Plant vs mammal extracellular vesicles: new tools in therapeutic drug delivery

Mechanisms devoted to the secretion of proteins via extracellular vesicles (EVs) have been found in mammals, yeasts, and plants. Since they transport a number of leader-less proteins to the plasma membrane or the extracellular space, EVs are considered part of Unconventional protein secretion (UPS) routes. UPS involving EVs are a relatively new field in plants. Aside from their role in plant physiology and immunity, plant extracts containing EVs have also been shown to be beneficial for human health. Therefore, exploring the use of plant EVs in biomedicine and their potential as drug delivery tools is an exciting avenue. Here we give a summary of the state of knowledge on plant EVs, their crosstalk with mammalian systems and potential research routes that could lead to practical applications in therapeutic drug delivery.

Exosomes have been the hidden treasure of the cell in terms of cellular interactions, transportation and therapy. The native exosomes (NEx) secreted by the parent cells hold promising aspects in cancer diagnosis and therapy. NEx has low immunogenicity, high biocompatibility, low toxicity and high stability which enables them to be an ideal prognostic biomarker in cancer diagnosis. However, due to heterogeneity, NEx lacks specificity and accuracy to be used as therapeutic drug delivery vehicle in cancer therapy. Transforming these NEx with their innate structure and multiple receptors to engineered exosomes (EEx) can provide better opportunities in the field of cancer theranostics. The surface of the NEx exhibits numeric receptors which can be modified to pave the direction of its therapeutic drug delivery in cancer therapy. Through surface membrane, EEx can be modified with increased drug loading potentiality and higher target specificity to act as a therapeutic nanocarrier for drug delivery. This review provides insights into promising aspects of NEx as a prognostic biomarker and drug delivery tool along with its need for the transformation to EEx in cancer theranostics. We have also highlighted different methods associated with NEx transformations, their nano-bio interaction with recipient cells and major challenges of EEx for clinical application in cancer theranostics.

Microneedles (MNs) are emerging as versatile tools for both therapeutic drug delivery and diagnostic monitoring. Unlike hypodermic needles, MNs achieve these applications with minimal or no pain and customizable designs, making them suitable for personalized medicine. Understanding the key design parameters and the challenges during contact with biofluids is crucial to optimizing their use across applications. This review summarizes the current fabrication techniques and design considerations tailored to meet the distinct requirements for drug delivery and biosensing applications. We further underscore the current state of theranostic MNs that integrate drug delivery and biosensing and propose future directions for advancing MNs toward clinical use.

Exosomes are spherical extracellular nanovesicles of endosomal origin, whose function is to encapsulate part of the contents of the parent cells producing them and transport this content to the target recipient cells using biological fluids. Due to their properties, exosomes are considered as potential biological drug delivery systems. For medical purposes, exosomes are isolated from various natural sources. The use of each type of exosome for therapeutic purposes has its advantages and is associated to varying degrees with several biological (stability, immunogenicity, toxicity) and technical (production scaling-up, standardization of isolation protocols, drug loading) problems. Exosomes derived from human cells have significant potential as therapeutic drug (TD) delivery vehicles due to their endogenous origin. However, simultaneously with the delivery of TD, they can carry potentially dangerous biomolecules. Farm animal milk-derived exosomes and exosome-like plant-derived extracellular vesicles have enormous therapeutic potential in themselves and are safe as drug delivery vehicles. However, data on their effects on the human body are limited. Artificial exosomes created with the help of nanobiotechnology can overcome many of the technical limitations inherent in natural exosomes. The review discusses the strengths and limitations of different types of natural and artificial exosomes as drug delivery nanocarriers, as well as challenges associated with their implementation in clinical practice.

Cancer stem cells (CSCs) represent a small portion of tumor cells with self-renewal ability in tumor tissues and are a key factor in tumor resistance, recurrence, and metastasis. CSCs produce a large number of exosomes through various mechanisms, such as paracrine and autocrine signaling. Studies have shown that CSC-derived exosomes (CSC-Exos) carry a variety of gene mutations and specific epigenetic modifications indicative of unique cell phenotypes and metabolic pathways, enabling exchange of information in the tumor microenvironment (TME) to promote tumor invasion and metastasis. In addition, CSC-Exos carry a variety of metabolites, especially proteins and miRNAs, which can activate signaling pathways to further promote tumor development. CSC-Exos have dual effects on cancer development. Due to advances in liquid biopsy technology for early cancer detection, CSCs-Exos may become an important tool for early cancer diagnosis and therapeutic drug delivery. In this article, we will review how CSC-Exos exert the above effects based on the above two aspects and explore their mechanism of action.

