Compritol solid lipid nanoparticle formulations enhance the protective effect of betulinic acid derivatives in human Müller cells against oxidative injury.

Müller cells maintain homeostatic functions in the retina. Their dysfunction leads to irreversible retinal diseases. Oxidative injury is a leading cause of retinal cytotoxicity. Our previous studies reported several betulinic acid (BA) derivatives can protect Müller cells from oxidative injury but achieving pharmacologically effective concentrations in the Müller cells could be a limitation. To optimise cellular delivery, we encapsulated the BA analogues H3, H5 and H7 into the clinically approved Compritol 888 and HD5 ATO solid lipid nanoparticles (SLNs) using the micro-emulsion method. The cytoprotective effects of these SLN-formulations were determined in human MIO-M1 cells. We found cytoprotection by H3 and H5 SLN-formulations was significantly enhanced, which was evident at concentrations much lower than those required with the free agents. Both SLN-formulations prolonged the duration of action of these agents. The most effective agent H5 delivered in 888 ATO SLNs attenuated glutamate-induced ROS formation and the associated necrosis in MIO-M1 cells. Overall, SLNs have emerged as promising delivery carriers for BA derivatives enhancing their protective effects against oxidative injury in human Müller cells. Our study is the first to show SLNs can be a viable route to delivery agents with improved efficacy and stability into human Müller cells favoring the treatment/prevention of retinal diseases.

New Multiscale Characterization Methodology for Effective Determination of Isolation-Structure-Function Relationship of Extracellular Vesicles.

Extracellular vesicles (EVs) have been lauded as next-generation medicines, but very few EV-based therapeutics have progressed to clinical use. Limited clinical translation is largely due to technical barriers that hamper our ability to mass produce EVs, i.e., to isolate, purify, and characterize them effectively. Technical limitations in comprehensive characterization of EVs lead to unpredicted biological effects of EVs. Here, using a range of optical and non-optical techniques, we showed that the differences in molecular composition of EVs isolated using two isolation methods correlated with the differences in their biological function. Our results demonstrated that the isolation method determines the composition of isolated EVs at single and sub-population levels. Besides the composition, we measured for the first time the dry mass and predicted sedimentation of EVs. These parameters were likely to contribute to the biological and functional effects of EVs on single cell and cell cultures. We anticipate that our new multiscale characterization approach, which goes beyond traditional experimental methodology, will support fundamental understanding of EVs as well as elucidate the functional effects of EVs in in vitro and in vivo studies. Our findings and methodology will be pivotal for developing optimal isolation methods and establishing EVs as mainstream therapeutics and diagnostics. This innovative approach is applicable to a wide range of sectors including biopharma and biotechnology as well as to regulatory agencies.

Nano-Enhanced Drug Delivery and Therapeutic Ultrasound for Cancer Treatment and Beyond.

While ultrasound is most widely known for its use in diagnostic imaging, the energy carried by ultrasound waves can be utilized to influence cell function and drug delivery. Consequently, our ability to use ultrasound energy at a given intensity unlocks the opportunity to use the ultrasound for therapeutic applications. Indeed, in the last decade ultrasound-based therapies have emerged with promising treatment modalities for several medical conditions. More recently, ultrasound in combination with nanomedicines, i.e., nanoparticles, has been shown to have substantial potential to enhance the efficacy of many treatments including cancer, Alzheimer disease or osteoarthritis. The concept of ultrasound combined with drug delivery is still in its infancy and more research is needed to unfold the mechanisms and interactions of ultrasound with different nanoparticles types and with various cell types. Here we present the state-of-art in ultrasound and ultrasound-assisted drug delivery with a particular focus on cancer treatments. Notably, this review discusses the application of high intensity focus ultrasound for non-invasive tumor ablation and immunomodulatory effects of ultrasound, as well as the efficacy of nanoparticle-enhanced ultrasound therapies for different medical conditions. Furthermore, this review presents safety considerations related to ultrasound technology and gives recommendations in the context of system design and operation.

Placenta Stem/Stromal Cell-Derived Extracellular Vesicles for Potential Use in Lung Repair.

