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Anticancer boron-containing prodrugs responsive to oxidative stress from the tumor microenvironment.European Journal of Medicinal Chemistry Dec 2020Boronic acid (and ester) prodrugs targeting the overexpressed level of reactive oxygen species within tumor microenvironment represent a promising area for the discovery... (Review)
Review
Boronic acid (and ester) prodrugs targeting the overexpressed level of reactive oxygen species within tumor microenvironment represent a promising area for the discovery of new selective anticancer chemotherapy. This strategy that emerged only ten years ago is exponentially growing and could demonstrate its clinical usefulness in the near future. Herein, the previously described small-molecule and macromolecular anticancer prodrugs activated by carbon-boron oxidation are gathered. This review reports on the most interesting derivatives mentioned in the literature based on the in vitro and in vivo activity when available. Eventually, the pharmacological applicability of this strategy is discussed, in particular, the kinetic aspect of the prodrug oxidation and the selectivity of this reaction towards certain ROS from the tumor microenvironment are specified.
Topics: Animals; Antineoplastic Agents; Boron Compounds; Humans; Neoplasms; Oxidative Stress; Prodrugs; Reactive Oxygen Species; Tumor Microenvironment
PubMed: 32858470
DOI: 10.1016/j.ejmech.2020.112670 -
Antioxidants & Redox Signaling Nov 2020Sulfur has a critical role in protein structure/function and redox status/signaling in all living organisms. Although hydrogen sulfide (HS) and sulfane sulfur (SS) are... (Review)
Review
Sulfur has a critical role in protein structure/function and redox status/signaling in all living organisms. Although hydrogen sulfide (HS) and sulfane sulfur (SS) are now recognized as central players in physiology and pathophysiology, the full scope and depth of sulfur metabolome's impact on human health and healthy longevity has been vastly underestimated and is only starting to be grasped. Since many pathological conditions have been related to abnormally low levels of HS/SS in blood and/or tissues, and are amenable to treatment by HS supplementation, development of safe and efficacious HS donors deserves to be undertaken with a sense of urgency; these prodrugs also hold the promise of becoming widely used for disease prevention and as antiaging agents. Supramolecular tuning of the properties of well-known molecules comprising chains of sulfur atoms (diallyl trisulfide [DATS], S) was shown to lead to improved donors such as DATS-loaded polymeric nanoparticles and SG1002. Encouraging results in animal models have been obtained with SG1002 in heart failure, atherosclerosis, ischemic damage, and Duchenne muscular dystrophy; with TC-2153 in Alzheimer's disease, schizophrenia, age-related memory decline, fragile X syndrome, and cocaine addiction; and with DATS in brain, colon, gastric, and breast cancer. Mode-of-action studies on allyl polysulfides, benzyl polysulfides, ajoene, and 12 ring-substituted organic disulfides and thiosulfonates led several groups of researchers to conclude that the anticancer effect of these compounds is not mediated by HS and is only modulated by reactive oxygen species, and that their central model of action is selective protein S-thiolation. SG1002 is likely to emerge as the HS donor of choice for acquiring knowledge on this gasotransmitter's effects in animal models, on account of its unique ability to efficiently generate HS without byproducts and in a slow and sustained mode that is dose independent and enzyme independent. Efficient tuning of HS donation characteristics of DATS, dibenzyl trisulfide, and other hydrophobic HS prodrugs for both oral and parenteral administration will be achieved not only by conventional structural modification of a lead molecule but also through the new "supramolecular tuning" paradigm.
Topics: Animals; Chemical Phenomena; Clinical Trials as Topic; Dietary Supplements; Dose-Response Relationship, Drug; Drug Development; Drug Evaluation, Preclinical; Humans; Hydrogen Sulfide; Immunomodulation; Molecular Structure; Prodrugs; Reactive Oxygen Species; Stem Cells; Structure-Activity Relationship; Sulfides; Sulfur Compounds
PubMed: 32370538
DOI: 10.1089/ars.2020.8060 -
Acta Biomaterialia Aug 2023Prodrug assembled nanoparticles integrate the merits of both prodrug and nanoparticle, which significantly improve pharmacokinetic parameters, enhance tumorous...
