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Chemical Communications (Cambridge,... Oct 2023Bioorthogonal catalysis, a class of catalytic reactions that are mediated by abiotic metals and proceed in biological environments without interfering with native... (Review)
Review
Bioorthogonal catalysis, a class of catalytic reactions that are mediated by abiotic metals and proceed in biological environments without interfering with native biochemical reactions, has gained ever-increasing momentum in prodrug delivery over the past few decades. Albeit great progress has been attained in developing new bioorthogonal catalytic reactions and optimizing the catalytic performance of transition metal catalysts (TMCs), the use of TMCs to activate chemotherapeutics at the site of interest remains a challenging endeavor. To translate the bioorthogonal catalysis-mediated prodrug activation paradigm from flasks to animals, TMCs with targeting capability and stimulus-responsive behavior have been well-designed to perform chemical transformations in a controlled manner within highly complex biochemical systems, rendering on-demand drug activation to mitigate off-target toxicity. Here, we review the recent advances in the development of controllable bioorthogonal catalysis systems, with an emphasis on different strategies for engineering TMCs to achieve precise control over prodrug activation. Furthermore, we outline the envisaged challenges and discuss future directions of controllable bioorthogonal catalysis for disease therapy.
Topics: Animals; Prodrugs; Transition Elements; Metals; Catalysis; Activation, Metabolic
PubMed: 37791560
DOI: 10.1039/d3cc04286c -
ACS Chemical Biology Apr 2022The limited therapeutic effects of immunotherapy for most types of cancer stimulates the pursuit for efficient methods to improve its response rate. Herein we report the...
The limited therapeutic effects of immunotherapy for most types of cancer stimulates the pursuit for efficient methods to improve its response rate. Herein we report the design and synthesis of a cascade-responsive molecular prodrug for tandem chemoimmunotherapy. This molecular prodrug first releases doxorubicin (DOX) in the mildly acidic tumor microenvironment (TME) to induce immunogenic cell death (ICD) of tumor cells. Caspase 3/7 released during tumor cell apoptosis liberates NLG919 from the prodrug, which inhibits the activity of indoleamine 2,3-dioxygenase (IDO) and results in relief of TME immunosuppression. Meanwhile, tumor-associated antigens and immune stimulatory cytokines released during ICD activate the immune response against the tumor, leading to synergistic chemoimmunotherapy. The efficacy of this prodrug is validated by and experiments, demonstrating the success of this strategy for cancer treatment.
Topics: Cell Line, Tumor; Dendrimers; Doxorubicin; Humans; Immunotherapy; Nanoparticles; Neoplasms; Prodrugs; Receptors, Chimeric Antigen; Tumor Microenvironment
PubMed: 35285234
DOI: 10.1021/acschembio.1c00933 -
Acta Biomaterialia Oct 2022Selective in situ activation of prodrugs or generation of bioactive drugs is an important approach to reducing the side effects of chemotherapy. Herein, a tailored...
Selective in situ activation of prodrugs or generation of bioactive drugs is an important approach to reducing the side effects of chemotherapy. Herein, a tailored ROS-activable prodrug nanomedicine (Cu-SK@DTC-PPB) was developed as the prodrug activation nanoamplifier for highly selective antitumor therapy. Cu-SK@DTC-PPB was rationally constructed by the diethyldithiocarbamate (DTC) prodrug DTC-PPB and the nanoscale coordinated framework Cu-SK based on copper and the ROS generator shikonin (SK). Cu, SK and DTC were kept in the inactive state in the fabricated Cu-SK@DTC-PPB. In the presence of ROS within tumors, DTC-PPB can be activated to release less cytotoxic DTC, which can rapidly chelate Cu from the Cu-SK framework to synthesize highly cytotoxic Cu(DTC) and induce SK to release in a cascade. The released SK can generate ROS to increase the intracellular ROS level, further activating DTC-PPB to release more DTC. That is, Cu-SK@DTC-PPB can undergo a self-amplifying positive feedback loop to induce numerous bioactive Cu(DTC) formation and SK release triggered by a small amount of ROS within the tumor microenvironment, which endows the transformation of "less toxic-to-high toxic" and thus significantly improve its selectivity towards tumors. Therefore, this study provides a new strategy of prodrug activation for tumor therapy with high efficiency and low toxicity. STATEMENT OF SIGNIFICANCE: Owing to the striking difference in ROS level between cancer cells and normal cells, ROS-responsive prodrugs are regarded as a promising approach for tumor-specific therapy. However, the stability and responsiveness of prodrugs are hard to balance. Preferable sensitivity may cause premature activation while favorable stability may lead to incomplete prodrug activation and insufficient active drug release. This study provides a tailored ROS-responsive prodrug activation nanoamplifier with favorable stability and effective prodrug activation capacity. The nanoamplifier can undergo a self-amplifying positive feedback loop to achieve numerous bioactive drugs generation in situ under ROS triggers within the tumor microenvironment, showing the enhanced antitumor therapeutic effect. Thus, this study provides a new strategy for prodrug activation and tumor-specific therapy.
