Engineering Extracellular Vesicles with the Tools of Enzyme Prodrug Therapy
Gregor FuhrmannRona ChandrawatiParesh A. ParmarTimothy J. KeaneStephanie A. MaynardSérgio BertazzoMolly M. Stevens
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Abstract Extracellular vesicles (EVs) have recently gained significant attention as important mediators of intercellular communication, potential drug carriers, and disease biomarkers. These natural cell‐derived nanoparticles are postulated to be biocompatible, stable under physiological conditions, and to show reduced immunogenicity as compared to other synthetic nanoparticles. Although initial clinical trials are ongoing, the use of EVs for therapeutic applications may be limited due to undesired off‐target activity and potential “dilution effects” upon systemic administration which may affect their ability to reach their target tissues. To fully exploit their therapeutic potential, EVs are embedded into implantable biomaterials designed to achieve local delivery of therapeutics taking advantage of enzyme prodrug therapy (EPT). In this first application of EVs for an EPT approach, EVs are used as smart carriers for stabilizing enzymes in a hydrogel for local controlled conversion of benign prodrugs to active antiinflammatory compounds. It is shown that the natural EVs' antiinflammatory potential is comparable or superior to synthetic carriers, in particular upon repeated long‐term incubations and in different macrophage models of inflammation. Moreover, density‐dependent color scanning electron microscopy imaging of EVs in a hydrogel is presented herein, an impactful tool for further understanding EVs in biological settings.Keywords:
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The prodrug concept has been used to improve undesirable properties of drugs since the late 19th century, although it was only at the end of the 1950s that the actual term prodrug was introduced for the first time. Prodrugs are inactive, bioreversible derivatives of active drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then elicit its desired pharmacological effect in the body. In most cases, prodrugs are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the active parent drug. However, some prodrugs lack an obvious carrier or promoiety but instead result from a molecular modification of the prodrug itself, which generates a new active compound. Numerous prodrugs designed to overcome formulation, delivery, and toxicity barriers to drug utilization have reached the market. In fact, approximately 20% of all small molecular drugs approved during the period 2000 to 2008 were prodrugs. Although the development of a prodrug can be very challenging, the prodrug approach represents a feasible way to improve the erratic properties of investigational drugs or drugs already on the market. This review introduces in depth the rationale behind the use of the prodrug approach from past to present, and also considers the possible problems that can arise from inadequate activation of prodrugs.
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Background: The Carrier linked prodrug as per literature is known to be a pharmacologically inactive chemical derivative and could be used to change the physicochemical properties of compounds. Codrugs is a type of carrier linked prodrug, and consist of two usually synergistic drugs or moieties attached to each other. Keywords: Prodrugs, codrugs, carrier linked prodrugs, spacer, benorylate.
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This chapter contains sections titled: Introduction Immunogenicity of Therapeutic Proteins Immune Mechanisms Related to Protein Immunogenicity Aggregates and Immunogenicity Conclusions References
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Abstract Extracellular vesicles (EVs) constitute an intricate system of molecular exchange that has recently gained tremendous interest. However, sustainable sources of safe biological EVs remain scarce and elusive. This study explores and defines the use of food industry by‐products (BP) as a circular source of safe biocompatible EVs. Averaged diameter and molecular compositions indicate a large yield of exosomes and high abundancy of membrane lipids with signaling capacity in these vesicles. Complex proteomes mimicking those circulating in human blood plasma are also identified. Furthermore, BP‐EVs do not show relevant cytotoxicity and display excellent oral and intravenous bioavailability together with specific organ targeting capacity. Collectively, it is believed that the novel findings reported here will open substantial venues for the use of BP as an optimal source of biocompatible nanovesicles in manifold applications of the biotechnological and biomedical fields.
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Abstract Directed enzyme prodrug therapy is a highly promising anti-cancer strategy. However, the current technology is limited by inefficient prodrug activation and the dose-limiting toxicity associated with the prodrugs being tested; to overcome these limitations, the dinitrobenzamide mustard prodrugs, PR-104A and SN27686, have been developed. The present study will assess both of these prodrugs for their potential uses in a novel magnetic-nanoparticle directed enzyme prodrug therapy strategy by determining their kinetic parameters, assessing the products formed during enzymatic reduction using HPLC and finally their ability to cause cell death in the ovarian cancer cell line, SK-OV-3. It was shown for the first time that the dinitrobenzamide mustard prodrugs are able to be reduced by the genetically modified nitroreductases, NfnB-cys and YfkO-cys, and that these enzyme/prodrug combinations can induce a significant cell death in the SK-OV-3 cell line, highlighting the potential for both enzyme/prodrug combinations for use in magnetic-nanoparticle directed enzyme prodrug therapy.
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A prodrug is a medicine that is primarily used after administration, that is metabolized into a pharmacologically active drug. A prodrug is generally a precursor form of a drug. A prodrug is used to selectively improve the drug that directly interacts with cells used in any form of treatment like chemotherapy. The drug, when taken separately, does not have much effect, whereas, a drug taken in after the administration of prodrug acts very effectively. Prodrugs are often used in the pharmaceutical field. Prodrug alters certain properties of prodrugs, such as physicochemical properties to enhance their efficacy and reduce their toxicity. The cancer cells are first injected with a gene that expresses an enzyme that has the ability to convert a non-toxic prodrug into its active cytotoxic form. Various applications of prodrugs include improving drug penetration through biological membranes, increasing site-specificity of a drug; it mainly improves patient's acceptance. Prodrugs stabilize the active drug and prevent drug metabolism. This review was written with an aim to highlight the important aspects of prodrugs and its use in cancer therapy.
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Chemotherapy is one of the main tumor therapy in clinic,but the system toxicity of antitumor agent and its low concentration in the specific tumor position are still important disturbing factors in tumor treatment.Prodrug,which is from the modification of active drug constructure or pharmaceutical dosage form,greatly overcome the defect of chemotherapy agent and open a new way in target tumor treatment.At present,new advanced antitumor prodrugs contain directed-enzyme activated prodrug,carrier prodrug,lipophilic prodrug and so on.Several antitumor prodrugs have been reviewed.
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