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EBioMedicine Jun 2020The rapid development of nanotechnology results in the emergence of nanomedicines, but the effective delivery of drugs to tumor sites remains a great challenge.... (Review)
Review
The rapid development of nanotechnology results in the emergence of nanomedicines, but the effective delivery of drugs to tumor sites remains a great challenge. Prodrug-based cancer nanomedicines thus emerged due to their unique advantages, including high drug load efficiency, reduced side effects, efficient targeting, and real-time controllability. A distinctive characteristic of prodrug-based nanomedicines is that they need to be activated by a stimulus or multi-stimulus to produce an anti-tumor effect. A better understanding of various responsive approaches could allow researchers to perceive the mechanism of prodrug-based nanomedicines effectively and further optimize their design strategy. In this review, we highlight the stimuli-responsive pathway of prodrug-based nanomedicines and their anticancer applications. Furthermore, various types of prodrug-based nanomedicines, recent progress and prospects of stimuli-responsive prodrug-based nanomedicines and patient data in the clinical application are also summarized. Additionally, the current development and future challenges of prodrug-based nanomedicines are discussed. We expect that this review will be valuable for readers to gain a deeper understanding of the structure and development of prodrug-based cancer nanomedicines to design rational and effective drugs for clinical use.
Topics: Humans; Hydrogen-Ion Concentration; Nanoparticles; Neoplasms; Oxidative Stress; Prodrugs
PubMed: 32505922
DOI: 10.1016/j.ebiom.2020.102821 -
Advanced Drug Delivery Reviews Jul 2023Long-acting formulations are designed to reduce dosing frequency and simplify dosing schedules by providing an extended duration of action. One approach to obtain... (Review)
Review
Long-acting formulations are designed to reduce dosing frequency and simplify dosing schedules by providing an extended duration of action. One approach to obtain long-acting formulations is to combine long-acting prodrugs (LA-prodrug) with existing or emerging drug delivery technologies (DDS). The design criteria for long-acting prodrugs are distinct from conventional prodrug strategies that alter absorption, distribution, metabolism, and excretion (ADME) parameters. Our review focuses on long-acting prodrug delivery systems (LA-prodrug DDS), which is a subcategory of long-acting formulations where prodrug design enables DDS formulation to achieve an extended duration of action that is greater than the parent drug. Here, we define LA-prodrugs as the conjugation of an active pharmaceutical ingredient (API) to a promoiety group via a cleavable covalent linker, where both the promoiety and linker are selected to enable formulation and administration from a drug delivery system (DDS) to achieve an extended duration of action. These LA-prodrug DDS results in an extended interval where the API is within a therapeutic range without necessarily altering ADME as is typical of conventional prodrugs. The conversion of the LA-prodrug to the API is dependent on linker cleavage, which can occur before or after release from the DDS. The requirement for linker cleavage provides an additional tool to prolong release from these LA-prodrug DDS. In addition, the physicochemical properties of drugs can be tuned by promoiety selection for a particular DDS. Conjugation with promoieties that are carriers or amenable to assembly into carriers can also provide access to formulations designed for extending duration of action. LA-prodrugs have been applied to a wide variety of drug delivery strategies and are categorized in this review by promoiety size and complexity. Small molecule promoieties (typically MW < 1000 Da) have been used to improve encapsulation or partitioning as well as broaden APIs for use with traditional long-acting formulations such as solid drug dispersions. Macromolecular promoieties (typically MW > 1000 Da) have been applied to hydrogels, nanoparticles, micelles, dendrimers, and polymerized prodrug monomers. The resulting LA-prodrug DDS enable extended duration of action for active pharmaceuticals across a wide range of applications, with target release timescales spanning days to years.
