Therapeutic Peptides Are Preferentially Solubilized in Specific Microenvironments within PEG-PLGA Polymer Nanoparticles.

Polymeric nanoparticles are a highly promising drug delivery formulation. However, a lack of understanding of the molecular mechanisms that underlie their drug solubilization and controlled release capabilities has hindered the efficient clinical translation of such technologies. Polyethylene glycol-poly(lactic-co-glycolic) acid (PEG-PLGA) nanoparticles have been widely studied as cancer drug delivery vehicles. In this letter, we use unbiased coarse-grained molecular dynamics simulations to model the self-assembly of a PEG-PLGA nanoparticle and its solubulization of the anticancer peptide, EEK, with good agreement with previously reported experimental structural data. We applied unsupervised machine learning techniques to quantify the conformations that polymers adopt at various locations within the nanoparticle. We find that the local microenvironments formed by the various polymer conformations promote preferential EEK solubilization within specific regions of the NP. This demonstrates that these microenvironments are key in controlling drug storage locations within nanoparticles, supporting the rational design of nanoparticles for therapeutic applications.

Small extracellular vesicles: Non-negligible vesicles in tumor progression, diagnosis, and therapy.

Small extracellular vesicles (sEVs) such as exosomes are nanoscale membranous particles (<200 nm) that have emerged as crucial targets for liquid biopsy and as promising drug delivery vehicles. They play a significant role in tumor progression as intercellular messengers. They can serve as biomarkers for tumor diagnosis and as drug carriers for cancer treatment. This article reviews recent studies on sEVs in oncology and explores their potential as biomarkers and drug delivery vehicles. Following tumorigenesis, sEVs in the tumor microenvironment (TME) and circulatory system undergo modifications to regulate various events in the TME, including angiogenesis, epithelial-mesenchymal transition (EMT), and tumor immunity, with either pro- or anti-tumor effects. sEVs have been investigated for use as diagnostic and prognostic biomarkers for a variety of tumors, including lung cancer, melanoma, breast cancer, prostate cancer, and hepatocellular carcinoma. sEVs can be used for cancer therapy by packaging drugs or proteins into them through pre- and post-isolation modification techniques. The clinical trials of sEVs as biomarkers and drug carriers are also summarized. Finally, the challenges in the use of sEVs are described and the possible approaches to tackling them are suggested. Overall, sEVs will advance the precision cancer medicine and has shown great potential in clinical applications.

Rational design of oral drugs targeting mucosa delivery with gut organoid platforms.

Effective oral drugs and vaccines require high delivery efficiency across the gastrointestinal epithelia and protection of medically effective payloads (i.e., immunogens) against gastric damage. In this study, hollowed nanocarriers (NCs: silica nanospheres and gold nanocages) with poly-l-lysine (PLL) coating and mammalian orthoreovirus cell attachment protein σ1 functionalization (NC-PLL-σ1) were explored as functional oral drug delivery vehicles (ODDVs). The transport of these ODDVs to mucosal lymphoid tissues could be facilitated by microfold cells (M-cells) mediated transcytosis (via σ1-α2-3-linked sialic acids adherence) across gastrointestinal epithelia. PLL coating provided protection and slow-release of rhodamine 6 G (R6G), a model payload. The transport effectiveness of these ODDVs was tested on intestinal organoid monolayers in vitro. When compared with other experimental groups, the fully functionalized ODDV system (with PLL-σ1) demonstrated two significant advantages: a significantly higher transport efficiency (198% over blank control at 48 h); and protection of payloads which led to both better transport efficiency and extended-release of payloads (61% over uncoated carriers at 48 h). In addition, it was shown that the M cell presence in intestinal organoid monolayers (modulated by Rank L stimulation) was a determining factor on the transport efficiency of the ODDVs: more M-cells (induced by higher Rank L) in the organoid monolayers led to higher transport efficiency for ODDV-delivered model payload (R6G). The fully functionalized ODDVs showed great potential as effective oral delivery vehicles for drugs and vaccines.

