Clinical Implications of Exosomes: Targeted Drug Delivery for Cancer Treatment.
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ABSTRACT:
SUBMITTER: Massey AE
PROVIDER: S-EPMC8156384 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Nanomaterials and nanostructures have shown fascinating performances in various biomedicine fields, from cosmetic to cancer diagnosis and therapy. Engineered nanomaterials can encapsulate both lipophilic and hydrophilic substances/drugs to eliminate their limitations in the free forms, such as low bioavailability, multiple drug administration, off-target effects, and various side effects. Moreover, it is possible to deliver the loaded cargo to the desired site of action using engineered nanomaterials. One approach that has made nanocarriers more sophisticated is the "biomimetic" concept. In this scenario, biomolecules (e.g., natural proteins, peptides, phospholipids, cell membranes) are used as building blocks to construct nanocarriers and/or modify agents. For instance, it has been reported that specific cells tend to migrate to a particular site during specific circumstances (e.g., inflammation, tumor formation). Employing the cell membrane of these cells as a coating for nanocarriers confers practical targeting approaches. Accordingly, we introduce the biomimetic concept in the current study, review the recent studies, challenge the issues, and provide practical solutions.
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Project description:Among extracellular vesicles, exosomes have gained great attention for their role as therapeutic vehicles for delivering various active pharmaceutical ingredients (APIs). Exosomes "armed" with anti-cancer therapeutics possess great potential for an efficient intracellular delivery of anti-cancer APIs and enhanced targetability to tumor cells. Various technologies are being developed to efficiently incorporate anti-cancer APIs such as genetic materials (miRNA, siRNA, mRNA), chemotherapeutics, and proteins into exosomes and to induce targeted delivery to tumor burden by exosomal surface modification. Exosomes can incorporate the desired therapeutic molecules via direct exogenous methods (e.g., electroporation and sonication) or indirect methods by modifying cells to produce "armed" exosomes. The targeted delivery of "armed" exosomes to tumor burden could be accomplished either by "passive" targeting using the natural tropism of exosomes or by "active" targeting via the surface engineering of exosomal membranes. Although anti-cancer exosome therapeutics demonstrated promising results in preclinical studies, success in clinical trials requires thorough validation in terms of chemistry, manufacturing, and control techniques. While exosomes possess multiple advantages over synthetic nanoparticles, challenges remain in increasing the loading efficiency of anti-cancer agents into exosomes, as well as establishing quantitative and qualitative analytical methods for monitoring the delivery of in vivo administered exosomes and exosome-incorporated anti-cancer agents to the tumor parenchyma.
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Project description:Exosomes are cell-derived vesicles containing heterogeneous active biomolecules such as proteins, lipids, mRNAs, receptors, immune regulatory molecules, and nucleic acids. They typically range in size from 30 to 150 nm in diameter. An exosome's surfaces can be bioengineered with antibodies, fluorescent dye, peptides, and tailored for small molecule and large active biologics. Exosomes have enormous potential as a drug delivery vehicle due to enhanced biocompatibility, excellent payload capability, and reduced immunogenicity compared to alternative polymeric-based carriers. Because of active targeting and specificity, exosomes are capable of delivering their cargo to exosome-recipient cells. Additionally, exosomes can potentially act as early stage disease diagnostic tools as the exosome carries various protein biomarkers associated with a specific disease. In this review, we summarize recent progress on exosome composition, biological characterization, and isolation techniques. Finally, we outline the exosome's clinical applications and preclinical advancement to provide an outlook on the importance of exosomes for use in targeted drug delivery, biomarker study, and vaccine development.
