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Chemical Society Reviews Nov 2023Prodrugs have emerged as a major strategy for addressing clinical challenges by improving drug pharmacokinetics, reducing toxicity, and enhancing treatment efficacy. The... (Review)
Review
Prodrugs have emerged as a major strategy for addressing clinical challenges by improving drug pharmacokinetics, reducing toxicity, and enhancing treatment efficacy. The emergence of new bioorthogonal chemistry has greatly facilitated the development of prodrug strategies, enabling their activation through chemical and physical stimuli. This "on-demand" activation using bioorthogonal chemistry has revolutionized the research and development of prodrugs. Consequently, prodrug activation has garnered significant attention and emerged as an exciting field of translational research. This review summarizes the latest advancements in prodrug activation by utilizing bioorthogonal chemistry and mainly focuses on the activation of small-molecule prodrugs and antibody-drug conjugates. In addition, this review also discusses the opportunities and challenges of translating these advancements into clinical practice.
Topics: Prodrugs
PubMed: 37905601
DOI: 10.1039/d2cs00889k -
Advanced Science (Weinheim,... Sep 2021This article provides a broad spectrum about the nanoprodrug fabrication advances co-driven by prodrug and nanotechnology development to potentiate cancer treatment. The... (Review)
Review
This article provides a broad spectrum about the nanoprodrug fabrication advances co-driven by prodrug and nanotechnology development to potentiate cancer treatment. The nanoprodrug inherits the features of both prodrug concept and nanomedicine know-how, attempts to solve underexploited challenge in cancer treatment cooperatively. Prodrugs can release bioactive drugs on-demand at specific sites to reduce systemic toxicity, this is done by using the special properties of the tumor microenvironment, such as pH value, glutathione concentration, and specific overexpressed enzymes; or by using exogenous stimulation, such as light, heat, and ultrasound. The nanotechnology, manipulating the matter within nanoscale, has high relevance to certain biological conditions, and has been widely utilized in cancer therapy. Together, the marriage of prodrug strategy which shield the side effects of parent drug and nanotechnology with pinpoint delivery capability has conceived highly camouflaged Trojan horse to maneuver cancerous threats.
Topics: Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Prodrugs
PubMed: 34323373
DOI: 10.1002/advs.202101454 -
Journal of Controlled Release :... May 2022Azobenzene-based molecules show unique trans-cis isomerization upon ultraviolet light irradiation, which induce the change of polarity, crystallinity, stability, and... (Review)
Review
Azobenzene-based molecules show unique trans-cis isomerization upon ultraviolet light irradiation, which induce the change of polarity, crystallinity, stability, and binding affinity with pharmacological target. Moreover, azobenzene is the substrate of azoreductase that is often overexpressed in many pathological sites, e.g. hypoxic solid tumor. Therefore, azobenzene can be a multifunctional molecule in material science, pharmaceutical science and biomedicine because of its sensitivity to light, hypoxia and certain enzymes, hence showing potential application in site-specific smart therapy. Herein we focus on the employment of azobenzene and its derivatives for engineering triggered prodrugs and drug delivery systems, and provide an overview of photoswitchable azo-based prodrugs, the associated problems regarding the reversible isomerization and tissue penetration of ultraviolet (UV) light, as well as the potential solutions. We also present the advance of azo-bearing delivery vehicles wherein azobenzene acts as the linker, capping agent, and building block, and discuss the corresponding mechanisms for controlled cargo release, endocytosis enhancement and sensitization of free radical cancer therapy.
Topics: Azo Compounds; Drug Delivery Systems; Prodrugs; Ultraviolet Rays
PubMed: 35339578
DOI: 10.1016/j.jconrel.2022.03.041 -
Drug Development Research Aug 2022The salification and prodrug approaches modulate the physicochemical properties and absorption, distribution, metabolism, excretion, and toxicity parameters of drugs and... (Review)
Review
The salification and prodrug approaches modulate the physicochemical properties and absorption, distribution, metabolism, excretion, and toxicity parameters of drugs and lead candidates. The "phosphate" is one of the key counterions/promoiety used in the salt formation and prodrug synthesis. Salification with phosphoric acid enhances the aqueous solubility and thereby facilitates the administration of a drug by the parenteral route. Phosphate moiety in prodrug synthesis mainly improves permeability by lipophilic substitution. Histamine phosphate is the first phosphate salt, and hydrocortisone phosphate was the first prodrug approved by FDA in 1939 and 1952, respectively. The orange book enlists 12 phosphate salts and 17 phosphate prodrugs. Phosphate prodrugs, namely combretastatin A-4 diphosphate, combretastatin A-4 phosphate, lufotrelvir, TP-1287, pyridoxal phosphate, riboflavin phosphate, and psilocybin are clinical candidates. This review focuses on the FDA-approved phosphate salts and prodrugs from 1939 to 2021. The biopharmaceutical advantage of phosphate salts and prodrugs over the parent molecule is also deliberated.
