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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 -
Journal of Medicinal Chemistry Nov 2021Intracellular phosphorylation of therapeutic nucleoside analogues into their active triphosphate metabolites is a prerequisite for their pharmacological activity....
Intracellular phosphorylation of therapeutic nucleoside analogues into their active triphosphate metabolites is a prerequisite for their pharmacological activity. However, the initial phosphorylation of these unnatural nucleosides into their monophosphate derivatives can be a rate-limiting step in their activation. To address this, we herein report the development of the aryloxy pivaloyloxymethyl prodrugs (POMtides) as a novel and effective nucleoside monophosphate prodrug technology and its successful application to the anticancer nucleoside analogue 5-fluoro-2'-deoxyuridine (FdUR).
Topics: Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Nucleosides; Phosphorylation; Prodrugs
PubMed: 34734726
DOI: 10.1021/acs.jmedchem.1c01490 -
Advanced Healthcare Materials Nov 2021Theranostic prodrugs that can precisely monitor drug activation with synergistic therapeutic effects are highly desirable for personalized medicine. In this study, a...
Theranostic prodrugs that can precisely monitor drug activation with synergistic therapeutic effects are highly desirable for personalized medicine. In this study, a theranostic heterodimeric prodrug, CyNH-SS-DOX, with synchronous and independent dual-channel fluorescence turn-on and dual-prodrug activation for synergistic cancer therapy is developed. A hemicyanine fluorescent drug, CyNH , with good therapeutic effects found in this work, is conjugated to doxorubicin (DOX) through a disulfide linker to form CyNH-SS-DOX. Before activation, both the fluorescence of DOX and CyNH are in the off state and the toxicity is low. In the presence of intracellular glutathione, both the fluorescence of DOX and CyNH at different channels are turned on. Meanwhile, DOX and CyNH are activated in a synergistic anticancer effect. It is believed that CyNH-SS-DOX is promising for monitoring prodrug activation in dual-fluorescence channels and for enhancing therapeutic efficacy with few side effects.
Topics: Drug Liberation; Fluorescence; Humans; Neoplasms; Precision Medicine; Prodrugs
PubMed: 34453773
DOI: 10.1002/adhm.202101144 -
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 -
Journal of Materials Chemistry. B Feb 2022Imaging-guided chemo-phototherapy based on a single nanoplatform has a great significance to improve the efficiency of cancer therapy and diagnosis. However, high drug...
Imaging-guided chemo-phototherapy based on a single nanoplatform has a great significance to improve the efficiency of cancer therapy and diagnosis. However, high drug content, no burst release and real-time tracking of nanodrugs are the three main challenges for this kind of multifunctional nanotheranostics. In this work, we developed an innovative theranostic nanoplatform based on a Pt(IV) prodrug and a near-infrared (NIR) photosensitizer. A Pt(IV) prodrug and a cyanine dye (HOCyOH, Cy) were copolymerized and incorporated into the main chain of a polyprodrug (PCPP), which self-assembled into nanoparticles (NPs) with ∼27.61% Cy loading and ∼9.37% Pt loading, respectively. PCPP NPs enabled reduction-triggered backbone cleavage of polyprodrugs and bioactive Pt(II) release; Cy could be activated under 808 nm laser irradiation to produce local hyperthermia and reactive oxygen species (ROS) for phototherapy. Moreover, PCPP NPs with extremely high Cy and Pt heavy metal contents in the backbone of the polyprodrug could directly track the nanodrugs themselves near-infrared fluorescence (NIRF) imaging, photothermal imaging, and computed tomography (CT) imaging and . As revealed by trimodal imaging, PCPP NPs were found to exhibit excellent tumor accumulation and antitumor efficiency after intravenous injection into H22-tumor-bearing mice. The dual-drug backboned polyprodrug nanoplatform exhibited great potential for bioimaging and combined chemo-phototherapy.
Topics: Animals; Coloring Agents; Drug Delivery Systems; Mice; Neoplasms; Phototherapy; Platinum; Prodrugs
PubMed: 35080231
DOI: 10.1039/d1tb02682h -
Nanomedicine : Nanotechnology, Biology,... Aug 2022Glioblastoma multiforme (GBM) is the intracranial malignancy with the highest rates of morbidity and mortality. Chemotherapy is often ineffective against GBM due to the...
Glioblastoma multiforme (GBM) is the intracranial malignancy with the highest rates of morbidity and mortality. Chemotherapy is often ineffective against GBM due to the presence of the blood-brain barrier (BBB); however, the application of nanotechnology is expected to overcome this limitation. Poly(lactic-co-glycolic acid) (PLGA) is a degradable and nontoxic functional polymer with good biocompatibility that is widely used in the pharmaceutical industry. Previous studies have shown that the ability of PLGA nanoparticles (NPs) to penetrate the BBB is largely determined by their size; however, determination of the optimal PLGA NP size requires further research. Here, we report a tandutinib-based prodrug (proTan), which responds to the GBM microenvironment, that was combined with NPs to overcome the BBB. AMD3100-PLGA NPs loaded with proTan inhibited tumor growth and effectively prolonged the survival of tumor-bearing mice.