Extracellular vesicles (EVs) are small bilipid layer-enclosed vesicles that can be secreted by all tested types of brain cells. Being a key intercellular communicator, EVs have emerged as a key contributor to the pathogenesis of various neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease through delivery of bioactive cargos within the central nervous system (CNS). Importantly, CNS cell-derived EVs can be purified via immunoprecipitation, and EV cargos with altered levels have been identified as potential biomarkers for the diagnosis and prognosis of NDs. Given the essential impact of EVs on the pathogenesis of NDs, pathological EVs have been considered as therapeutic targets and EVs with therapeutic effects have been utilized as potential therapeutic agents or drug delivery platforms for the treatment of NDs. In this review, we focus on recent research progress on the pathological roles of EVs released from CNS cells in the pathogenesis of NDs, summarize findings that identify CNS-derived EV cargos as potential biomarkers to diagnose NDs, and comprehensively discuss promising potential of EVs as therapeutic targets, agents, and drug delivery systems in treating NDs, together with current concerns and challenges for basic research and clinical applications of EVs regarding NDs.

Since the discovery of dendrimers in 1978, it has received serious attention as a drug carrier polymer most especially in cancer chemotherapeutics where precision and targeted delivery of drug to tumor cells is most desirable. Dendrimers are mostly synthetic, hyper-branched, tree-like globular, nano-sized polymers with excellent physicochemical properties that can be utilized in the formulation, design and delivery of drugs, vaccine and genes to specific receptors in the body. This review focused on the synthesis, types and applications of dendrimers in the delivery of cytotoxic drugs. The review shows that in the last decade, dendrimers have proved to be promising nanocarriers for various drugs including anti-inflammatory, antimicrobial, and anticancer drugs. The application of dendrimers as scaffolds of prodrugs is particularly interesting. Dendrimers are relatively more stable compared with other nano drug carriers and are suitable in formulating drugs for different routes of administration. As more and newer dendrimers are introduced into the market, they will have increasing role in therapeutic delivery of drugs, vaccines and gene.Keywords: Dendrimers, Targeted drug delivery and Cancer chemotherapy

Introduction: As a part of increasing interest in nanobiotechnology, nanoparticle-based drug discovery as well as development and drug delivery constitute an important area in nanomedicine, and it is also driven by search for new drugs by the pharmaceutical industry. Nanomaterials for pharmaceutical application include carbon nanotubes (CNTs).Areas covered: This article describes the properties of CNTs, both single-walled CNTs (SWCNTs) and multiwalled CNTs (MWCNTs) with relevance to drug discovery and development. Pharmacokinetics of CNTs as well as CNT-based drug delivery is discussed. The article also looks at how the scope for pharmaceutical applications of CNTs is broadened by conjugation with other molecules and presents the potential therapeutic applications. Finally, the toxicology of CNTs is considered with measures under investigation for reducing it. Literature on CNTs, from the past 5 years, was reviewed and selected publications relevant to drug discovery, development, and delivery were included in the bibliography.Expert opinion: Carbon nanotubes combine more properties relevant to drug development and delivery than any other nanomaterial. Although a tremendous amount of basic research has been done on CNTs during the past decade, little of this is nearing translation into human applications. No CNT-based medicine has reached clinical trials. Nevertheless, CNT conjugation with other molecules has extended the horizons for their potential therapeutic applications. The most promising of these is PEGylation, which extends the survival of CNTs in circulation. Potential future applications of CNTs include combination of diagnostics and therapeutic drug delivery as well as a component of multimodal therapies for tissue regeneration.

Microneedle patches (MNPs) have been developed as a minimally invasive way to deliver drugs, vaccines, and cosmeceuticals via the skin. These patches contain arrays of solid needles measuring hundreds of microns in length that act by breaching the stratum corneum barrier, thereby creating microchannels that minimize stimulation of nerve endings and painlessly delivering drugs into or across the skin. MNPs offer several advantages in comparison to hypodermic needles and conventional transdermal drug delivery systems. While constrained by some limiting issues, like difficulties in the delivery of large doses, this technology offers great potential to administer a range of different types of molecules, whether small molecules or macromolecules, either locally or systemically. MNPs can be made from different materials into different geometries using various microfabrication technologies tailored for each specific application. Recent clinical trials have supported the safety, efficacy, and improved patient acceptance of MNPs compared to injections. Altogether, MNP-based drug delivery via the skin has great potential to affect future medicine and improve human health via vaccination, as well as delivery of therapeutic drugs and cosmeceuticals.

