During late endosome maturation, cargo molecules are sorted into intralumenal vesicles (ILVs) of multivesicular endosomes (MVEs), and are either delivered to lysosomes for degradation or fused with the plasma membranes for exosome release. The mechanism underlying formation of exosomal ILVs and cargo sorting into ILVs destined for exosome release is still unclear. Here we show that inhibitory G protein (Gi)-coupled sphingosine 1-phosphate (S1P) receptors regulate exosomal MVE maturation. Gi-coupled S1P receptors on MVEs are constitutively activated through a constant supply of S1P via autocrine activation within organelles. We also found that the continuous activation of Gi-coupled S1P receptors on MVEs is essential for cargo sorting into ILVs destined for exosome release. Our results reveal a mechanism underlying ESCRT-independent maturation of exosomal MVEs.

Ongoing activition of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes

The receptor‐binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike (S) protein plays a central role in mediating the first step of virus infection to cause disease: virus binding to angiotensin‐converting enzyme 2 (ACE2) receptors on human host cells Therefore, S/RBD is an ideal target for blocking and neutralization therapies to prevent and treat coronavirus disease 2019 (COVID‐19) Using a target‐based selection approach, we developed oligonucleotide aptamers containing a conserved sequence motif that specifically targets S/RBD Synthetic aptamers had high binding affinity for S/RBD‐coated virus mimics (KD≈7 nM) and also blocked interaction of S/RBD with ACE2 receptors (IC50≈5 nM) Importantly, aptamers were able to neutralize S protein‐expressing viral particles and prevent host cell infection, suggesting a promising COVID‐19 therapy strategy [ABSTRACT FROM AUTHOR] Copyright of Angewandte Chemie is the property of John Wiley & Sons, Inc and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use This abstract may be abridged No warranty is given about the accuracy of the copy Users should refer to the original published version of the material for the full abstract (Copyright applies to all Abstracts )

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ange.202100345

Neutralizing Aptamers Block S/RBD-ACE2 Interactions and Prevent Host Cell Infection.

Tumor-derived exosomes have emerged as promising cancer biomarkers and attracted increasing interest in non-invasive cancer diagnosis and treatment monitoring. However, the identification and quantification of exosomes in clinical samples such as blood remains challenging due to the difficulty in trade-off between recognition specificity and isolation efficiency. Here we have developed an aptamer-based fluorescence polarization assay for exosome quantification, which is a separation-free, amplification-free and sensitive approach enabling direct quantification of exosomes in human plasma. While the key specificity of this assay is based on the aptamer's inherent affinity to membrane proteins on exosomes, exosomes’ inherent huge mass/volume acts as mass-based fluorescence polarization amplifier. Our assay allows quantitative analysis of exosomes in the range of 5 × 102 to 5 × 105 particles per μL with a detect limitation of 500 particles per μL for the cell line deprived exosomes. The total assay time is about 30 min with just one mix-and-read step to achieve high sensitivity. We have also demonstrated quantification of exosomes from lung cancer patients and healthy donors in clinical samples. This work describes a new and simple liquid biopsy assay to directly detect exosomes in the biological matrix, which facilitates cancer diagnosis and therapy monitoring.

Aptamer-based fluorescence polarization assay for separation-free exosome quantification

Solid dispersion is the preferred technology to prepare efficacious forms of BCS class-II/IV APIs. To prepare solid dispersions, there exist a wide variety of polymeric carriers with interesting physicochemical and thermochemical characteristics available at the disposal of a formulation scientist. Since the advent of the solid dispersion technology in the early 1960s, there have been more than 5000 scientific papers published in the subject area. This review discusses the polymeric carrier properties of most extensively used polymers PVP, Copovidone, PEG, HPMC, HPMCAS, and Soluplus® in the solid dispersion technology. The literature trends about preparation techniques, dissolution, and stability improvement are analyzed from the Scopus® database to enable a formulator to make an informed choice of polymeric carrier. The stability and extent of dissolution improvement are largely dependent upon the type of polymeric carrier employed to formulate solid dispersions. With the increasing acceptance of transfer dissolution setup in the research community, it is required to evaluate the crystallization/precipitation inhibition potential of polymers under dynamic pH shift conditions. Further, there is a need to develop a regulatory framework which provides definition and complete classification along with necessarily recommended studies to characterize and evaluate solid dispersions.

/pdf/overview-of-extensively-employed-polymeric-carriers-in-solid-4xrv4azl8m.pdf

Overview of Extensively Employed Polymeric Carriers in Solid Dispersion Technology

Small extracellular vesicles in cancer.