Topics: Animals; Cell Line, Tumor; Drug Carriers; Drug Delivery Systems; Esterases; Glioblastoma; Lactic Acid; Mice; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prodrugs; Tumor Microenvironment
PubMed: 35811067
DOI: 10.1016/j.nano.2022.102581 -
International Journal of Biological... Sep 2023Hyaluronic acid (HA) represents a natural polysaccharide which has attracted significant attention owing to its improved tumor targeting capacity, enzyme degradation... (Review)
Review
Hyaluronic acid (HA) represents a natural polysaccharide which has attracted significant attention owing to its improved tumor targeting capacity, enzyme degradation capacity, and excellent biocompatibility. Its receptors, such as CD44, are overexpressed in diverse cancer cells and are closely related with tumor progress and metastasis. Accordingly, numerous researchers have designed various kinds of HA-based drug delivery platforms for CD44-mediated tumor targeting. Specifically, the HA-based nanoprodrugs possess distinct advantages such as good bioavailability, long circulation time, and controlled drug release and retention ability and have been extensively studied during the past years. In this review, the potential strategies and applications of HA-modified nanoprodrugs for drug molecule delivery in anti-tumor therapy are summarized.
Topics: Humans; Prodrugs; Hyaluronic Acid; Nanomedicine; Drug Delivery Systems; Neoplasms; Hyaluronan Receptors; Cell Line, Tumor; Nanoparticles
PubMed: 37506794
DOI: 10.1016/j.ijbiomac.2023.125993 -
Wiley Interdisciplinary Reviews.... Jan 2020Block copolymer prodrugs (BCPs) have emerged as one of the most promising anticancer drug delivery strategies, which can self-assemble into nanoparticles with optimal... (Review)
Review
Block copolymer prodrugs (BCPs) have emerged as one of the most promising anticancer drug delivery strategies, which can self-assemble into nanoparticles with optimal physicochemical properties including sizes, morphologies, surface properties, and integration of multifunction for improved in vivo applications. Moreover, the utility of stimuli-responsive linkages to conjugate drugs onto the polymer backbones can achieve efficient and targeting drug release. Several BCP micellar delivery systems have been pushed ahead into the clinical trials, which showed great promising potentials for cancer therapy. In recent years, various novel and more efficient BCP systems have been developed for better in vivo performance. In this focus article, we focus on the recent advances of BCPs including the synthesis, self-assembly, and applications for cancer therapy. The synthetic methods are first introduced, and the self-assembly of BCPs for in vivo anticancer applications is discussed along the line of varying endogenous stimuli-responsive linkages including amide or ester bonds, pH, reduction, and oxidation-responsive linkages. Finally, conclusions along with the brief future perspectives are presented. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Humans; Hydrogen-Ion Concentration; Nanomedicine; Neoplasms; Polymers; Prodrugs
PubMed: 31452353
DOI: 10.1002/wnan.1585 -
Current Topics in Medicinal Chemistry 2021Uncaging chemistry catalyzed by transition metals is developed from deprotection reactions and metal-organic catalytic reactions. Also, it has the characteristics of... (Review)
Review
Uncaging chemistry catalyzed by transition metals is developed from deprotection reactions and metal-organic catalytic reactions. Also, it has the characteristics of high efficiency, simplicity and rapidity in the living biological system. In the past decade, metal encapsulation systems (such as nanoparticles) and metal complexes have been developed to reveal the reactivity of transition metals (including palladium, ruthenium, and gold) in biological systems. Metal nanostructures provide huge possibilities for targeted drug delivery, detection, diagnosis and imaging. So far, palladium, ruthenium and gold nano-architectures have dominated the field, but there are some problems that hinder their wide application in clinical practice. In this review, based on palladium, ruthenium, gold and their complexes, the application of prodrug design through uncaging reaction has been widely discussed.
Topics: Animals; Drug Design; Gold; Humans; Palladium; Prodrugs; Ruthenium
PubMed: 34170808
DOI: 10.2174/1568026621666210624113313 -
Medicinal Research Reviews May 2024The burgeoning prodrug strategy offers a promising avenue toward improving the efficacy and specificity of cytotoxic drugs. Elevated intracellular levels of glutathione... (Review)
Review
The burgeoning prodrug strategy offers a promising avenue toward improving the efficacy and specificity of cytotoxic drugs. Elevated intracellular levels of glutathione (GSH) have been regarded as a hallmark of tumor cells and characteristic feature of the tumor microenvironment. Considering the pivotal involvement of elevated GSH in the tumorigenic process, a diverse repertoire of GSH-triggered prodrugs has been developed for cancer therapy, facilitating the attenuation of deleterious side effects associated with conventional chemotherapeutic agents and/or the attainment of more efficacious therapeutic outcomes. These prodrug formulations encompass a spectrum of architectures, spanning from small molecules to polymer-based and organic-inorganic nanomaterial constructs. Although the GSH-triggered prodrugs have been gaining increasing interests, a comprehensive review of the advancements made in the field is still lacking. To fill the existing lacuna, this review undertakes a retrospective analysis of noteworthy research endeavors, based on a categorization of these molecules by their diverse recognition units (i.e., disulfides, diselenides, Michael acceptors, and sulfonamides/sulfonates). This review also focuses on explaining the distinct benefits of employing various chemical architecture strategies in the design of these prodrug agents. Furthermore, we highlight the potential for synergistic functionality by incorporating multiple-targeting conjugates, theranostic entities, and combinational treatment modalities, all of which rely on the GSH-triggering. Overall, an extensive overview of the emerging field is presented in this review, highlighting the obstacles and opportunities that lie ahead. Our overarching goal is to furnish methodological guidance for the development of more efficacious GSH-triggered prodrugs in the future. By assessing the pros and cons of current GSH-triggered prodrugs, we expect that this review will be a handful reference for prodrug design, and would provide a guidance for improving the properties of prodrugs and discovering novel trigger scaffolds for constructing GSH-triggered prodrugs.
Topics: Humans; Prodrugs; Retrospective Studies; Antineoplastic Agents; Glutathione; Cell Line, Tumor
PubMed: 38140851
DOI: 10.1002/med.22007