Topics: Indoles; Leucine; Phosphates; Prodrugs; Pyrrolidinones; Salts; Solubility
PubMed: 35656613
DOI: 10.1002/ddr.21953 -
Chemical Society Reviews Apr 2020Classic prodrug strategies rely on covalent modification of active drugs to provide systems with superior pharmacokinetic properties than the parent drug and facilitate... (Review)
Review
Classic prodrug strategies rely on covalent modification of active drugs to provide systems with superior pharmacokinetic properties than the parent drug and facilitate administration. Supramolecular chemistry is providing a new approach to developing prodrug-like systems, wherein the characteristics of a drug are modified in a beneficial manner by creating host-guest complexes that then permit the stimulus-induced release of the active species in a controlled manner. These complexes are termed "supramolecular prodrugs". In this review, we outline the concept of supramolecular drugs via host-guest chemistry and detail progress made in the area. This summary is designed to highlight the many advantages of supramolecular prodrugs, including ease-of-preparation, molecular-level protection, sensitive response to bio-stimuli, traceless release, and adaptability to different drugs. Limitations of the approach and opportunities for future growth are also detailed.
Topics: Biomarkers; Biotransformation; Oxidation-Reduction; Prodrugs
PubMed: 32181453
DOI: 10.1039/c9cs00622b -
Nature Communications Aug 2023Precise and efficient image-guided immunotherapy holds great promise for cancer treatment. Here, we report a self-accelerated nanoplatform combining an...
Precise and efficient image-guided immunotherapy holds great promise for cancer treatment. Here, we report a self-accelerated nanoplatform combining an aggregation-induced emission luminogen (AIEgen) and a hypoxia-responsive prodrug for multifunctional image-guided combination immunotherapy. The near-infrared AIEgen with methoxy substitution simultaneously possesses boosted fluorescence and photoacoustic (PA) brightness for the strong light absorption ability, as well as amplified type I and type II photodynamic therapy (PDT) properties via enhanced intersystem crossing process. By formulating the high-performance AIEgen with a hypoxia-responsive paclitaxel (PTX) prodrug into nanoparticles, and further camouflaging with macrophage cell membrane, a tumor-targeting theranostic agent is built. The integration of fluorescence and PA imaging helps to delineate tumor site sensitively, providing accurate guidance for tumor treatment. The light-induced PDT effect could consume the local oxygen and lead to severer hypoxia, accelerating the release of PTX drug. As a result, the combination of PDT and PTX chemotherapy induces immunogenic cancer cell death, which could not only elicit strong antitumor immunity to suppress the primary tumor, but also inhibit the growth of distant tumor in 4T1 tumor-bearing female mice. Here, we report a strategy to develop theranostic agents via rational molecular design for boosting antitumor immunotherapy.
Topics: Female; Animals; Mice; Prodrugs; Immunotherapy; Cell Membrane; Fluorescence; Hypoxia; Paclitaxel; Neoplasms
PubMed: 37626073
DOI: 10.1038/s41467-023-40996-2 -
Bioorganic & Medicinal Chemistry Letters Jun 2022Bis-amidate derivatives have been viewed as attractive phosphonate prodrug forms because of their straightforward synthesis, lack of phosphorus stereochemistry, plasma...
Bis-amidate derivatives have been viewed as attractive phosphonate prodrug forms because of their straightforward synthesis, lack of phosphorus stereochemistry, plasma stability and nontoxic amino acid metabolites. However, the efficiency of bis-amidate prodrug forms is unclear, as prior studies on this class of prodrugs have not evaluated their activation kinetics. Here, we synthetized a small panel of bis-amidate prodrugs of butyrophilin ligands as potential immunotherapy agents. These compounds were examined relative to other prodrug forms delivering the same payload for their stability in plasma and cell lysate, their ability to stimulate T cell proliferation in human PBMCs, and their activation kinetics in a leukemia co-culture model of T cell cytokine production. The bis-amidate prodrugs demonstrate high plasma stability and improved cellular phosphoantigen activity relative to the free phosphonic acid. However, the efficiency of bis-amidate activation is low relative to other prodrugs that contain at least one ester such as aryl-amidate, aryl-acyloxyalkyl ester, and bis-acyloxyalkyl ester forms. Therefore, bis-amidate prodrugs do not drive rapid cellular payload accumulation and they would be more useful for payloads in which slower, sustained-release kinetics are preferred.