Prodrug assembled nanoparticles integrate the merits of both prodrug and nanoparticle, which significantly improve pharmacokinetic parameters, enhance tumorous accumulation and decrease adverse effects, while they are challenged by disassembly upon dilution in blood, masking the superiority of nanoparticles (NPs). Herein, a reversibly "double locked" hydroxycamptothecin (HCPT) prodrug nanoparticle decorated with cyclic RGD peptide (cRGD) is developed for safe and efficient chemotherapy of orthotopic lung cancer in mice. HCPT prodrug is constructed from acetal (ace)-linked cRGD-PEG-ace-HCPT-ace-acrylate polymer, which is self-assembled into the nanoparticles with "the first lock" of HCPT. Then the nanoparticles undergo the in situ UV-crosslinking of the acrylate residues for constructing "the second lock" of HCPT. The obtained "double locked" nanoparticles (T-DLHN) with simple and well-defined construction are demonstrated to possess extremely high stability against 100-fold dilution and acid-triggered "unlock" including de-crosslinking and liberation of the pristine HCPT. In an orthotopic lung tumor of mouse model, T-DLHN reveals a prolonged circulation time of about 5.0 h, superb lung tumor-homing capacity with tumorous drug uptake of about 7.15%ID/g, resulting in significantly boosted anti-tumor activity and reduced adverse effects. Hence, these nanoparticles utilizing "double lock" and acid-triggered "unlock" strategies represent a unique and promising nanoplatform for safe and efficient drug delivery. STATEMENT OF SIGNIFICANCE: Prodrug assembled nanoparticles have the unique properties of the well-defined structure, systemic stability, improved pharmacokinetics, passive targeting and decreased adverse effects. However, prodrug assembled NPs would disassemble against extensive dilution in the blood circulation when intravenously injected into the body. Herein, we have designed a cRGD-directed reversibly "double-locked" HCPT prodrug nanoparticle (T-DLHN) for safe and efficient chemotherapy of orthotopic A549 human lung tumor xenografts. Upon intravenous injection, T-DLHN can overcome the shortcoming of disassembly against extensive dilution, prolong the circulation time due to the "double locked" configuration and then mediate targeted drug delivery into the tumors. After uptaken into the cells, T-DLHN undergoes concurrent de-crosslinking and liberation of HCPT under acidic condition for enhanced chemotherapeutic efficacy with negligible adverse effects.
Topics: Humans; Mice; Animals; Prodrugs; Cell Line, Tumor; Camptothecin; Drug Delivery Systems; Lung Neoplasms; Nanoparticles
PubMed: 37220820
DOI: 10.1016/j.actbio.2023.05.030 -
Molecular Pharmaceutics Sep 2023Tanshinone IIA (TS-IIA) and salvianic acid A (SAA) are the main pharmacological active constituents of Danshen, which exhibit potent effects on atherosclerosis. A...
Tanshinone IIA (TS-IIA) and salvianic acid A (SAA) are the main pharmacological active constituents of Danshen, which exhibit potent effects on atherosclerosis. A combination of TS-IIA and SAA might exert a synergistic antiatherosclerotic effect. However, the opposite solubility profiles of TS-IIA and SAA might lead to difficulty in achieving a synergistic combined effect of the two active components. Therefore, in this work, we fabricated a ROS-responsive prodrug micelle for the codelivery of TS-IIA and SAA (TS-IIA-PM) by self-assembling amphiphilic block copolymer PEG-SAA/PLA-APBA. The amphiphilic polymer was characterized by H NMR, FTIR, and alizarin red S competition tests. The ROS responsiveness of TS-IIA-PM was evidenced by time-course monitoring of particle size and morphology changes and drug release behavior in the presence of 1 mM HO. We found TS-IIA-PM was stable according to its critical micelle concentration and the unchanged particle sizes in 10% FBS for 7 days. The results of and tests revealed that TS-IIA-PM was safe and biocompatible. Furthermore, it was observed that TS-IIA and prodrug micelle could produce synergistic antiatherosclerotic effect based on the results of the antioxidant study, which was further confirmed by a series of pharmocodynamics studies, such as DiI-oxLDL uptake study, oil red O staining, cholesterol efflux study, inflammatory cytokine analysis, CD68 immunostaining, and lipid disposition staining studies. Collectively, TS-IIA-PM holds great potential for the safe and efficient codelivery of TS-IIA and SAA for synergistic antiatherosclerosis.
Topics: Prodrugs; Micelles; Reactive Oxygen Species; Hydrogen Peroxide; Polymers
PubMed: 37524050
DOI: 10.1021/acs.molpharmaceut.3c00127 -
Journal of Medicinal Chemistry Aug 2022A novel theranostic co-prodrug has been designed by combining a co-prodrug from CDDO-Me and SAHA with a biotin-coupled near-infrared (NIR) probe hemicyanine via...