Topics: Humans; Prodrugs; Drug Delivery Systems
PubMed: 37160248
DOI: 10.1016/j.addr.2023.114860 -
Chembiochem : a European Journal of... Sep 2023Prodrugs are pharmacologically inactive, chemically modified derivatives of active drugs, which, following in vivo administration, are converted to the parent drugs... (Review)
Review
Prodrugs are pharmacologically inactive, chemically modified derivatives of active drugs, which, following in vivo administration, are converted to the parent drugs through chemical or enzymatic cleavage. The prodrug approach holds tremendous potential to create the enhanced version of an existing pharmacological agent and leverage those improvements to augment the drug molecules' bioavailability, targeting ability, therapeutic efficacy, safety, and marketability. Especially in cancer therapy, prodrug application has received substantial attention. A prodrug can effectively broaden the therapeutic window of its parent drug by enhancing its release at targeted tumor sites while reducing its access to healthy cells. The spatiotemporally controlled release can be achieved by manipulating the chemical, physical, or biological stimuli present at the targeted tumor site. The critical strategy comprises drug-carrier linkages that respond to physiological or biochemical stimuli in the tumor milieu to yield the active drug form. This review will focus on the recent advancements in the development of various fluorophore-drug conjugates that are widely used for real-time monitoring of drug delivery. The use of different stimuli-cleavable linkers and the mechanisms of linker cleavage will be discussed. Finally, the review will conclude with a critical discussion of the prospects and challenges that might impede the future development of such prodrugs.
Topics: Humans; Prodrugs; Drug Delivery Systems; Drug Carriers; Neoplasms
PubMed: 37341379
DOI: 10.1002/cbic.202300155 -
Biochimie Feb 2023Bacteria protect themselves from the toxicity of antimicrobial metabolites they produce through several strategies. In one resistance mechanism, bacteria assemble a... (Review)
Review
Bacteria protect themselves from the toxicity of antimicrobial metabolites they produce through several strategies. In one resistance mechanism, bacteria assemble a non-toxic precursor on an N-acyl-d-asparagine prodrug motif in the cytoplasm, then export it to the periplasm where a dedicated d-amino peptidase hydrolyzes the prodrug motif. These prodrug-activating peptidases contain an N-terminal periplasmic S12 hydrolase domain and C-terminal transmembrane domains (TMDs) of varying lengths: type I peptidases contain three transmembrane helices, and type II peptidases have an additional C-terminal ABC half-transporter. We review studies which have addressed the role of the TMD in function, the substrate specificity, and the biological assembly of ClbP, the type I peptidase that activates colibactin. We use modeling and sequence analyses to extend those insights to other prodrug-activating peptidases and ClbP-like proteins which are not part of prodrug resistance gene clusters. These ClbP-like proteins may play roles in the biosynthesis or degradation of other natural products, including antibiotics, may adopt different TMD folds, and have different substrate specificity compared to prodrug-activating homologs. Finally, we review the data supporting the long-standing hypothesis that ClbP interacts with transporters in the cell and that this association is important for the export of other natural products. Future investigations of this hypothesis as well as of the structure and function of type II peptidases will provide a complete account of the role of prodrug-activating peptidases in the activation and secretion of bacterial toxins.
Topics: Peptide Hydrolases; Prodrugs; Escherichia coli; Escherichia coli Proteins
PubMed: 36803695
DOI: 10.1016/j.biochi.2022.07.019 -
European Journal of Medicinal Chemistry Feb 2017In this review we highlight the most modern trends in the prodrug strategy. In drug research and development, the prodrug concept has found a number of useful... (Review)
Review
In this review we highlight the most modern trends in the prodrug strategy. In drug research and development, the prodrug concept has found a number of useful applications. Selected examples of this approach are provided in this paper and they are classified according to the aim of their design.
Topics: Absorption, Physicochemical; Animals; Cell Membrane Permeability; Drug Discovery; Humans; Prodrugs; Solubility; Water
PubMed: 27823878
DOI: 10.1016/j.ejmech.2016.10.061 -
Current Topics in Medicinal Chemistry 2021Prodrug design is an effective method proven to improve the drug-like properties of a molecule, and it has been widely used in the drug development of various diseases.... (Review)
Review
Prodrug design is an effective method proven to improve the drug-like properties of a molecule, and it has been widely used in the drug development of various diseases. Due to the complexity of the central nervous system (CNS), the development of CNS drugs has high requirements related to the pharmaceutical, pharmacokinetic, and pharmacodynamic properties of the molecules. Prodrug design has now been widely and successfully applied to improve these properties. We conducted a mini-review to promote the use of the prodrug strategies in CNS drug development. To facilitate the description, we chose drug indications as a clue, then presented and discussed some representative CNS prodrugs. Finally, a brief summary and outlook about this area were presented.