In this high-tech era, the targeted drug delivery system has various progressions in the delivery of cancerous drugs. In the current review, the main purpose is to address the valuable needs of a targeted drug delivery system in all aspects of the safety and therapeutic delivery of drugs. The main objective is to introduce the drug carriers with their benefits. The targeted drug delivery system is superior to the traditional drug delivery system because they overcome the pros and cons and deliver the dosage form at the targeted site without exhibiting any side effects. The positive benefit of this system is that they reduce the dose dumping and provides the optimized delivery of drugs. The current review article elaborates on the different drug carriers used in the targeted drug delivery system such as liposomes, microspheres, and nanoparticles with their importance, merits, and demerits. This article mainly concentrates on the applications and some other important facts related to the targeted drug delivery carriers.

Introduction: Next-generation scaffolds for bone tissue engineering (BTE) should exhibit the appropriate combination of mechanical support and morphological guidance for cell proliferation and attachment while at the same time serving as matrices for sustained delivery of therapeutic drugs and/or biomolecular signals, such as growth factors. Drug delivery from BTE scaffolds to induce the formation of functional tissues, which may need to vary temporally and spatially, represents a versatile approach to manipulating the local environment for directing cell function and/or to treat common bone diseases or local infection. In addition, drug delivery from BTE is proposed to either increase the expression of tissue inductive factors or to block the expression of others factors that could inhibit bone tissue formation. Composite scaffolds which combine biopolymers and bioactive ceramics in mechanically competent 3D structures, including also organic–inorganic hybrids, are being widely developed for BTE, where the affinity and interaction between biomaterials and therapeutic drugs or biomolecular signals play a decisive role in controlling the release rate.Areas covered: This review covers current developments and applications of 3D composite scaffolds for BTE which exhibit the added capability of controlled delivery of therapeutic drugs or growth factors. A summary of drugs and biomolecules incorporated in composite scaffolds and approaches developed to combine biopolymers and bioceramics in composites for drug delivery systems for BTE is presented. Special attention is given to identify the main challenges and unmet needs of current designs and technologies for developing such multifunctional 3D composite scaffolds for BTE.Expert opinion: One of the major challenges for developing composite scaffolds for BTE is the incorporation of a drug delivery function of sufficient complexity to be able to induce the release patterns that may be necessary for effective osseointegration, vascularization and bone regeneration. Loading 3D scaffolds with different biomolecular agents should produce a codelivery system with different, predetermined release profiles. It is also envisaged that the number of relevant bioactive agents that can be loaded onto scaffolds will be increased, whilst the composite scaffold design should exploit synergistically the different degradation profiles of the organic and inorganic components.

