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Advanced Materials (Deerfield Beach,... Nov 2023Ultrasound, featuring deep tissue penetration and noninvasiveness, offers a new opportunity to activate functional materials in a tumor-selective manner. However, very...
Ultrasound, featuring deep tissue penetration and noninvasiveness, offers a new opportunity to activate functional materials in a tumor-selective manner. However, very few direct ultrasound-responsive redox systems are applicable under therapeutic ultrasound (1 MHz). Herein, the investigations on nanoprodrug of DHE@PEG-SS-DSPE are reported, which exhibit glutathione-activated release of dihydroethidium (DHE) in tumor cells. DHE is stable with good biosafety and is transformed into cytotoxic ethidium to induce DNA damage under medical ultrasound irradiation, accompanied by the generation of reactive oxygen species. Further, DHE@PEG-SS-DSPE could effectively induce ferroptosis through glutathione depletion, lipid peroxide accumulation, and downregulation of glutathione peroxidase 4. In vivo studies confirmed that DHE@PEG-SS-DSPE nanoparticles effectively inhibit both the growth of solid tumors and the expression of metastasis-related proteins in mice, thus effectively inhibiting lung metastasis. This DHE-based prodrug nanosystem could lay a foundation for the design of ultrasound-driven therapeutic agents.
Topics: Mice; Animals; Prodrugs; Neoplasms; Antineoplastic Agents; Reactive Oxygen Species; Lung Neoplasms; Nanoparticles; Glutathione; Cell Line, Tumor
PubMed: 37792315
DOI: 10.1002/adma.202308205 -
Biosensors May 2022In this study, a brush-like polymer with aggregation-induced emission (AIE) features was synthesized for drug delivery and intracellular drug tracking. The polymer...
In this study, a brush-like polymer with aggregation-induced emission (AIE) features was synthesized for drug delivery and intracellular drug tracking. The polymer consisting of tetraphenylethene (TPE) chain-end as well as oligo-poly (ethylene glycol) (PEG) and hydrazine functionalities was successfully synthesized through copper (0)-mediated reversible-deactivation radical polymerization (Cu-mediated RDRP). Anticancer drug doxorubicin (DOX) was conjugated to the polymer and formed a prodrug named TPE-PEGA-Hyd-DOX, which contains 11% DOX. The hydrazone between DOX and polymer backbone is a pH-sensitive linkage that can control the release of DOX in slightly acidic conditions, which can precisely control the DOX release rate. The drug release of 10% after 96 h in normal cell environments compared with about 40% after 24 h in cancer cell environments confirmed the influence of the hydrazone bond. The ratiometric design of fluorescent intensities with peaks at 410 nm (emission due to AIE feature of TPE) and 600 nm (emission due to ACQ feature of DOX) provides an excellent opportunity for this product as a precise intracellular drug tracker. Cancer cells confocal microscopy showed negligible DOX solution uptake, but an intense green emission originated from prodrug uptake. Moreover, a severe red emission in the DOX channel confirmed a promising level of drug release from the prodrug in the cytoplasm. The merged images of cancer cells confirmed the high performance of the TPE-PEGA-Hyd-DOX compound in the viewpoints of cellular uptake and drug release. This polymer prodrug successfully demonstrates low cytotoxicity in healthy cells and high performance in killing cancer cells.
Topics: Doxorubicin; Hydrazones; Hydrogen-Ion Concentration; Polyethylene Glycols; Polymers; Prodrugs
PubMed: 35735521
DOI: 10.3390/bios12060373 -
Angewandte Chemie (International Ed. in... Mar 2022Metastatic cancer is difficult to cure because of its uncontrollable nature and side effects during treatment. We constructed a reactive oxygen species (ROS)-activated...
Metastatic cancer is difficult to cure because of its uncontrollable nature and side effects during treatment. We constructed a reactive oxygen species (ROS)-activated smart theranostic prodrug system based on an ROS active site linked with both a targeting group and an anticancer drug for efficient regional chemotherapy of metastatic cancers. The optimized prodrug (Bio-(8)-MB-CPT) with biotin as the targeting group displayed high sensitivity towards ROS and selectively targeting ability towards cervical cancer cells, showing highly efficient drug release (up to 92 %) in vitro. Bio-(8)-MB-CPT thus exerted strong toxicity towards cervical cancer cells, but unlike the parent drug (camptothecin), showed no toxicity towards normal cells. Moreover, the prodrug displayed significantly enhanced antitumor efficacy in vivo and eradicated the tumor with no obvious side effects (inhibition of the tumor reached up to 99.9 %).
