Search

Different techniques developed for the encapsulation of biological drugs within polymeric nanoparticles.

Angiotensin-converting enzyme 2 (ACE2) is protective in cardiovascular disease, lung injury and diabetes yet paradoxically underlies our susceptibility to SARs-CoV2 infection and the fatal heart and lung disease it can induce. Furthermore, diabetic patients have chronic, systemic inflammation and altered ACE2 expression resulting in increased risk of severe COVID-19 and the associated mortality. A drug that could increase ACE2 activity and inhibit cellular uptake of severe acute respiratory syndrome coronavirus 2 (SARs-CoV2), thus decrease infection, would be of high relevance to cardiovascular disease, diabetes and SARs-CoV2 infection. While the need for such a drug lead was highlighted over a decade ago receiving over 600 citations,1 to date, no such drugs are available.2 Here, we report the development of a novel ACE2 stimulator, designated ‘2A’(international PCT filed), which is a 10 amino acid peptide derived from a snake venom, and demonstrate its in vitro and in vivo efficacy against SARs-CoV2 infection and associated lung inflammation. Peptide 2A also provides remarkable protection against glycaemic dysregulation, weight loss and disease severity in a mouse model of type 1 diabetes. No untoward effects of 2A were observed in these pre-clinical models suggesting its strong clinical translation potential.

We have for the first time reported 120 nm silver/iron oxide hybrid nano-popcorns with surface plasmon resonance tuned at near-infrared (NIR) range for imaging and therapeutic applications. The nano-popcorns displayed excellent photothermal thrombolytic effect and anticancer activity in a concentration-dependent manner upon NIR laser irradiation, benefiting the photothermal treatment of thrombosis and cancer. At low concentrations, the nano-popcorns exhibited relatively good reactive oxygen species (ROS) scavenging capability. Notably, the nano-popcorns exerted excellent magnetic resonance imaging (MRI) T2-signal after being sequestered within cells or binding on the surface of the thrombus, becoming a promising imaging agent for cell labeling and thrombus detection. Cytotoxicity, biodistribution studies, and histology analysis demonstrated no significant toxicity caused by the nano-popcorns. There was no long-term retention of the nano-popcorns in the mouse organs at the dose treated. These results give insight into the potential of using these nano-popcorns for diagnosis and treatment of diseases related to ROS, cancer, and thrombosis.

Reactive oxygen species (ROS) play an essential role in the progression of many chronic diseases like atherosclerosis and rheumatoid arthritis. For decades, antioxidant compounds have always been considered as potential treatments for these ROS-related diseases. Concomitantly, noninvasive imaging systems such as magnetic resonance imaging (MRI) have also been widely used in the diagnosis of diseases, especially atherosclerosis. In this study, we investigated the feasibility to develop chitosan nanococktails containing both nanoceria and superparamagnetic iron oxide nanoparticles for ROS-related theranostics. Nanoceria utilized as therapeutic modules capable of ROS scavenging and iron-oxide nanoparticles utilized as imaging agents for MRI have been synthesized separately. Subsequently, two versions of theranostic chitosan nanococktails containing both nanoceria and iron oxide nanoparticles (Chit-IOCO and Chit-TPP-IOCO) were successfully synthesized via two different mechanisms, electrostatic self-assembly, and ionic gelation. In vitro studies such as cytotoxicity, MRI, and ROS scavenging were performed. These theranostic nanococktails demonstrated effective ROS scavenging and MRI contrast as a potential platform for treatment and diagnosis of ROS-related diseases. Results indicated that both Chit-IOCO and Chit-TPP-IOCO can reduce the ROS level of the lipopolysaccharide-stimulated macrophage J774A.1 to the baseline level. Chit-IOCO was less toxic to the cells than Chit-TPP-IOCO. In addition, Chit-IOCO exhibited higher MRI relaxivity than Chi-TPP-IOCO (308 and 150 mM-1 s-1, respectively), indicating that Chi-IOCO was more effective than Chit-TPP-IOCO as an MRI contrast agent in macrophages. Taken together, Chit-IOCO nanococktail demonstrates outstanding potential for treatment and diagnosis of ROS-related diseases. Potentially, this nanococktail can be easily modified to include new modules, allowing future application of personalized medicine.