In September of last year, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored an AIDS Program Panel meeting entitled `CNS as an HIV-1 Reservoir: BBB and Drug Delivery'. The main objective of this highly focused meeting was to discuss the latest understandings of systemic drug delivery to the brain and the dif®culties which may be associated with developing optimal treatment for HIV-1-associated CNS disorders. To address this issue the participants, which consisted of clinical and basic science experts in AIDS and HIV-1/CNS infection along with vascular cell biologists, pharmacologists and brain tumor biologists, initially had a general discussion on the pathogenesis of HIV-1-induced neurological dysfunction. The participants presented their views in three sessions: NeuroAIDS, the Blood-Brain Barrier (BBB), and drug delivery to the CNS; to attempt to clarify many uncertainties pertaining to current treatment modalities for HIV-1-induced pathology in the brain. Once general concepts of the neuropathogenesis of HIV-1-induced disease were discussed, special effort was made to de®ne the areas of research which require increased attention, such as the identi®cation of ef®cient mechanisms of CNS drug delivery for the treatment of neurological dysfunction seen in AIDS patients. The current model as to how HIV-1 infection of the CNS occurs was acknowledged. According to this model, the virus may either access the CNS through traf®cking of infected leukocytes into the brain, and/or through transfer of the virus via the brain endothelium. In addition to microglia, the major viral reservoir in the CNS, restricted infection of astrocytes and brain endothelial cells was further emphasized. It was noted that HIV-1 strains present in CNS-speci®c cellular targets are genetically distinct from those in the periphery. It is the CNS variants that may develop resistance to current antiviral therapies as a result of a sub-optimal level of pharmacological agents in the brain, which in turn, may provide a reservoir of virus in the brain. Much focus was given to the signi®cance of studying chemokine receptors as attachment sites for HIV-1. It was noted that neurons contain such receptors, however since the infection of neurons by HIV-1 is still uncertain, it remains unclear as to how expression of such receptors relates to earlier reports of limited, if any, infection of neurons in the AIDS brain. On a different note, it was also suggested that chemokines and their receptors may be involved in mediating the in ux of infected macrophages into the CNS. In light of the high degree of diversity in these classes of receptors, further study is required to decipher their direct and indirect roles in HIV-1-induced CNS pathology. Nevertheless, the current data suggest that viral receptors and co-receptors may serve as potential targets for the development of therapeutic strategies against HIV-1 in brain. With regard to the BBB and drug delivery, experts on cerebral vasculature commented on the complex nature of BBB integrity and the effect of HIV-1 infection on BBB permeability in infected individuals. Earlier observations have noted an enhanced permeability of the BBB in HIV-1 subjects based on the detection of increased levels of serum proteins, evidence of in ammation of the brain parenchyma, and an increase in the expression of cell adhesion molecules in the brain. However, neuroimaging studies have failed to support these observations. It was, therefore, suggested that BBB permeability should be tested with compounds such as dextrancoated iron conjugates through the use of animal models in order to clarify this important issue. Several in vitro models of the BBB were presented with special emphasis on perturbation of its integrity by HIV-1. Although some appear to represent suitable in vitro models, correlation of the in vitro ®ndings is limited due to the acute nature of changes in the in vitro models as opposed to chronic changes in vitro. Another topic that attracted a great deal of attention was the delivery of therapeutic drugs across the BBB. There was a consensus among the participants that HIV-1 within the CNS may be protected from the currently used highly aggressive anti-retroviral therapy (HAART). It was emphasized that assessment of the viral load and the presence of *Correspondence: S Amini Journal of NeuroVirology (1999) 5, 113 ± 114 a

Are extracellular vesicles new hope in clinical drug delivery for neurological disorders?

Exosomes are extracellular vesicles with nano size range. The use of exosomes as drug delivery vehicle has useful advantages compared to other vesicular systems. Exosomes are nonimmunogenic, nontoxic, and stable with good composition and potency for crossing blood brain barrier. They can be used as theranostic agents and vaccine therapy. The exosomes are a new choice for nonimmunogenic targeted drug delivery vehicle. Introduction : Exosomes are nano size vesicles secreted by different cell types. The main role of exosomes in the body is a cell to cell communication. They are not immunogenic due to similar structure as body cells. They can cross blood brain barrier, stable in the blood circulation, biocompatible, with low toxicity, suitable size, and structure. These endogenous vesicles can be used for drug delivery, immunevaccines and as diagnostic agents. Methods: The following databases were reviewed for bibliography of using exosomes as delivery agents: Web of science, Scopus, Medline, and Embase. Results : Exosomes can deliver different kinds of cargos (RNA, proteins and small molecules) to the target cells. Exosome as a biomarker of diseases (cancer, cardiovascular disease, MS, etc) personalized therapy with the exosomes that generated from induced pluripotent stem cell (iPSC) derived that used for patient specific and disease specific cell therapy. They have specific role in tissue repair and regeneration, vaccines for immunotherapy (phase II of clinical trial). The strategies to introduce drugs into exosomes are active and passive loading. Artificial exosome mimetics can be isolated from exosome secreting cell lines but these exosomes in comparison with autologous are immunogenic. Isolation techniques of exosomes are ultracentrifugation, electron microscopy, and SDS page. Exosomes were mainly taken up by macrophages in the liver after IV administration. Exosomes characterization methods are biophysical, molecular and microfluidics. Conclusion: Exosomes are good carriers for delivery of drugs and genes to the target without immunogenic reaction. They can be used as immunovacines for the cancer treatment by activating immune system against tumor cells. Exosomes can substitution the liposomes because of their size, structure, non-immunogenicity and their natural composition. Key words : Exosomes, Extracellular vesicles, Drug delivery, Nano carrier, Immunovaccine

Tumor-derived extracellular vesicles: Regulators of tumor microenvironment and the enlightenment in tumor therapy