Topics: Cell Line, Tumor; Copper; Ditiocarb; Humans; Nanoparticles; Neoplasms; Prodrugs; Reactive Oxygen Species; Tumor Microenvironment
PubMed: 36084924
DOI: 10.1016/j.actbio.2022.08.072 -
European Journal of Pharmaceutical... Nov 2017Prodrugs offer a versatile strategy to overcome flaws of viable drug candidates or clinically approved drugs. However, the strategic importance of prodrugs in the... (Review)
Review
Prodrugs offer a versatile strategy to overcome flaws of viable drug candidates or clinically approved drugs. However, the strategic importance of prodrugs in the pharmaceutical industry has often been challenged, and prodrugs are often considered as the last option after lead optimization and when the selected drug candidate has faced significant pharmaceutical and pharmacokinetic limitations. Based on recent success in marketed drugs, prodrug strategy should clearly be considered already in early stages of lead optimization. During the past five years or so, prodrugs have accounted for about 10% of all small molecular weight drugs that have come to the market. In 2015 alone, the FDA approved seven prodrugs, which gives a prodrug prevalence of over 20% among the small molecules or over 15% among the total amount of the FDA approved drugs that year. A great number of various prodrugs are also undergoing late stage clinical trials. The pharmaceutical industry will therefore continue to depend on prodrugs for the foreseeable future. In this review, we will present the state of the art in the design of the prodrugs launched by the FDA since 2015. We will also provide an overview of some interesting late stage clinical prodrug candidates. We hope this review will demonstrate potential of prodrug strategies and facilitates the use of prodrugs in drug discovery projects.
Topics: Animals; Drug Approval; Drug Design; Humans; Prodrugs
PubMed: 28782609
DOI: 10.1016/j.ejps.2017.08.002 -
Journal of Controlled Release :... Jun 2015Application of nanotechnology in the medical field (i.e., nanomedicine) plays an important role in the development of novel drug delivery methods. Nanoscale drug... (Review)
Review
Application of nanotechnology in the medical field (i.e., nanomedicine) plays an important role in the development of novel drug delivery methods. Nanoscale drug delivery systems can indeed be customized with specific functionalities in order to improve the efficacy of the treatments. However, despite the progresses of the last decades, nanomedicines still face important obstacles related to: (i) the physico-chemical properties of the drug moieties which may reduce the total amount of loaded drug; (ii) the rapid and uncontrolled release (i.e., burst release) of the encapsulated drug after administration and (iii) the instability of the drug in biological media where a fast transformation into inactive metabolites can occur. As an alternative strategy to alleviate these drawbacks, the prodrug approach has found wide application. The covalent modification of a drug molecule into an inactive precursor from which the drug will be freed after administration offers several benefits such as: (i) a sustained drug release (mediated by chemical or enzymatic hydrolysis of the linkage between the drug-moiety and its promoiety); (ii) an increase of the drug chemical stability and solubility and, (iii) a reduced toxicity before the metabolization occurs. Lipids have been widely used as building blocks for the design of various prodrugs. Interestingly enough, these lipid-derivatized drugs can be delivered through a nanoparticulate form due to their ability to self-assemble and/or to be incorporated into lipid/polymer matrices. Among the several prodrugs developed so far, this review will focus on the main achievements in the field of lipid-based prodrug nanocarriers designed to improve the efficacy of anticancer drugs. Gemcitabine (Pubchem CID: 60750); 5-fluorouracil (Pubchem CID: 3385); Doxorubicin (Pubchem CID: 31703); Docetaxel (Pubchem CID: 148124); Methotrexate (Pubchem CID: 126941); Paclitaxel (Pubchem CID: 36314).
Topics: Animals; Antineoplastic Agents; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Drug Delivery Systems; Humans; Liposomes; Neoplasms; Particle Size; Prodrugs
PubMed: 25617724
DOI: 10.1016/j.jconrel.2015.01.021 -
International Journal of Pharmaceutics Sep 2019Water solubility has been identified as a critical parameter and the main responsible by affecting poor performance of oral drug delivery. Poorly soluble drugs can... (Review)
Review
Water solubility has been identified as a critical parameter and the main responsible by affecting poor performance of oral drug delivery. Poorly soluble drugs can originate unsatisfactory ADME properties leading to low oral bioavailability, insufficient chemical stability, low half-life, fast pre-systemic metabolism and difficulties in formulation. In this context, the prodrug design is an alternative in order to improve physicochemical, biopharmaceutical and pharmacokinetic properties such as permeability, solubility, bioavailability, chemical stability and metabolism of molecules presenting poor drug-like properties. In this article we highlight the importance of the prodrug design in the early stages of drug discovery and development process, in an attempt to diminish the attrition rate and end up falling into the valley of death. Selected examples of this strategy are provided in this review and they are classified by some basic functional groups that are amenable to the prodrug approach with the aim of increasing aqueous solubility of poorly water-soluble compounds. Over the past decade, the number of approved prodrugs is considerable among all drugs launched in the market, emphasizing the importance of this tool on drug design. It is reported that 10% of all marketed drug worldwide can be classified as prodrugs. Furthermore, prodrugs designed to be more water soluble launched in the past decade are summarized in a table to have a closer look and finally state that the prodrug design is an amenable approach to increase water solubility.
