicity, biocompatibility, high gas permeability, and optical transparency. However, the intrinsic hydrophobic nature of PDMS makes cell seeding challenging when applied on PDMS surface. The hydrophobicity of the PDMS surface also allows the non-specific absorption/adsorption of small molecules and biomolecules that might affect the cellular behaviour and functions. Hydrophilic modification of PDMS surface is indispensable for successful cell seeding. This review collates different techniques with their advantages and disadvantages that have been used to improve PDMS hydrophilicity to facilitate endothelial cells seeding in PDMS devices.

Lysophosphatidic acid receptor 5 transactivation of TGFBR1 stimulates the mRNA expression of proteoglycan synthesizing genes XYLT1 and CHST3.

Lysophosphatidic acid (LPA) via transactivation dependent signalling pathways contributes to a plethora of physiological and pathophysiological responses. In the vasculature, hyperelongation of glycosaminoglycan (GAG) chains on proteoglycans leads to lipid retention in the intima resulting in the early pathogenesis of atherosclerosis. Therefore, we investigated and defined the contribution of transactivation dependent signalling in LPA mediated GAG chain hyperelongation in human vascular smooth muscle cells (VSMCs). LPA acting via the LPA receptor 5 (LPAR5) transactivates the TGFBR1 to stimulate the mRNA expression of GAG initiation and elongation genes xylosyltransferase-1 (XYLT1) and chondroitin 6-sulfotransferase-1 (CHST3), respectively. We found that LPA stimulates ROS and Akt signalling in VSMCs, however they are not associated in LPAR5 transactivation of the TGFBR1. We observed that LPA via ROCK dependent pathways transactivates the TGFBR1 to stimulate genes associated with GAG chain elongation. We demonstrate that GPCR transactivation of the TGFBR1 occurs via a universal biochemical mechanism and the identified effectors represent potential therapeutic targets to inhibit pathophysiological effects of GPCR transactivation of the TGFBR1.

Investigating the Effect of Biomaterials Such as Poly-(l-Lactic Acid) Particles on Collagen Synthesis In Vitro: Method Is Matter.

Poly-l-lactic acid (PLLA), a synthetic, biocompatible, biodegradable polymer, has been safely used in several clinical applications in recent decades. Typically, SculptraTM, the commercially injectable PLLA in the form of microparticles, has been used as facial volumizer in the treatment of lipoatrophy in HIV patients. It also has various applications in tissue engineering by improving cell proliferation and adhesion. Sculptra™ can be categorised as a stimulatory filler as it stimulates the synthesis and deposition of fibrous tissue and collagen. Collagen is one of the most significant components of the extracellular matrix and beneficial for the normal physiology. It is also the structural component of a human body. In most of the studies, the effect of Sculptra on collagen synthesis was investigated in vivo and the majority of the data were from clinical and histological reports. There is only one study reporting this effect in vitro using fibroblasts. Here, we investigated whether PLLA in the form of nanoparticles can provide the same effect on collagen synthesis in fibroblasts as Sculptra. We surprisingly found that there was no stimulation of collagen in fibroblasts alone, whereas the co-cultures of fibroblast and macrophage had shown collagen stimulation by PLLA nanoparticles. It is also confirmed that collagen synthesis was caused by fibroblasts but not macrophages. Although further study needs to be conducted to evaluate its mechanism, our findings showed that choosing an appropriate method is essential for investigating the effect of PLLA or other biomaterials on collagen synthesis by fibroblasts in vitro.