Topics: Animals; Central Nervous System; Drug Design; Humans; Prodrugs
PubMed: 34315372
DOI: 10.2174/1568026621666210727163827 -
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 -
Molecular Therapy : the Journal of the... May 2021The inclusion of genes that control cell fate (so-called suicide, or kill-switch, genes) into gene therapy vectors is based on a compelling rationale for the safe and... (Review)
Review
The inclusion of genes that control cell fate (so-called suicide, or kill-switch, genes) into gene therapy vectors is based on a compelling rationale for the safe and selective elimination of aberrant transfected cells. Prodrug-activated systems were developed in the 1980s and 1990s and rely on the enzymatic conversion of non-active prodrugs to active metabolites that lead to cell death. Although considerable effort and ingenuity has gone into vector design for gene therapy, less attention has been directed at the efficacy or associated adverse effects of the prodrug systems employed. In this review, we discuss prodrug systems employed in clinical trials and consider their role in the field of gene therapy. We highlight potential drawbacks associated with the use of specific prodrugs, such as systemic toxicity of the activated compound, the paucity of data on biodistribution of prodrugs, bystander effects, and destruction of genetically modified cells, and how these can inform future advances in cell therapies.
Topics: Combined Modality Therapy; Genetic Therapy; Humans; Neoplasms; Prodrugs; Tissue Distribution
PubMed: 33831557
DOI: 10.1016/j.ymthe.2021.04.006 -
Chemical Communications (Cambridge,... Sep 2021Central nervous system (CNS) disease is one of the most notorious arch-criminals of human health across the world. Although considerable efforts have been devoted to... (Review)
Review
Central nervous system (CNS) disease is one of the most notorious arch-criminals of human health across the world. Although considerable efforts have been devoted to promote the development of CNS drugs, ideal therapeutical effects are yet far from enough. The blood-brain barrier remains a major player that impedes the full potential of CNS therapeutical agents as it blocks the entry of CNS drugs into the brain. The past few decades have witnessed the upspring of prodrug strategies as a promising method to accelerate CNS drug development. The prodrug strategy with the ability to overcome the formidable blood-brain barrier enhances the delivery to the brain and hence improves the effects of the CNS therapeutics. In this Feature Article, we summarize the reported barriers and strategies for CNS therapeutics and spotlight prodrug design strategies to improve the efficiency of crossing the blood-brain barrier.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Brain; Central Nervous System Agents; Central Nervous System Diseases; Humans; Prodrugs
PubMed: 34486590
DOI: 10.1039/d1cc02940a -
Current Topics in Medicinal Chemistry 2021Synthetic nucleoside or nucleotide analogues played a key role to the development of antiviral agents in past decades. However, low membrane permeability and... (Review)
Review
Synthetic nucleoside or nucleotide analogues played a key role to the development of antiviral agents in past decades. However, low membrane permeability and insufficient cellular phosphorylation impaired the biological activity of polar nucleoside drugs because they have to penetrate the cell membrane and be phosphorylated to active metabolite stepwise by intracellular enzymes. To overcome these limitations, diverse lipophilic prodrug modifications based on nucleoside mono-, di-, and triphosphate were designed and put into practice to efficiently deliver nucleoside into the target site, and bypass the rate-limited phosphorylation step. As the most successful prodrug strategy, ProTide technology has led to the discovery of three FDA-approved antiviral agents, including sofosbuvir, tenofovir alafenadmide, and remdesivir, which has been authorized for emergency use in patients of COVID-19 in the US. In recent years, nucleoside di- and triphosphate prodrugs have also made the significant progress. This review will focus on the summary of design approach and metabolic activation path of different nucleotide prodrug strategies. The potential application of nucleotide prodrugs for the treatment of COVID-19 was also described due to the pandemic of SARS-CoV-2.
Topics: Antiviral Agents; Drug Design; Humans; Nucleosides; Nucleotides; Prodrugs; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34323189
DOI: 10.2174/1568026621666210728094019