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Project description:BackgroundRecently, increased attention has been given on exosomes as ideal nanocarriers of drugs owing to their intrinsic properties that facilitate the transport of biomolecular cargos. However, large-scale exosome production remains a major challenge in the clinical application of exosome-based drug delivery systems. Considering its biocompatibility and stability, bovine milk is a suitable natural source for large-scale and stable exosome production. Because the active-targeting ability of drug carriers is essential to maximize therapeutic efficacy and minimize side effects, precise membrane functionalization strategies are required to enable tissue-specific delivery of milk exosomes with difficulty in post-isolation modification.MethodsIn this study, the membrane functionalization of a milk exosome platform modified using a simple post-insertion method was examined comprehensively. Exosomes were engineered from bovine milk (mExo) with surface-tunable modifications for the delivery of tumor-targeting doxorubicin (Dox). The surface modification of mExo was achieved through the hydrophobic insertion of folate (FA)-conjugated lipids.ResultsWe have confirmed the stable integration of functionalized PE-lipid chains into the mExo membrane through an optimized post-insertion technique, thereby effectively enhancing the surface functionality of mExo. Indeed, the results revealed that FA-modified mExo (mExo-FA) improved cellular uptake in cancer cells via FA receptor (FR)-mediated endocytosis. The designed mExo-FA selectively delivered Dox to FR-positive tumor cells and triggered notable tumor cell death, as confirmed by in vitro and in vivo analyses.ConclusionsThis simple and easy method for post-isolation modification of the exosomal surface may be used to develop milk-exosome-based drug delivery systems.
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Project description:ObjectivesExosomes are essential mediators of intercellular communication as they transport proteins and RNAs between cells. Owing to their tumor-targeting capacity, immune compatibility, low toxicity, and long half-life, mesenchymal stem cell-derived exosomes have great potential for the development of novel antitumor strategies. In this context, the role of exosomes produced by adipose-derived mesenchymal stem cells (ADSCs) for the treatment of bladder cancer (BC) remains unclear. Here, we investigated the use of ADSCs as a source of therapeutic exosomes, as well as their efficacy in delivering the tumor suppressor miR-138-5p in BC.MethodsADSCs stably expressing miR-138-5p were established using Lentivirus infection, and ADSC-derived miR-138-5p exosomes (Exo-miR-138-5p) were isolated from the cell culture medium. The effect of Exo-miR-138-5p on BC cell migration, invasion, and proliferation was evaluated in vitro using wound healing, transwell invasion, and proliferation assays. The in vivo effect of Exo-miR-138-5p was investigated using a subcutaneous xenograft mouse model.ResultsExo-miR-138-5p prevented the migration, invasion, and proliferation of BC cells in vitro. Moreover, ADSC-derived exosomes could penetrate tumor tissues and successfully deliver miR-138-5p to suppress the growth of xenograft tumors in vivo.ConclusionsThe present results reveal that ADSC-derived exosomes are an effective delivery vehicle for small molecule drugs in vivo, and exosome-delivered miR-138-5p is a promising therapeutic agent for BC treatment.
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Project description:Exosomes as nanosized vesicles are emerging as drug delivery systems for therapeutics owing to their natural origin, their ability to mediate intercellular communication, and their potential to encapsulate various biological molecules such as proteins and nucleic acids within the lipid bilayer membrane or in the lumen. Exosomes contain endogenous components (proteins, lipids, RNA) that could be used to deliver cargoes to target cells, offering an opportunity to diagnose and treat various diseases. Owing to their ability to travel safely in extracellular fluid and to transport cargoes to target cells with high efficacy, exosomes offer enhanced delivery of cargoes in vivo. However, several challenges related to the stabilization of the exosomes, the production of sufficient amounts of exosomes with safety and efficacy, the efficient loading of drugs into exosomes, the clearance of exosomes from circulation, and the transition from the bench scale to clinical production may limit their development and clinical use. For the clinical use of exosomes, it is important to understand the molecular mechanisms behind the transport and function of exosome vesicles. This review exploits techniques related to the isolation and characterization of exosomes and their drug delivery potential to enhance the therapeutic outcome and stabilization methods. Further, routes of administration, clinical trials, and regulatory aspects of exosomes will be discussed in this review.
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