Many acute and chronic lung injuries are incurable and rank as the fourth leading cause of death globally. While stem cell treatment for lung injuries is a promising approach, there is growing evidence that the therapeutic efficacy of stem cells originates from secreted extracellular vesicles (EVs). Consequently, EVs are emerging as next-generation therapeutics. While EVs are extensively researched for diagnostic applications, their therapeutic potential to promote tissue repair is not fully elucidated. By housing and delivering tissue-repairing cargo, EVs refine the cellular microenvironment, modulate inflammation, and ultimately repair injury. Here, the potential use of EVs derived from two placental mesenchymal stem/stromal cell (MSC) lines is presented; a chorionic MSC line (CMSC29) and a decidual MSC cell line (DMSC23) for applications in lung diseases. Functional analyses using in vitro models of injury demonstrate that these EVs have a role in ameliorating injuries caused to lung cells. It is also shown that EVs promote repair of lung epithelial cells. This study is fundamental to advancing the field of EVs and to unlock the full potential of EVs in regenerative medicine.

Animal models of smoke inhalation injury and related acute and chronic lung diseases.

Smoke inhalation injury leads to various acute and chronic lung diseases and thus is the dominant cause of fire-related fatalities. In a search for an effective treatment and validation of therapies different classes of animal models have been developed, which include both small and large animals. These models have advanced our understanding of the mechanism of smoke inhalation injury, enabling a better understanding of pathogenesis and pathophysiology and development of new therapies. However, none of the animal models fully mirrors human lungs and their pathologies. All animal models have their limitations in replicating complex clinical conditions associated with smoke inhalation injury in humans. Therefore, for a correct interpretation of the results and to avoid bias, a precise understanding of similarities and differences of lungs between different animal species and humans is critical. We have reviewed and presented comprehensive comparison of different animal models and their clinical relevance. We presented an overview of methods utilized to induce smoke inhalation injuries, airway micro-/macrostructure, advantages and disadvantages of the most commonly used small and large animal models.

None of us is the same as all of us: resolving the heterogeneity of extracellular vesicles using single-vesicle, nanoscale characterization with resonance enhanced atomic force microscope infrared spectroscopy (AFM-IR).

Extracellular vesicles (EVs) are highly specialized, nanoscale messengers that deliver biological signals and in doing so mediate intercellular communication. Increasing evidence shows that within populations of EVs, important properties including morphology, membrane composition, and content vary substantially. This heterogeneity arises in response to the nature, state, and environmental conditions of the cell source. However, currently there are no effective approaches, which unequivocally discriminate differences between individual EVs, which critically hampers progress in this emerging scientific area. Measuring EV heterogeneity is paramount to our understanding of how EVs influence the physiological and pathological functions of their target cells. Moreover, understanding EV heterogeneity is essential for their application as diagnostics and therapeutics. We propose an innovative approach using resonance enhanced atomic force microscope infrared spectroscopy (AFM-IR) to identify the nanoscale structural composition of EVs, as demonstrated and validated using EVs derived from two types of placenta stem cells. The particular strength of this approach is that it is a label-free and ultra-high sensitivity technique that has the power to measure individual EV heterogeneity. New insights gained by this method into EV heterogeneity will have a profound impact not only on our basic understanding of EV biology but also on disease diagnostics and the emerging area of EV-therapies.

Nanoparticulate carriers: an emerging tool for breast cancer therapy.

Breast cancer is a leading cause of death for women in the world. Cancer has the potential to spread to different organs around the body, and form metastases that can even develop after surgical removal of the primary tumour. Nanotechnology offers new promising strategies for the treatment of breast cancer, and has emerged as a powerful tool for fighting cancer. Nanoparticles can be fabricated to perform more than one task simultaneously, and can have a number of roles, such as acting as a therapeutic agent, drug delivery vehicle and/or tumour imaging agent. This review will focus on various forms of nanoparticles serving as potential agents for cancer therapeutics, illustrating their use in breast cancer therapies. This article also highlights the properties, current progress in the design and engineering of nanoparticles.