Supramolecular Chemotherapy with Cucurbit[n]urils as Encapsulating Hosts.

The cucurbit[n]urils (CB[n]) belong to the field of relatively young supramolecules which act as containers for a large variety of guests and are being explored extensively for their numerous biomedical applications. This includes drug formulation and delivery, controlled drug release, photodynamic therapy, sensing for bioanalytical purposes, etc. These supramolecular host-guest systems have distinctive recognition properties and have successfully been shown to enhance the in vitro and in vivo utility of various chemotherapeutic agents. The CB[n]s are tailored to optimize their application in payload delivery and diagnostics and in lowering the toxicity of existing drugs. This review has listed the recent studies on working mechanisms and host-guest complexation of the biologically vital molecules with CB[n] and highlighted their implementation in anticancer therapeutics. Various modifications in CB-drug inclusion compounds like CB supramolecular nanoarchitectures along with application in photodynamic therapy, which has shown potential as targeted drug delivery vehicles in cancer chemotherapy, have also been discussed.

Exosome Mediated Cancer Therapeutic Approach:Present Status and Future Prospectives.

The unique extracellular vesicles (EVs) or exosomes formed by the sequential invagination of the plasma membrane are diverse and encompass important constituents with biological functions. Speculations on its cell independent biological functions are significant and pose them as vital biomarkers and as drug delivery vehicles especially in cancer. EVs possess theragnostic values and are known to elicit specific immune response. Exosomes can also serve as potential nanocarriers for delivering miRNA, siRNA, anti-cancer drugs and membrane-associated proteins. Exosomes play a crucial role in regulating tumour progression, metastasis, and angiogenesis. This review thus portrays the multiple facets of exosomes, in concert with the source for exosomes production and further on its regulation and intercellular communication. The review also explores the recent advances, present status and the future prospective in the application of exosomes in cancer therapeutics and cancer diagnostics.

Advances in the Study of Exosomes as Drug Delivery Systems for Bone-Related Diseases.

Bone-related diseases are major problems and heavy burdens faced by modern society. Current clinical approaches for the treatment of these pathological conditions often lead to complications and have limited therapeutic efficacy. In this context, the development of nanotherapeutic platforms, such as extracellular vesicles, can improve the relevant therapeutic effects. In particular, exosomes are nano-sized, lipid bilayer extracellular vesicles secreted by many cells in mammals. Due to their innate capacity to transport materials-including proteins, lipids, and genes-among cells, as well as their innate attraction to target cells, they are considered to be a crucial medium for cell communication and are involved in a number of biological processes. Exosomes have been used as drug delivery vehicles in recent bone tissue engineering studies, in order to regulate bone homeostasis. However, the precise workings of the exosome regulatory network in maintaining bone homeostasis and its potential for treating bone injury remain unclear. To provide a fresh perspective for the study of exosomes in drug delivery and bone-related diseases, in this paper, we review recent studies on the roles of exosomes for drug delivery in bone homeostasis and bone-related diseases, as well as the composition and characteristics of exosomes and their regulatory roles in bone homeostasis and bone-related diseases, aiming to provide new ideas for the therapeutic application of exosomes in the treatment of bone-related diseases.

Nano/Microcarriers in Drug Delivery: Moving the Timeline to Contemporary.

Treatment of various diseases, especially cancer treatment, includes the potential use of different types of nanoparticles and nanostructures as drug carriers. However, searching for less toxic and more efficient therapy requires further progress, wherein recent developments in medicine increasingly include the use of various advanced nanostructures. Their more successful application might be achieved by leveling imbalances between the potentiality of different nanostructures and the demands required for their safe use. Biocompatibility, biodegradability, prolonged circulation time and enhanced accumulation and uptake by cells are some of the key preconditions for their usage in efficient drug delivery. Thanks to their greatly tunable functions, they are major building blocks for manufacturing novel materials. Nevertheless, given that their toxicity is questionable, their practical application is challenging. Hereof, before entering the sphere of human consumption, it is of critical importance to perform more studies regarding their toxicity and drug distribution. This review emphasizes recent advances in nanomedicine, employing different kinds of conventionally used nanoparticles as well as novel nanoparticles and nanostructures. Special emphasis is placed on micro/nanomotors (MNMs), discussing their opportunities, limitations, challenges and possible applications in drug delivery and outlining some perspectives in the nanomedicine area.

