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Advanced Materials (Deerfield Beach,... Feb 2024Advanced chemotherapeutic strategies including prodrug and nanocatalytic medicine have significantly advanced tumor-selective theranostics, but delicate prodrug...
Advanced chemotherapeutic strategies including prodrug and nanocatalytic medicine have significantly advanced tumor-selective theranostics, but delicate prodrug screening, tedious synthesis, low degradability/biocompatibility of inorganic components, and unsatisfied reaction activity complicate treatment efficacies. Here, the intrinsic anticancer bioactivity of liquid metal nanodroplets (LMNDs) is explored through galvanic replacement. By utilizing a mechano-degradable ligand, the resultant size of the aqueous LMND is unexpectedly controlled as small as ≈20 nm (LMND20). It is demonstrated that LMND20 presents excellent tumor penetration and biocompatibility and activates tumor-selective carrier-to-drug conversion, synchronously depleting Cu ions and producing Ga ions through galvanic replacement. Together with abundant generation of reactive oxygen species, multiple anticancer pathways lead to selective apoptosis and anti-angiogenesis of breast cancer cells. Compared to the preclinical/clinical anticancer drugs of tetrathiomolybdate and Ga(NO ) , LMND20 administration significantly improves the therapeutic efficacy and survival in a BCap-37 xenograft mouse model, yet without obvious side effects.
Topics: Humans; Animals; Mice; Nanomedicine; Neoplasms; Antineoplastic Agents; Prodrugs; Metals; Ions; Cell Line, Tumor
PubMed: 37948543
DOI: 10.1002/adma.202307817 -
ACS Chemical Biology May 2021In light of the continued threat of antimicrobial-resistant bacteria, new strategies to expand the repertoire of antimicrobial compounds are necessary. Prodrugs are an...
In light of the continued threat of antimicrobial-resistant bacteria, new strategies to expand the repertoire of antimicrobial compounds are necessary. Prodrugs are an underexploited strategy in this effort. Here, we report on the enhanced antimicrobial activity of a prodrug toward bacteria having an enzyme capable of its activation. A screen led us to the sulfurol ester of the antibiotic -3-(4-chlorobenzoyl)acrylic acid. An endogenous esterase makes sensitive to this prodrug. Candidate esterases were identified, and their heterologous production made sensitive to the ester prodrug. Taken together, these data suggest a new approach to the development of antimicrobial compounds that takes advantage of endogenous enzymatic activities to target specific bacteria.
Topics: Acrylates; Anti-Infective Agents; Bacillus subtilis; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Escherichia coli; Esterases; Esters; Mycobacterium smegmatis; Prodrugs; Structure-Activity Relationship
PubMed: 33877811
DOI: 10.1021/acschembio.0c00894 -
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 -
European Journal of Medicinal Chemistry Oct 2023The chemotherapeutic drug of doxorubicin (DOX) has witnessed widespread applications for treating various cancers. DOX-treated dying cells bear cellular modifications... (Review)
Review
The chemotherapeutic drug of doxorubicin (DOX) has witnessed widespread applications for treating various cancers. DOX-treated dying cells bear cellular modifications which allow enhanced presentation of tumor antigen and neighboring dendritic cell activation. Furthermore, DOX also facilitate the immune-mediated clearance of tumor cells. However, disadvantages such as severe off-target toxicity, and prominent hydrophobicity have resulted in unsatisfactory clinical therapeutic outcomes. The effective delivery of DOX drug molecules is still challenging despite the rapid advances in nanotechnology and biomaterials. Huge progress has been witnessed in DOX nanoprodrugs owing to their brilliant benefits such as tumor stimuli-responsive drug release capacity, high drug loading efficiency and so on. This review summarized recent progresses of DOX prodrug-based nanomedicines to provide deep insights into future development and inspire researchers to explore DOX nanoprodrugs with real clinical applications.
Topics: Humans; Prodrugs; Drug Delivery Systems; Nanomedicine; Doxorubicin; Neoplasms; Nanoparticles; Cell Line, Tumor
PubMed: 37441851
DOI: 10.1016/j.ejmech.2023.115612 -
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 -
Cancer Letters Oct 2022Identifying a universal biomarker for cancer treatment remains a major challenge in cancer therapy. Extracellular exposure of phosphatidylserine (PS) is tightly... (Review)
Review
Identifying a universal biomarker for cancer treatment remains a major challenge in cancer therapy. Extracellular exposure of phosphatidylserine (PS) is tightly regulated and is an "eat me" signal for phagocytosis in healthy cells. Although cancer cells and vasculature express high levels of externalized PS, they do not undergo apoptosis, making them a promising biomarker for cancer treatment. Annexin A5 (ANXA5) is the native binding partner of PS and can actively target and deliver chemotherapies to the tumor microenvironment (TME) via PS expression. ANXA5 acts as a bridge between the innate and adaptive immune systems and contributes to an immunostimulatory profile in the TME. ANXA5-enzyme prodrug therapies allow for systemic delivery of prodrugs and targeted killing at the tumor site. ANXA5-carbon nanotube conjugates have been used to physically ablate tumors via photothermal therapy. This review aims to explore the expression of PS in cancer cells and how ANXA5 has been used as a chemotherapeutic and targeting agent for cancer.
Topics: Annexin A5; Apoptosis; Humans; Neoplasms; Phagocytosis; Phosphatidylserines; Prodrugs; Tumor Microenvironment
PubMed: 35940392
DOI: 10.1016/j.canlet.2022.215857 -
Theranostics 2022Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly...
Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly heterogeneous in different tumor types and patients, we propose ultrasound-directed enzyme-prodrug therapy (UDEPT) as a means to increase enzyme access and availability for prodrug activation locally. We synthesized β-glucuronidase-sensitive self-immolative doxorubicin prodrugs with different spacer lengths between the active drug moiety and the capping group. We evaluated drug conversion, uptake and cytotoxicity in the presence and absence of the activating enzyme β-glucuronidase. To trigger the cell release of β-glucuronidase, we used high-intensity focused ultrasound to aid in the conversion of the prodrugs into their active counterparts. More efficient enzymatic activation was observed for self-immolative prodrugs with more than one aromatic unit in the spacer. In the absence of β-glucuronidase, the prodrugs showed significantly reduced cellular uptake and cytotoxicity compared to the parent drug. High-intensity focused ultrasound-induced mechanical destruction of cancer cells resulted in release of intact β-glucuronidase, which activated the prodrugs, restored their cytotoxicity and induced immunogenic cell death. These findings shed new light on prodrug design and activation, and they contribute to novel UDEPT-based mechanochemical combination therapies for the treatment of cancer.
Topics: Doxorubicin; Glucuronidase; Humans; Neoplasms; Prodrugs
PubMed: 35832083
DOI: 10.7150/thno.69168 -
Chemistry & Biodiversity Nov 2023This article emphasizes the importance of prodrugs and their diverse spectrum of effects in the field of developing novel drugs for a variety of biological applications.... (Review)
Review
This article emphasizes the importance of prodrugs and their diverse spectrum of effects in the field of developing novel drugs for a variety of biological applications. Prodrugs are chemicals that are supplied inactively, but then go through enzymatic and chemical transformation in vivo to release the active parent medication that can have the desired pharmacological effect. By adding an inactive chemical moiety, prodrugs are improved in a number of ways that contribute to their potency and durability. For the purpose of illustrating the usefulness of the prodrug approach, this review covers examples of prodrugs that have been made available or are now undergoing human trials. Additionally, it included lists of the most common functional groups, carrier linkers, and reactive chemicals that can be used to create prodrugs. The current study also provides a brief introduction, several chemical methods and modifications for creating prodrugs and mutual prodrugs, as well as an explanation of recent advancements and difficulties in the field of prodrug design. The primary chemical carriers employed in the creation of prodrugs, such as esters, amides, imides, NH-acidic carriers, amines, alcohols, carbonyl, carboxylic, and azo-linkages, are also discussed. This review also discusses glycosidic and triglyceride mutually activated prodrugs, which aim to deliver the drugs after bioconversion at the intended site of action. The article also discusses the extensive chemistry and wide variety of applications of recently approved prodrugs, such as antibacterial, anti-inflammatory, cardiovascular, antiplatelet, antihypertensive, atherosclerotic, antiviral, etc. In order to illustrate the prodrug and mutual drug concept's various applications and highlight its many triumphs in overcoming the formulation and delivery of problematic pharmaceuticals, this work represents a thorough guide that includes the synthetic moiety for the reader.
Topics: Humans; Prodrugs; Chemistry, Pharmaceutical; Drug Design; Amides; Amines
PubMed: 37833241
DOI: 10.1002/cbdv.202301169 -
European Journal of Medicinal Chemistry Jan 2022The synthesis and in vitro anti-HIV activity of a novel series of pronucleotides are reported. These prodrugs were characterized by a phosphorodithiolate structure,...
The synthesis and in vitro anti-HIV activity of a novel series of pronucleotides are reported. These prodrugs were characterized by a phosphorodithiolate structure, incorporating two O-pivaloyl-2-oxyethyl substituents as biolabile phosphate protections. The compounds were obtained following an original one-pot three-step procedure, involving the formation of a phosphorodithioite intermediate which is in situ oxidized. In vitro, comparative anti-HIV evaluations demonstrate that such original prodrugs are able to allow the efficient intracellular release of the corresponding 5'-mononucleotide. The pronucleotide of 2',3'-dideoxyadenosine (ddA) 3 exhibited a very potent antiretroviral effect with 50% effective concentration (EC) values in nanomolar concentration range in various cell lines. In primary monocytes/macrophages, this derivative was 500 times more potent in inhibiting HIV replication (EC 0.23 pM) than ddA and the selectivity index of the prodrug is fifty times higher than the one of the parent nucleoside.
Topics: Anti-HIV Agents; Cells, Cultured; Dose-Response Relationship, Drug; HIV-1; Humans; Microbial Sensitivity Tests; Molecular Structure; Nucleosides; Prodrugs; Structure-Activity Relationship; Sulfhydryl Compounds; Virus Replication
PubMed: 34695774
DOI: 10.1016/j.ejmech.2021.113914 -
Molecules (Basel, Switzerland) Nov 2020Prodrugs, which remain inert until they are activated under appropriate conditions at the target site, have emerged as an attractive alternative to drugs that lack... (Review)
Review
Prodrugs, which remain inert until they are activated under appropriate conditions at the target site, have emerged as an attractive alternative to drugs that lack selectivity and show off-target effects. Prodrugs have traditionally been activated by enzymes, pH or other trigger factors associated with the disease. In recent years, bioorthogonal chemistry has allowed the creation of prodrugs that can be chemically activated with spatio-temporal precision. In particular, tetrazine-responsive bioorthogonal reactions can rapidly activate prodrugs with excellent biocompatibility. This review summarized the recent development of tetrazine bioorthogonal cleavage reaction and great promise for prodrug systems.
Topics: Activation, Metabolic; Animals; Cycloaddition Reaction; Drug Delivery Systems; Heterocyclic Compounds; Humans; Prodrugs
PubMed: 33266075
DOI: 10.3390/molecules25235640