Topics: Esters; Humans; Ligands; Lymphocyte Activation; Organophosphonates; Prodrugs
PubMed: 35405283
DOI: 10.1016/j.bmcl.2022.128724 -
European Journal of Medicinal Chemistry Mar 2023In modern drug discovery and development, the prodrug approach has become a crucial strategy for enhancing the pharmacokinetic profiles of drugs. A prodrug is a chemical...
In modern drug discovery and development, the prodrug approach has become a crucial strategy for enhancing the pharmacokinetic profiles of drugs. A prodrug is a chemical compound, which gets metabolized into a pharmacologically active form (drug) inside the body after its administration. In the current work, we report 'smProdrugs' (http://cheminfolab.in/databases/prodrug/), which is one of the first exclusive databases on small molecule prodrugs. It stores the structures, physicochemical properties and experimental ADMET data manually curated from literature. SmProdrugs lists 626 small molecule prodrugs and their active compounds with the above mentioned experimental data from 1808 research articles and 61 patents have been stored. The information page of each record gives the structures and properties of the prodrug and the active drug side by side which makes it easy for the user to instantly compare them. The structural modifications in the prodrug/active drugs are highlighted in a different colour for easy comparison. Experimental data has been curated from the downloaded PubMed and patent articles and were catalogued in a tabular form with more than 25 fields under sub-sections i) name and structures of the prodrugs and their active compounds, ii) mode of activation of the prodrug and enzyme/biocatalyst involved in the conversion, iii) indications/disease, iv) pharmacological target, v) experimental pharmacokinetic properties such as solubility, absorption, volume of distribution, half-life, clearance etc. and vi) information on the purpose/gain from the prodrug strategies. Considering the ever expanding utility of the prodrug approach smProdrugs will be of great use to the scientific community working on rational design of small molecule prodrugs.
Topics: Prodrugs; Drug Discovery; Chemical Phenomena; Solubility; Biological Availability
PubMed: 36724634
DOI: 10.1016/j.ejmech.2023.115153 -
Molecules (Basel, Switzerland) Mar 2020Bacterial resistance to present antibiotics is emerging at a high pace that makes the development of new treatments a must. At the same time, the development of novel... (Review)
Review
Bacterial resistance to present antibiotics is emerging at a high pace that makes the development of new treatments a must. At the same time, the development of novel antibiotics for resistant bacteria is a slow-paced process. Amid the massive need for new drug treatments to combat resistance, time and effort preserving approaches, like the prodrug approach, are most needed. Prodrugs are pharmacologically inactive entities of active drugs that undergo biotransformation before eliciting their pharmacological effects. A prodrug strategy can be used to revive drugs discarded due to a lack of appropriate pharmacokinetic and drug-like properties, or high host toxicity. A special advantage of the use of the prodrug approach in the era of bacterial resistance is targeting resistant bacteria by developing prodrugs that require bacterium-specific enzymes to release the active drug. In this article, we review the up-to-date implementation of prodrugs to develop medications that are active against drug-resistant bacteria.
Topics: Anti-Bacterial Agents; Bacterial Infections; Biotransformation; Drug Design; Drug Development; Drug Resistance, Bacterial; Humans; Prodrugs; Structure-Activity Relationship
PubMed: 32231026
DOI: 10.3390/molecules25071543 -
Wiley Interdisciplinary Reviews.... Nov 2020Nanomaterials-based prodrug activation systems have been widely explored in cancer therapy, aiming at overcoming limited dosage formulation, systemic toxicity, and... (Review)
Review
Nanomaterials-based prodrug activation systems have been widely explored in cancer therapy, aiming at overcoming limited dosage formulation, systemic toxicity, and insufficient pharmacokinetic performance of parent drugs. For better delivery control, various stimuli systems, especially nanomaterials-based ones, have come to the forefront. Among them, near-infrared (NIR) light takes advantage of on-demand/site-specific regulation and non-invasiveness. In this review, we will address the developments of nanomaterials-based prodrug over the last decade, the activation mechanisms, and bioapplications under NIR light triggering. The advantages and limitations of NIR-triggered prodrug activation strategies and the perspectives of the next-generation prodrug nanomedicine will also be summarized. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.
Topics: Drug Delivery Systems; Humans; Infrared Rays; Nanomedicine; Nanostructures; Neoplasms; Prodrugs
PubMed: 32394638
DOI: 10.1002/wnan.1643