Exosomes as Delivery Systems for Targeted Tumour Therapy: A Systematic Review and Meta-analysis of In vitro Studies.

BACKGROUND: Delivery systems with low immunogenicity and toxicity are believed to enhance the efficacy of specific targeted drug delivery to cancer cells. Exosomes are potential natural nanosystems that can enhance the delivery of therapeutic agents for targeted cancer therapy. OBJECTIVE: This study provides a precise effect size of exosomes as nanovesicles for in vitro delivery of anticancer agents. METHODS: In this systematic review and meta-analysis, the efficacy of exosomes as nanocarriers for the delivery of therapeutic molecules was investigated using the random-effects model. We did comprehensive literature searches through CINAHL, Cochrane, PubMed, Scopus, and Science Direct of in vitro studies that reported exosomes as delivery systems for cancer therapy. RESULTS: After the screening of eligible articles, a total of 50 studies were enrolled for the metaanalysis. The results showed that cancer cells treated with exosome-loaded anticancer agents for at least 6 h significantly decreased cell viability and increased cytotoxicity with the standardized mean difference (SMD) of -1.47 (-2.18, -0.76; (p<0.0001) and -1.66 (-2.71, -0.61; p<0.002). Exosomes effectively delivered drugs and exogenous miRNAs, siRNAs, viruses, and enzymes to cancer cells in vitro. CONCLUSION: This meta-analysis provides evidence of exosomes as efficient nanocarriers for the delivery of anticancer drugs.

Interactions of Antibacterial Naphthoquinones with Mesoporous Silica Surfaces: A Physicochemical and Theoretical Approach.

1,4-naftoquinone (NQ) molecules have been extensively evaluated as potent antibacterial compounds; however, their use is limited, since they have low water solubility and exhibit toxicities in healthy eukaryotic cells. A possible path to overcoming these challenges is the use of particulate vehicles, such as SBA-15, which is a biocompatible and biodegradable mesoporous silica material, that may enhance drug delivery and decrease dosages. In this work, an isotherm model-based adsorption of three NQs into SBA-15 microparticles was evaluated. Interactions between NQs and SBA-15 microparticles were modeled at the B3LYP/6-31+G(d,p) level of theory to understand the nature of such interactions. The results demonstrated that the adsorption of NQ, 2NQ, and 5NQ into SBA-15 fit the Freundlich adsorption model. According to theorical studies, physisorption is mediated by hydrogen bonds, while the most stable interactions occur between the carbonyl group of NQ and silica surfaces. Both experimental and theoretical results contribute to a deeper understanding of the use of SBA-15 or similar particles as nanovehicles in such a way that NQs can be modified in carbonyl or C3 to enhance adsorptions. The theoretical and experimental results were in accordance and contribute to a deeper understanding of how interactions between NQ-type molecules and SiO2 materials occur.

Extracellular Vesicles as Drug Targets and Delivery Vehicles for Cancer Therapy.

Extracellular vesicles (EVs) are particles that are released from cells into the extracellular space both under pathological and normal conditions. It is now well established that cancer cells secrete more EVs compared to non-cancerous cells and that, captivatingly, several proteins that are involved in EV biogenesis and secretion are upregulated in various tumours. Recent studies have revealed that EVs facilitate the interaction between cancer cells and their microenvironment and play a substantial role in the growth of tumours. As EVs are involved in several aspects of cancer progression including angiogenesis, organotropism, pre-metastatic niche formation, fostering of metastasis, and chemoresistance, inhibiting the release of EVs from cancer and the surrounding tumour microenvironment cells has been proposed as an ideal strategy to treat cancer and associated paraneoplastic syndromes. Lately, EVs have shown immense benefits in preclinical settings as a novel drug delivery vehicle. This review provides a brief overview of the role of EVs in various hallmarks of cancer, focusing on (i) strategies to treat cancer by therapeutically targeting the release of tumour-derived EVs and (ii) EVs as valuable drug delivery vehicles. Furthermore, we also outline the drawbacks of the existing anti-cancer treatments and the future prospective of EV-based therapeutics.