A novel theranostic co-prodrug has been designed by combining a co-prodrug from CDDO-Me and SAHA with a biotin-coupled near-infrared (NIR) probe hemicyanine via redox-responsive linker thiolactate to enhance the tumor theranostic efficacy and reduce the toxic side effects using both active and passive targeting strategies. displayed reactive oxygen species (ROS)- and glutathione (GSH)-dependent release of NIR fluorescence and two parent drugs. Furthermore, the administration of caused selective illumination of the tumor tissues for >24 h, thereby guiding precise removal of a tumor from intraoperative mice. Importantly, exhibited highly efficient tumor inhibition, exerted selective combination therapy through prodrug mode, and minimized the adverse effects. Finally, induced mitochondrial depolarization, DNA damage, and cell apoptosis through ROS generation and downregulation of HDAC6 protein, as verified by H2AX, Bax, cleaved-PARP, and Mcl-1 proteins. Thus, we suggest that can provide a new platform for both precise diagnosis-guided tumor removal and selective combination therapy with high safety.
Topics: Animals; Cell Line, Tumor; Drug Therapy, Combination; Glutathione; Mice; Nanoparticles; Neoplasms; Oleanolic Acid; Oxidation-Reduction; Precision Medicine; Prodrugs; Reactive Oxygen Species; Theranostic Nanomedicine
PubMed: 35877176
DOI: 10.1021/acs.jmedchem.2c00130 -
ACS Applied Materials & Interfaces Jun 2022Nanoprodrugs with responsive release properties integrate the advantages of stimuli-responsive prodrugs and nanotechnology. They would provide ultimate opportunity in...
Nanoprodrugs with responsive release properties integrate the advantages of stimuli-responsive prodrugs and nanotechnology. They would provide ultimate opportunity in fighting atherosclerosis. In this study, we synthesized a redox-responsive nanoprodrug of simvastatin (TPTS) by conjugating α-tocopherol polyethylene glycol derivative to the pharmacophore of simvastatin with a thioketal linker. TPTS formed nanoparticles and released parent simvastatin in the presence of hydrogen peroxide. Moreover, by taking advantage of the self-assembly behavior of TPTS, we developed a fibronectin-targeted delivery system (TPTS/C/T) to codelivery simvastatin prodrug and ticagrelor. In vitro and in vivo experiments indicated that TPTS and TPTS/C/T had good stability, which could reduce off-target leakage of drugs. They greatly inhibited the M1-type polarization of macrophages; reduced intracellular reactive oxygen species level and inflammatory cytokine; and TNF-α, MCP-1, and IL-1β were secreted by macrophage cells, thus providing enhanced anti-inflammatory and antioxidant effects compared with free simvastatin. TPTS/C/T realized targeted drug release to plaques and synergistic therapeutic effects of simvastatin and ticagrelor on atherosclerosis treatment in an ApoE-/- mouse model, resulting in excellent atherosclerosis therapeutic efficacy and a promising biosafety profile. Therefore, this study provides a new method for manufacturing statin nanodrugs and a new design idea for related responsive drug release nanosystems for atherosclerosis.
Topics: Animals; Atherosclerosis; Drug Liberation; Fibronectins; Mice; Nanoparticles; Prodrugs; Reactive Oxygen Species; Simvastatin; Ticagrelor
PubMed: 35618653
DOI: 10.1021/acsami.2c02354 -
Mini Reviews in Medicinal Chemistry 2021Non-steroidal anti-inflammatory drugs (NSAIDs) are agents that are used for various properties such as analgesic activity, anti-inflammatory activity, antipyretic... (Review)
Review
Non-steroidal anti-inflammatory drugs (NSAIDs) are agents that are used for various properties such as analgesic activity, anti-inflammatory activity, antipyretic activity, etc. But this class of drugs is associated with different side effects such as dyspepsia, gastroduodenal ulcers, gastrointestinal (GI) bleeding and perforation. The prodrug approach is quite beneficial to curb these side effects. Prodrugs are the inactive compounds that, on metabolism get converted into an active metabolite exhibiting desired activities. Commonly used approaches for synthesizing prodrugs are amide, esters, and mutual prodrugs by suppressing the free carboxylic groups responsible for these side effects. In this review, different schemes reported for the synthesis of NSAIDs that are devoid of undesired side effects such as irritation to gastric mucosa, gastrotoxicity, and ulcerogenicity have been compiled. Docking studies and the structure-activity relationship of some compounds are also discussed. The paper shall help the researchers to understand the methods to expedite the synthesis by carrying out substitutions of various groups of the parent compound and establish the mechanism of action of these derivatives of masking the unwanted side effects.
Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Gastric Mucosa; Humans; Peptic Ulcer; Prodrugs
PubMed: 33390114
DOI: 10.2174/1389557521666201231140554 -
Bioorganic & Medicinal Chemistry Sep 2021The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for...
The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two l-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3'-isobutyryl ester 5a, the 5'-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.
Topics: Adenosine; Animals; Antiviral Agents; Chlorocebus aethiops; Male; Mice, Inbred ICR; Microbial Sensitivity Tests; Prodrugs; SARS-CoV-2; Vero Cells; Mice
PubMed: 34450570
DOI: 10.1016/j.bmc.2021.116364 -
Acta Biomaterialia Oct 2023Immunotherapy is an emerging antitumor modality with high specificity and persistence, but its application for resected tumor treatment is impeded by the low...
Immunotherapy is an emerging antitumor modality with high specificity and persistence, but its application for resected tumor treatment is impeded by the low availability of tumor-specific antigens and strong immunosuppression in the wound margin. Here a nanoengineered hydrogel is developed for eliciting robust cooperative ferroptosis-immunotherapeutic effect on resected tumors. Specifically, β-cyclodextrin (β-CD) is first grafted onto oxidized sodium alginate (OSA) through Schiff base ligation, which could trap cRGD-modified redox-responsive Withaferin prodrugs (WA-cRGD) to obtain the hydrogel building blocks (Gel@WA-cRGD). Under Ca-mediated crosslinking, Gel@WA-cRGD rapidly forms physiologically stable hydrogels, of which the porous network is used to deliver programmed cell death ligand 1 antibodies (aPD-L1). After injection into the post-surgical wound cavity, the β-CD-entrapped WA-cRGD is detached by the local acidity and specifically internalized by residual tumor cells to trigger ferroptosis, thus releasing abundant damage-associated molecular patterns (DAMPs) and tumor-derived antigens for activating the antigen-presenting cell-mediated cross-presentation and downstream cytotoxic T cell (CTL)-mediated antitumor responses. Furthermore, aPD-L1 could block PD-1/PD-L1 interaction and enhance the effector function of CTLs to overcome tumor cell-mediated immunosuppression. This cooperative hydrogel-based antitumor strategy for ferroptosis-immunotherapy may serve as a generally-applicable approach for postoperative tumor management. STATEMENT OF SIGNIFICANCE: To overcome the immunosuppressive microenvironment in resected solid tumors for enhanced patient survival, here we report a nanoengineered hydrogel incorporated supramolecular redox-activatable Withaferin prodrug and PD-L1 antibody, which could elicit robust cooperative ferroptosis-immunotherapeutic effect against residual tumor cells in the surgical bed to prevent tumor relapse, thus offering a generally-applicable approach for postoperative tumor management.
Topics: Humans; Prodrugs; B7-H1 Antigen; Ferroptosis; Hydrogels; Neoplasm, Residual; Neoplasm Recurrence, Local; Immunotherapy; Antigens, Neoplasm; Tumor Microenvironment; Cell Line, Tumor
PubMed: 37544392
DOI: 10.1016/j.actbio.2023.08.002 -
Advanced Materials (Deerfield Beach,... Jul 2023Tumor-draining lymph nodes (TDLNs) are the first sites where tumor components reach and dendritic cells (DCs) present tumor-associated antigens to T cells. DCs rely on...
Tumor-draining lymph nodes (TDLNs) are the first sites where tumor components reach and dendritic cells (DCs) present tumor-associated antigens to T cells. DCs rely on autophagy to process tumor antigens into epitope peptides to form epitope-MHC complexes. Selective delivery of autophagy-stimulating drugs to TDLNs may be a precise strategy to boost chemotherapy-induced antitumor immunity. Here, a multistage stimulating strategy is proposed to activate the antitumor immunity cascade by inducing immunogenic death of tumor cells and elevating antigen presentation of DCs in TDLNs. A tumor-microenvironment-responsive "albumin-hitchhiking" micelle is established by self-assembling tumor-targeting oxaliplatin prodrug and lipophilized trehalose prodrug. This demonstrates that lipophilic modification of trehalose with a DSPE tail and the precise exposure in the tumor site enhances its binding to endogenous albumin and realizes TDLNs-selective reflux, where it upregulates antigen processing and presentation of DCs. This study introduces an approach for targeted delivery to TDLNs and provides insights into mechanisms of autophagy in tumor-specific immunity.
Topics: Humans; Dendritic Cells; Prodrugs; Trehalose; Neoplasms; Albumins; Autophagy; Epitopes; Lymph Nodes; Tumor Microenvironment
PubMed: 37114725
DOI: 10.1002/adma.202211055