Topics: Antineoplastic Agents; Camptothecin; Cell Line, Tumor; Drug Liberation; Female; Humans; Nanoparticles; Prodrugs; Reactive Oxygen Species; Theranostic Nanomedicine; Uterine Cervical Neoplasms
PubMed: 35068033
DOI: 10.1002/anie.202116807 -
Journal of the American Chemical Society Dec 2023The synergy of living microbial and small-molecular therapeutics has been widely explored for treating a variety of diseases, while current combination strategies often...
The synergy of living microbial and small-molecular therapeutics has been widely explored for treating a variety of diseases, while current combination strategies often suffer from low bioavailability, heterogeneous spatiotemporal distribution, and premature drug release. Here, the use of a triggerable prodrug nanocoating is reported to enable the on-demand activation of microbial and small-molecular therapeutics for combination treatment. As a proof-of-concept study, a reactive oxygen species-responsive aromatic thioacetal linker is employed to prepare cationic chitosan-drug conjugates, which can form a nanocoating on the surface of living bacteria via electrostatic interaction. Following administration, the wrapped bacteria can be prevented from insults by the shielding effect of the nanocoating and be co-delivered with the conjugated drug in a spatiotemporally synchronous manner. Upon reaching the lesion site, the upgraded reactive oxygen species trigger cleavage of the thioacetal linker, resulting in the release of the conjugated drug and a linker-derived therapeutic cinnamaldehyde. Meanwhile, a charge reversal achieved by the generation of negatively charged thiolated chitosan induces the dissociation of the nanocoating, leading to synchronous release of the living bacteria. The adequate activation of the combined therapeutics at the lesion site exhibits superior synergistic treatment efficacy, as demonstrated by an assessment using a mouse model of colitis. This work presents an appealing approach to combine living microbial and small-molecular therapeutics for advanced therapy of diseases.
Topics: Prodrugs; Reactive Oxygen Species; Chitosan; Drug Delivery Systems; Combined Modality Therapy; Nanoparticles; Cell Line, Tumor
PubMed: 37988674
DOI: 10.1021/jacs.3c10015 -
Molecules (Basel, Switzerland) Feb 2008Cholesterylbutyrate (Chol-but) was chosen as a prodrug of butyric acid. Butyrate is not often used in vivo because its half-life is very short and therefore too large... (Review)
Review
Cholesterylbutyrate (Chol-but) was chosen as a prodrug of butyric acid. Butyrate is not often used in vivo because its half-life is very short and therefore too large amounts of the drug would be necessary for its efficacy. In the last few years butyric acid's anti-inflammatory properties and its inhibitory activity towards histone deacetylases have been widely studied, mainly in vitro. Solid Lipid Nanoparticles (SLNs), whose lipid matrix is Chol-but, were prepared to evaluate the delivery system of Chol-but as a prodrug and to test its efficacy in vitro and in vivo. Chol-but SLNs were prepared using the microemulsion method; their average diameter is on the order of 100-150 nm and their shape is spherical. The antineoplastic effects of Chol-but SLNs were assessed in vitro on different cancer cell lines and in vivo on a rat intracerebral glioma model. The anti-inflammatory activity was evaluated on adhesion of polymorphonuclear cells to vascular endothelial cells. In the review we will present data on Chol-but SLNs in vitro and in vivo experiments, discussing the possible utilisation of nanoparticles for the delivery of prodrugs for neoplastic and chronic inflammatory diseases.
Topics: Animals; Cell Death; Cholesterol Esters; Humans; Lipids; Nanoparticles; Prodrugs
PubMed: 18305415
DOI: 10.3390/molecules13020230 -
Nucleic Acids Research Jan 2022Drug discovery relies on the knowledge of not only drugs and targets, but also the comparative agents and targets. These include poor binders and non-binders for...
Drug discovery relies on the knowledge of not only drugs and targets, but also the comparative agents and targets. These include poor binders and non-binders for developing discovery tools, prodrugs for improved therapeutics, co-targets of therapeutic targets for multi-target strategies and off-target investigations, and the collective structure-activity and drug-likeness landscapes of enhanced drug feature. However, such valuable data are inadequately covered by the available databases. In this study, a major update of the Therapeutic Target Database, previously featured in NAR, was therefore introduced. This update includes (a) 34 861 poor binders and 12 683 non-binders of 1308 targets; (b) 534 prodrug-drug pairs for 121 targets; (c) 1127 co-targets of 672 targets regulated by 642 approved and 624 clinical trial drugs; (d) the collective structure-activity landscapes of 427 262 active agents of 1565 targets; (e) the profiles of drug-like properties of 33 598 agents of 1102 targets. Moreover, a variety of additional data and function are provided, which include the cross-links to the target structure in PDB and AlphaFold, 159 and 1658 newly emerged targets and drugs, and the advanced search function for multi-entry target sequences or drug structures. The database is accessible without login requirement at: https://idrblab.org/ttd/.