Exosomes in Mastitis-Research Status, Opportunities, and Challenges.

Mastitis, which affects milk quality and yield, is one of the most common diseases in dairy cows, causing large economic losses. Cow mastitis is classified into clinical and subclinical types. Subclinical mastitis presents without obvious lesions in the udder or noticeable change in milk samples, indicating persistent chronic infection that is difficult to detect and treat. Therefore, finding specific biomarkers is of great significance for the early diagnosis and treatment of subclinical mastitis. As mediators of intercellular communication, exosomes have been shown to be extensively involved in various physiological and pathological processes in the body. Exosomes in milk, blood, and cell supernatant can carry stable cell source-specific nucleic acids, proteins, and metabolites. Hence, exosomes show great application prospects for early diagnosis, targeted therapy, and disease mechanism analysis. In this review, we summarize the biogenesis, biological functions, and methods of isolating and identifying exosomes and review the current status of exosome research related to mastitis. Finally, in view of the application of exosomes to diagnose, treat, and perform disease mechanism analysis in mastitis, deficiencies in recent research on mastitis exosomes are described, and the direction of future exosome research efforts in mastitis is proposed.

Research Progress on Bacterial Membrane Vesicles and Antibiotic Resistance.

As a result of antibiotic overuse, bacterial antibiotic resistance has become a severe threat to worldwide public health. The development of more effective antimicrobial therapies and alternative antibiotic strategies is urgently required. The role played by bacterial membrane vesicles (BMVs) in antibiotic resistance has become a current focus of research. BMVs are nanoparticles derived from the membrane components of Gram-negative and Gram-positive bacteria and contain diverse components originating from the cell envelope and cytoplasm. Antibiotic stress stimulates the secretion of BMVs. BMVs promote and mediate antibiotic resistance by multiple mechanisms. BMVs have been investigated as conceptually new antibiotics and drug-delivery vehicles. In this article, we outline the research related to BMVs and antibiotic resistance as a reference for the intentional use of BMVs to combat antibiotic resistance.

Delivery of Small Molecules by Syndiotactic Peptides for Breast Cancer Therapy.

The utilization of peptide-based drug delivery systems has been suboptimal due to their poor proteolytic susceptibility, poor cell permeability, and limited tumor homing capabilities. Earlier attempts in using d-enantiomers in peptide sequences increased proteolytic stability but have compromised the overall penetration capability. We designed a series of peptides (STRAPs) with a syndiotactic polypeptide backbone that can potentially form a spatial array of cationic groups, an important feature that facilitates cellular uptake. The peptides penetrate cell membranes through a combination of active and passive modes. Furthermore, the cellular uptake of the peptides was unaffected by the presence of or treatment with bovine serum and human plasma. The designed peptides successfully delivered methotrexate, an anticancer drug, to the in vitro and in vivo models of breast cancer, with the best performing peptide STRAP-4-MTX conjugate having an EC50 value of 1.34 µM. Peptide drug delivery in mouse xenograft models showed a greater reduction of primary tumor and metastasis of breast cancer, in comparison to methotrexate of the same dose. The in vivo biodistribution assay of the STRAP-4 peptide suggests that the peptide accumulates at the tumor site after 2 h of treatment, and in the absence of tumors, the peptide gets metabolized and excreted from the system.

Current Status, Opportunities, and Challenges of Exosomes in Oral Cancer Diagnosis and Treatment.