In the past decade, the study of exosomes, nanosized vesicles (50-150 nm) released into the extracellular space via the fusion of multivesicular bodies with the plasma membrane, has burgeoned with impressive achievements in theranostics applications. These nanosized vesicles have emerged as key players in homeostasis and in the pathogenesis of diseases owing to the variety of the cargos they can carry, the nature of the molecules packaged inside the vesicles, and the robust interactions between exosomes and target cells or tissues. Accordingly, the development of exosome-based liquid biopsy techniques for early disease detection and for monitoring disease progression marks a new era of precision medicine in the 21st century. Moreover, exosomes possess intrinsic properties - a nanosized structure and unique "homing effects" - that make them outstanding drug delivery vehicles. In addition, targeted exosome-based drug delivery systems can be further optimized using active targeting ligands such as nucleic acid aptamers. Indeed, the aptamers themselves can function as therapeutic and/or diagnostic tools based on their attributes of unique target-binding and non-immunogenicity. This review aims to provide readers with a current picture of the research on exosomes and aptamers and their applications in cancer theranostics, highlighting recent advances in their transition from the bench to the clinic.

/pdf/aptamer-guided-extracellular-vesicle-theranostics-in-xyd2g8n02h.pdf

Aptamer-guided extracellular vesicle theranostics in oncology

Physicochemical characterization is a crucial step for the successful development of solid dispersions, including the determination of drug crystallinity and molecular interactions. Typically, the detection of molecular interactions will assist in the explanation of different drug performances (e.g., dissolution, solubility, stability) in solid dispersions. Various prominent reviews on solid dispersions have been reported recently. However, there is still no overview of recent techniques for evaluating the molecular interactions that occur within solid dispersions of poorly water-soluble drugs. In this review, we aim to overview common methods that have been used for solid dispersions to identify different bond formations and forces via the determination of interaction energy. In addition, a brief background on the important role of molecular interactions will also be described. The summary and discussion of methods used in the determination of molecular interactions will contribute to further developments in solid dispersions, especially for quick and potent drug delivery applications.

https://www.mdpi.com/1999-4923/12/8/745/pdf

Molecular Interactions in Solid Dispersions of Poorly Water-Soluble Drugs.

Blueberries are consumed as healthy fruits that provide a variety of benefits to the nervous system. Scientists have found that blueberries can be used as a daily edible source for supplementation to prevent and minimize complexities of age-related diseases as well as to improve learning and memory in children. Anthocyanins are the most mentioned compounds among the components in blueberries, as they play a major role in providing the health benefits of this fruit. However, while they are highly active in impeding biological impairment in neuronal functions, they have poor bioavailability. This review focuses on neurological investigations of blueberries from in vitro cell studies to in vivo studies, including animal and human studies, with respect to their positive outcomes of neuroprotection and intervention in neurodegenerative conditions. Readers will also find information on the bioavailability of anthocyanins and the considerable factors affecting them so that they can make informed decisions regarding the daily consumption of blueberries. In this context, the ways in which blueberries or blueberry supplementation forms are consumed and which of these forms is best for maximizing the health benefits of blueberries should be considered important decision-making factors in the consumption of blueberries; all of these aspects are covered in this review. Finally, we discuss recent technologies that have been employed to improve the bioavailability of blueberry anthocyanins in the development of effective delivery vehicles supporting brain health.

https://www.mdpi.com/2218-273X/11/1/102/pdf

Blueberry Supplementation in Neuronal Health and Protective Technologies for Efficient Delivery of Blueberry Anthocyanins.

Background Ternary solid dispersions have been demonstrated to be an effective strategy in the improvement of drug absorption and bioavailability. Method The applications of the combination of hydrophilic polymers with the potential of hydrophobic polymer incorporation at moderate concentrations have been discussed in recent publications. Results In this paper, the general review of this specific type of solid dispersion will be provided with comprehensive understanding of polymer blends of either hydrophilic or hydrophobic polymers. A detailed description of miscible polymers has been developed in recent studies. In addition to dissolution rate improvement, the role of second polymers in crystal growth inhibition and in maintaining the amorphous state will be mentioned. Conclusion We also present a summary of characterization techniques commonly used to evaluate solid dispersion and polymer miscibility.

Thao T D Tran

Papers

Aptamer-guided extracellular vesicle theranostics in oncology

Molecular Interactions in Solid Dispersions of Poorly Water-Soluble Drugs.

Blueberry Supplementation in Neuronal Health and Protective Technologies for Efficient Delivery of Blueberry Anthocyanins.

Current Designs of Polymer Blends in Solid Dispersions for Improving Drug Bioavailability.

Current developments in the oral drug delivery of fucoidan.