Topics: Databases, Factual; Drug Discovery; Humans; Molecular Targeted Therapy; Prodrugs; Structure-Activity Relationship
PubMed: 34718717
DOI: 10.1093/nar/gkab953 -
Molecules (Basel, Switzerland) Oct 2014The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug... (Comparative Study)
Comparative Study
The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.
Topics: Administration, Oral; Animals; Biological Transport; Drug Delivery Systems; Drug Design; Humans; Membrane Transport Proteins; Permeability; Prodrugs
PubMed: 25317578
DOI: 10.3390/molecules191016489 -
Nano Letters Feb 2023Albumin has emerged as a versatile drug carrier. To harness albumin as a carrier for doxorubicin (DOX), we synthesized three acid-labile DOX prodrugs using stearic acid...
Albumin has emerged as a versatile drug carrier. To harness albumin as a carrier for doxorubicin (DOX), we synthesized three acid-labile DOX prodrugs using stearic acid (SA), oleic acid (OA), and linoleic acid (LA) as the albumin-binding motif, respectively. Different from conventional albumin nanodrugs (such as Abraxane, with a drug loading of 10%), the DOX prodrugs assembled albumin nanoparticles (NPs) have an ultrahigh drug loading (>35%). Noteworthy, we demonstrated that the saturation of fatty acids exerted great influence on colloidal stability of prodrug NPs, thus affecting their pharmacokinetics, tumor accumulation and antitumor efficacy. Furthermore, the hydrazone bond-bridged DOX prodrugs could remain intact in the bloodstream but allow DOX to be released in the acidic tumor environment, resulting in improved antitumor efficacy and safety. Our work gives novel insights into the structure-to-efficacy relationship of albumin-bound fatty acid prodrugs and provides a simple strategy for advanced albumin-bound nanomedicines.
Topics: Humans; Prodrugs; Drug Delivery Systems; Fatty Acids; Doxorubicin; Neoplasms; Structure-Activity Relationship; Nanoparticles; Hydrogen-Ion Concentration; Albumins; Cell Line, Tumor
PubMed: 36719151
DOI: 10.1021/acs.nanolett.2c04976 -
Lymph-Directed Self-Immolative Nitric Oxide Prodrug for Inhibition of Intractable Metastatic Cancer.Advanced Science (Weinheim,... Mar 2022There has been a significant clinical demand for lymph-directed anti-metastatic therapy as tumor-draining lymph nodes play pivotal roles in cancer metastasis which...
There has been a significant clinical demand for lymph-directed anti-metastatic therapy as tumor-draining lymph nodes play pivotal roles in cancer metastasis which accounts for more than 90% of tumor-related deaths. Despite the high potential of nitric oxide (NO) in anti-cancer therapy owing to its biocompatibility and tumor cell-specific cytotoxicity, the poor stability and lack of target specificity of present NO donors and delivery systems have limited its clinical applications. Herein, a redox-triggered self-immolative NO prodrug that can be readily conjugated to various materials containing free thiol groups such as albumin, is reported. The prodrug and its conjugates demonstrate smart release of NO donor via intramolecular cyclization under reductive conditions, followed by spontaneously generating NO in physiological conditions. The albumin-prodrug conjugate inhibits tumor metastasis by inducing cytotoxicity preferentially on tumor cells after efficiently draining into lymph nodes. This novel prodrug can contribute to the development of on-demand NO delivery systems for anti-metastatic therapy and other treatments.
Topics: Drug Delivery Systems; Humans; Neoplasms; Nitric Oxide; Oxidation-Reduction; Prodrugs
PubMed: 35317221
DOI: 10.1002/advs.202101935 -
Chemical Communications (Cambridge,... Aug 2018The term electroceutical has been used to describe implanted devices that deliver electrical stimuli to modify biological function. Herein, we describe a new concept in...
The term electroceutical has been used to describe implanted devices that deliver electrical stimuli to modify biological function. Herein, we describe a new concept in electroceuticals, demonstrating for the first time the electrochemical activation of metal-based prodrugs. This is illustrated by the controlled activation of Pt(iv) prodrugs into their active Pt(ii) forms within a cellular context allowing selectivity and control of where, when and how much active drug is generated.
Topics: Antineoplastic Agents; Apoptosis; Coordination Complexes; Electrochemical Techniques; Electrodes; HCT116 Cells; Humans; Organoplatinum Compounds; Oxidation-Reduction; Prodrugs
PubMed: 30066701
DOI: 10.1039/c8cc04151b