Oral cancer is one of the most common cancers in the world, with more than 300,000 cases diagnosed each year, of which oral squamous cell carcinoma accounts for more than 90%, with a 5-year survival rate of only 40-60%, and poor prognosis. Exploring new strategies for the early diagnosis and treatment of oral cancer is key to improving the survival rate. Exosomes are nanoscale lipid bilayer membrane vesicles that are secreted by almost all cell types. During the development of oral cancer, exosomes can transport their contents (DNA, RNA, proteins, etc) to target cells and promote or inhibit the proliferation, invasion, and metastasis of oral cancer cells by influencing the host immune response, drug-resistant metastasis, and tumour angiogenesis. Therefore, exosomes have great potential and advantages as biomarkers for oral cancer diagnosis, and as drug delivery vehicles or targets for oral cancer therapy. In this review, we first describe the biogenesis, biological functions, and isolation methods of exosomes, followed by their relationship with oral cancer. Here, we focused on the potential of exosomes as oral cancer biomarkers, drug carriers, and therapeutic targets. Finally, we provide an insightful discussion of the opportunities and challenges of exosome application in oral cancer diagnosis and treatment, intending to offer new ideas for the clinical management of oral cancer.

Extracellular vesicles in cancer therapy.

Extracellular vesicles (EVs), including a variety of membrane-enclosed nanosized particles carrying cell-derived cargo, mediate a major type of intercellular communication in physiological and pathological processes. Both cancer and non-cancer cells secrete EVs, which can travel to and influence various types of cells at the primary tumor site as well as in distant organs. Tumor-derived EVs contribute to cancer cell plasticity and resistance to therapy, adaptation of tumor microenvironment, local and systemic vascular remodeling, immunomodulation, and establishment of pre-metastatic niches. Therefore, targeting the production, uptake, and function of tumor-derived EVs has emerged as a new strategy for stand-alone or combinational therapy of cancer. On the other hand, as EV cargo partially reflects the genetic makeup and phenotypic properties of the secreting cell, EV-based biomarkers that can be detected in biofluids are being developed for cancer diagnosis and for predicting and monitoring tumor response to therapy. Meanwhile, EVs from presumably safe sources are being developed as delivery vehicles for anticancer therapeutic agents and as anticancer vaccines. Numerous reviews have discussed the biogenesis and characteristics of EVs and their functions in cancer. Here, I highlight recent advancements in translation of EV research outcome towards improved care of cancer, including developments of non-invasive EV-based biomarkers and therapeutic agents targeting tumor-derived EVs as well as engineering of therapeutic EVs.

Diagnostic and Therapeutic Applications of Exosome Nanovesicles in Lung Cancer: State-of-The-Art.

Lung cancer is a malignant disease with high morbidity, mortality, and poor prognosis since conventional therapeutic approaches are not sufficient. Recently, with the discovery of exosomes, researchers have implemented new approaches in the diagnosis and treatment of various malignancies such as lung cancer. Investigation of lung cancer cell-derived exosomes and analysis of their profile by advanced techniques will assist researchers to take advantage of the specific properties of these multivesicular bodies. Also, scientists have presented various encouraging methods in the treatment of lung cancer with loading drugs, proteins, microRNAs, and siRNAs inside specific antigen-targeted exosomes. This review discusses the role of exosomes as novel prognostic biomarkers (containing lipids, surface and internal proteins, miRNAs, and lncRNAs) and therapeutic agents (e.g. vaccine and targeted drug delivery systems) in lung cancer.

In Silico Design of Chemically Modified Cell-Penetrating Peptides.

In the past few decades, a large number of cell-penetrating peptides (CPPs) have been discovered. These CPPs have a wide range of applications including drug delivery vehicles. Numerous in silico tools have been developed over the years to design and predict the cell-penetrating peptides that contain natural amino acids. The majority of natural cell-penetrating peptides have several limitations including stability, immunogenicity as well as got entrapped in the cell's endosomes. The chemical modification is commonly used to most of these limitations. An in silico tool called CellPPDMod have been developed by our group to predict cell-penetration potential of chemically modified peptides. This chapter is dedicated for designing therapeutically important cell-penetrating peptides using CellPPDMod ( http://webs.iiitd.edu.in/raghava/cellppdmod/ ).