Topics: Animals; Drug Design; Humans; Prodrugs; Solubility; Water
PubMed: 31301465
DOI: 10.1016/j.ijpharm.2019.118498 -
Advanced Healthcare Materials Nov 2023It is challenging to manage inflammatory diseases using traditional anti-inflammatory drugs due to their limited efficacy and systemic side effects, which are a result...
It is challenging to manage inflammatory diseases using traditional anti-inflammatory drugs due to their limited efficacy and systemic side effects, which are a result of their lack of selectivity, poor stability, and low solubility. Herein, it reports the development of a novel nanoparticle system, called ROS-CA-NPs, which is formed using polymer-cinnamaldehyde (CA) conjugates and is responsive to reactive oxygen species (ROS). ROS-CA-NPs exhibit excellent drug stability, tissue selectivity, and controlled drug release upon oxidative stress activation. Using mouse models of chronic rheumatoid arthritis and acute ulcerative colitis, this study demonstrates that the systemic administration of ROS-CA-NPs results in their accumulation at inflamed lesions and leads to greater therapeutic efficacy compared to traditional drugs. Furthermore, ROS-CA-NPs present excellent biocompatibility. The findings suggest that ROS-CA-NPs have the potential to be developed as safe and effective nanotherapeutic agents for a broad range of inflammatory diseases.
Topics: Animals; Mice; Prodrugs; Reactive Oxygen Species; Polymers; Anti-Inflammatory Agents; Nanoparticles
PubMed: 37540810
DOI: 10.1002/adhm.202301394 -
Angewandte Chemie (International Ed. in... Feb 2024Although the clearance of senescent cells has been proven to slow down the aging process and promote anti-cancer chemotherapy, the development of senolytics remains...
Although the clearance of senescent cells has been proven to slow down the aging process and promote anti-cancer chemotherapy, the development of senolytics remains challenging. Herein, we report a senolytic strategy enabled by senescent cell-sensitive bioorthogonal tetrazine ligation. Our design is based on linking dihydrotetrazine (Tz) to a galactose (Gal) moiety that serves both as a recognition moiety for senescence-associated β-galactosidase and a caging group for the control of tetrazine activity. Gal-Tz enables efficient click-release of a fluorescent hemicyanine and doxorubicin from a trans-cyclooctene-caged prodrug to detect and eliminate senescent HeLa and A549 cells over non-senescent counterparts with a 16.44 senolytic index. Furthermore, we leverage the strategy for the selective activation and delivery of proteolysis-targeting chimeras (PROTACs) as senolytics. PROTAC prodrug TCO-ARV-771 can be selectively activated by Gal-Tz and delivered into senescent HeLa and A549 cells to induce the degradation of bromodomain-containing protein 4. Senolytic PROTACs may offer an efficient way for intervention on cell senescence thanks to their unique capacity to degrade target proteins in a sub-stoichiometric and catalytic fashion. The results of this study establish the bioorthogonal tetrazine ligation approach as a viable strategy for selective removal of senescent cells.
Topics: Humans; Cell Line, Tumor; Senotherapeutics; Heterocyclic Compounds; Prodrugs; Cellular Senescence
PubMed: 38233359
DOI: 10.1002/anie.202315425 -
Journal of Inorganic Biochemistry Feb 2019Pt(IV) complexes act as prodrugs that are activated inside cancer cells releasing cytotoxic Pt(II) drugs such as cisplatin as well as two axial ligands. These ligands... (Review)
Review
Pt(IV) complexes act as prodrugs that are activated inside cancer cells releasing cytotoxic Pt(II) drugs such as cisplatin as well as two axial ligands. These ligands can be used to confer favorable pharmacological properties to the prodrug. They can be innocent spectators, targeting agents or bioactive moieties. When the ligands are bioactive moieties such as enzyme inhibitors or antiproliferative agents, the prodrug attacks several cellular targets at the same time acting as a multi-action prodrug. These compounds are very potent and often overcome resistance to cisplatin. Despite solid rationalization and careful design, often there is no correlation between the ability of the bioactive ligand to inhibit the target enzyme and the cytotoxicity. This might be because most bioactive ligands affect several cellular functions and not only the ones they were designed to inhibit. Thus, even "dual action" prodrugs might in reality be multi-action prodrugs. This class of multi-action Pt(IV) prodrugs seems to have great potential in the attempts to overcome resistance.
Topics: Antineoplastic Agents; Drug Delivery Systems; Humans; Platinum Compounds; Prodrugs
PubMed: 30471522
DOI: 10.1016/j.jinorgbio.2018.11.008 -
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