Overproduction of reactive oxygen species (ROS) is commonly known as a key factor in the progression of many chronic inflammation diseases such as atherosclerosis and rheumatoid arthritis. In this study, a metal oxide nanodot-coated layered double hydroxide (LDH) nanocomposite is constructed for theranostics of ROS-related diseases. This is the first time that both cerium oxide and iron oxide nanoparticles (NPs) were attached on the surface of LDH NPs through electrostatic interaction via a nanoengineering approach. LDHs served as nanocarriers, cerium oxide NPs served as therapeutic agents due to the antioxidant properties, and iron oxide NPs served as magnetic resonance imaging (MRI) contrast agents. In vitro studies have demonstrated that the constructed nanocomposites have good biocompatibility, good antioxidant capacity to reduce ROS level in the cells, as well as satisfying cell imaging effect in MRI. Functionalization of LDH surface with cerium oxide NPs and iron oxide NPs allows the simultaneous therapy and diagnosis of ROS-related diseases and may also allow biodistribution tracking of the therapeutic cerium oxide NPs.

[Image: see text] Toll-like receptors (TLRs) are dominant components of the innate immune system. Activated by both pathogen-associated molecular patterns and damage-associated molecular patterns, TLRs underpin the pathology of numerous inflammation related diseases that include not only immune diseases, but also cardiovascular disease (CVD), diabetes, obesity, and cancers. Growing evidence has demonstrated that TLRs are involved in multiple cardiovascular pathophysiologies, such as atherosclerosis and hypertension. Specifically, a trial called the Canakinumab Anti-inflammatory Thrombosis Outcomes Study showed the use of an antibody that neutralizes interleukin-1β, reduces the recurrence of cardiovascular events, demonstrating inflammation as a therapeutic target and also the research value of targeting the TLR system in CVD. In this review, we provide an update of the interplay between TLR signaling, inflammatory mediators, and atherothrombosis, with an aim to identify new therapeutic targets for atherothrombotic CVD.

Stem cell (SC) therapies displayed encouraging efficacy and clinical outcome in various disorders. Despite this huge hype, clinical translation of SC therapy has been disheartening due to contradictory results from clinical trials. The ability to monitor migration and engraftment of cells in vivo represents an ideal strategy in cell therapy. Therefore, suitable imaging approach to track MSCs would allow understanding of migratory and homing efficiency, optimal route of delivery and engraftment of cells at targeted location. Hence, longitudinal tracking of SCs is crucial for the optimization of treatment parameters, leading to improved clinical outcome and translation. Magnetic resonance imaging (MRI) represents a suitable imaging modality to observe cells non-invasively and repeatedly. Tracking is achieved when cells are incubated prior to implantation with appropriate contrast agents (CA) or tracers which can then be detected in an MRI scan. This review explores and emphasizes the importance of monitoring the distribution and fate of SCs post-implantation using current contrast agents, such as positive CAs including paramagnetic metals (gadolinium), negative contrast agents such as superparamagnetic iron oxides and 19 F containing tracers, specifically for the in vivo tracking of MSCs using MRI. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.

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.

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.

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 β-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.

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 β-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

19F magnetic resonance imaging (MRI) is a powerful noninvasive imaging technique that shows tremendous potential for the diagnosis and monitoring of human diseases. Fluorinated compounds are commonly used as 19F MRI contrast agents to develop “hot spot” imaging. To achieve high-resolution MR images, a high density of 19F nuclei is required in the contrast agents. However, because of the inherent hydrophobicity of fluorinated moieties, aggregation of 19F contrast agents with high fluorine content is often observed in aqueous solution, resulting in attenuated MR signal and low sensitivity, thus significantly limiting their further biological applications. Here we report the synthesis and characterization of a series of polymeric 19F MRI contrast agents with high fluorine content by copolymerizing the well-known fluorinated monomer 2,2,2-trifluoroethyl acrylate (TFEA) with a highly water-soluble monomer 2-(methylsulfinyl)ethyl acrylate (MSEA) using RAFT polymerization. We show that these polymeric contrast a...

As nanotechnologies advance into clinical medicine, novel methods for applying nanomedicine to cardiovascular diseases are emerging. Extensive research has been undertaken to unlock the complex pathogenesis of atherosclerosis. However, this complexity presents challenges to develop effective imaging and therapeutic modalities for early diagnosis and acute intervention. The choice of ligand-receptor system vastly influences the effectiveness of nanomedicine. This review collates current ligand-receptor systems used in targeting functionalized nanoparticles for diagnosis and treatment of atherosclerosis. Our focus is on the binding affinity and selectivity of ligand-receptor systems, as well as the relative abundance of targets throughout the development and progression of atherosclerosis. Antibody-based targeting systems are currently the most commonly researched due to their high binding affinities when compared with other ligands, such as antibody fragments, peptides, and other small molecules. However, antibodies tend to be immunogenic due to their size. Engineering antibody fragments can address this issue but will compromise their binding affinity. Peptides are promising ligands due to their synthetic flexibility and low production costs. Alongside the aforementioned binding affinity of ligands, the choice of target and its abundance throughout distinct stages of atherosclerosis and thrombosis is relevant to the intended purpose of the nanomedicine. Further studies to investigate the components of atherosclerotic plaques are required as their cellular and molecular profile shifts over time.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are key signaling molecules that play an important role in the inflammation and progression of many diseases such as cardiovascular disease, especially atherosclerosis. ROS are in particular a significant factor in the development of rheumatoid arthritis and other autoimmune diseases such as allergies. In this study, novel Fe3O4/CeO2 core-shell theranostic nanoparticles capable of reacting with ROS and of being detected by MRI were synthesized and thoroughly characterized. In vitro studies, such as measurement of cell uptake, magnetic resonance imaging, toxicity and ROS scavenging, were conducted. The results indicate that the novel Fe3O4/CeO2 theranostic nanoparticles are effective for scavenging ROS and show excellent magnetic resonance (MR) imaging performance. These theranostic nanomaterials, therefore, show great potential for the treatment and diagnosis of ROS-related inflammatory diseases.