Comprehensive overview of extracellular vesicle proteomics in meningioma: future strategy.

BACKGROUND: Meningioma arising from meninges is one among the various types of brain tumors. Others are, astrocytomas originating from astrocyte, oligodendrogliomas originating from oligodendrocyte, Ependymomas originating from ependymal cells and medulloblastomas originating from neurons. Current knowledge of molecular biology, genetics and epigenetics of meningioma is not sufficient. Therefore, In depth understanding of the mechanism of meningioma formation and progression is needed for its treatment and management. Grade I Grade I meningiomas are majorly classified as grade I, grade II and grade III. Meningioma can be indolent, slow growing or can be invasive and metastatic which can recurre. Grade I meningioma can be removed by surgery in comparison to invasive meningioma which may recurre with high propensity. This property of recurrence is responsible for high morbidity and mortality. Meningioma are majorly classified into three classes namely grade I, grade II, grade III. Protein biomarkers are considered as promising candidates for the diagnosis of meningioma. STUDY: Various studies done on differential expression of proteins have shown increased expression of EGFR, NEK9, EPS812, CKAP4, SET and STAT2, in all the three grades of meningioma. Additionally, some proteins like HK2 are overexpressed in grade II and grade III meningioma than in grade I meningioma. Protein Markers, found on extracellular vesicles of different grades of meningioma can serve the same purpose. A test done on a sample of any kind of body fluid like blood, tear, saliva, urine etc. for recognizing the circulating cancer cells or DNA and extracellular vesicles released from them to help detecting the early stage of cancer is known as liquid biopsy. Solid biopsy has several limitations as compared to liquid biopsy. This is because the samples can be easily collected and studied in case of liquid biopsy. Exosomes are related with liquid biopsy and hence provide platform for better diagnosis, prognosis and treatment of any type of cancer including meningioma. Exosomal tetraspanin are important example of exosomal biomarkers. The tetraspanin network is a molecular scaffold which connects various proteins for signal transduction. CONCLUSION: This study tells about the utility of proper knowledge of extracellular vesicle proteins and their profiles in different grades, which can help in better understanding of pathogenesis, diagnosis, prognosis and treatment of meningioma. In Addition to use of these proteins as biomarkers, role of exosomes in currently available therapeutic approaches has been discussed.

Graphene Nanoribbons: Prospects of Application in Biomedicine and Toxicity.

Graphene nanoribbons are a type of graphene characterized by remarkable electrical and mechanical properties. This review considers the prospects for the application of graphene ribbons in biomedicine, taking into account safety aspects. According to the analysis of the recent studies, the topical areas of using graphene nanoribbons include mechanical, chemical, photo- and acoustic sensors, devices for the direct sequencing of biological macromolecules, including DNA, gene and drug delivery vehicles, and tissue engineering. There is evidence of good biocompatibility of graphene nanoribbons with human cell lines, but a number of researchers have revealed toxic effects, including cytotoxicity and genotoxicity. Moreover, the damaging effects of nanoribbons are often higher than those of chemical analogs, for instance, graphene oxide nanoplates. The possible mechanism of toxicity is the ability of graphene nanoribbons to damage the cell membrane mechanically, stimulate reactive oxidative stress (ROS) production, autophagy, and inhibition of proliferation, as well as apoptosis induction, DNA fragmentation, and the formation of chromosomal aberrations. At the same time, the biodegradability of graphene nanoribbons under the environmental factors has been proven. In general, this review allows us to conclude that graphene nanoribbons, as components of high-precision nanodevices and therapeutic agents, have significant potential for biomedical applications; however, additional studies of their safety are needed. Particular emphasis should be placed on the lack of information about the effect of graphene nanoribbons on the organism as a whole obtained from in vivo experiments, as well as about their ecological toxicity, accumulation, migration, and destruction within ecosystems.