The early detection and accurate characterization of life-threatening diseases such as cardiovascular disease and cancer are critical to the design of treatment. Knowing whether or not a thrombus in a blood vessel is new (fresh) or old (constituted) is very important for physicians to decide a treatment protocol. We have designed smart MRI nano-sensors that can detect, sense and report the stage or progression of cardiovascular diseases such as thrombosis. The nanosensors were functionalized with fibrin-binding peptide to specifically target thrombus and were also labelled with fluorescent dye to enable optical imaging. We have demonstrated that our nanosensors were able to switch between the T1 and T2 signal depending on thrombus age or the presence or absence of thrombin at the thrombus site. The developed nanosensors appeared to be non-toxic when tested with Chinese Hamster Ovarian cells within the tested concentrations. The working principle demonstrated in this study can be applied to many other diseases such as cancer.

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.

Our research has focused on nanomaterials for the diagnosis and treatment of cardiovascular disease (CVD) such as thrombosis. These materials can be adapted for preserving and assessing organs for transplantation. Magnetic resonance imaging (MRI) has been used as a powerful and indispensable tool in medical research and clinical diagnosis. We have developed both targeted negative contrast agents and targeted dual positive/negative contrast agents for molecular imaging of thrombosis. The simultaneous use of positive and negative MRI imaging that employs the same contrast agents will significantly improve detection accuracy. Using the dual contrast agent, both T1- and T2-weighted MRI of thrombosis can be simultaneously recorded which enables self-confirmation of images and leads to a greater diagnostic accuracy1 . To prepare these targeted agents, we employed a single-chain antibody that targets activated platelets, a major player in thrombus formation. Our contrast agents can be adapted for assessing organs during and after transplantation. It has been reported that platelets are activated early during reperfusion after an ischaemia/reperfusion injury (IRI). Therefore, by targeting activated platelets and platelet accumulation, it is possible to noninvasively detect and assess IRI early, maximizing medical interventions. We have also developed smart MRI nanosensors based on iron oxide and gadolinium that can not only detect, but also sense and report the stage or progression of CVD such as thrombosis. The early detection and accurate characterization of life-threatening diseases such as CVD are critical to the design of treatment. Knowing whether a thrombus in a blood vessel is new/fresh or old/constituted is very important for physicians to decide on a treatment protocol. These nanosensors can be adapted, modified and applied for detecting and grading other diseases such as cancer, and also for sensitive detection of inflammatory reactions during organ preservation, perfusion and transplantation processes. It can be a useful technique to potentially allow other researchers to access information previously difficult to obtain. It can also be a new tool for clinicians to assess organs before and after transplantation, maximizing opportunities for medical intervention. Since our nanosensors are iron oxide and gadolinium based materials, they can also be used for preservation of organs/tissues. Recently researchers have reported a way to safely thaw frozen tissues with the aid of iron oxide nanoparticles2 . By suffusing the nanosensors over organs/tissues before freezing, they may help in the thawing process and may directly provide information on inflammatory reactions within the organs/tissues after thawing and reperfusion

This study aims to compare the relaxivities of ultra-small dual positive and negative contrast iron oxide nanoparticles (DCION) at different magnetic field strengths ranging from 4.7 to 16.4 T at physiological temperatures; and to investigate the effect of particle aggregation on relaxivities. Relaxivities of DCIONs were determined by magnetic resonance imaging scanners at 4.7, 7, 9.4, and 16.4 T. Both longitudinal (T 1) and transverse relaxation times (T 2) were measured by appropriate spin-echo sequences. It has been found that both longitudinal and transverse relaxivities are significantly dependent on the magnetic field strength. Particle aggregation also strongly affects the relaxivities. Awareness of the field strength and particle colloid stability is crucial for the comparison and evaluation of relaxivity values of these ultra-small iron oxide nanoparticles, and also for their medical applications as contrast agents.