-
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 -
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 -
Journal of Controlled Release :... Oct 2017Unsaturated fatty acids (UFAs), with the distinct advantages of good biocompatibility and innate tumor-targeting effect, have been widely investigated for the rational... (Review)
Review
Unsaturated fatty acids (UFAs), with the distinct advantages of good biocompatibility and innate tumor-targeting effect, have been widely investigated for the rational design of chemotherapy agent-unsaturated fatty acid (CA-UFA) prodrugs in cancer therapy. Among them, several CA-UFA prodrugs have successfully entered clinical trials and are promising prospects for potential clinical applications. In addition, CA-UFA prodrug-based nanoparticulate drug delivery systems (nano-DDS), which integrate the advantages of CA-UFA prodrugs and nano-DDS, have been emerging as versatile nano-carriers for the efficient delivery of chemotherapeutics. In this paper, we review the advanced drug delivery strategies based on UFA conjugates and focus on the recent advances in CA-UFA prodrugs and the emerging CA-UFA prodrug-based nano-DDS. First, we discuss the rational design of CA-UFA prodrugs in response to the multiple obstacles in chemotherapy, with particular emphasis on the latest progress in both preclinical studies and clinical trials. Moreover, the emerging CA-UFA prodrug-based nano-DDS are also addressed. Finally, the prospects and potential challenges of CA-UFA prodrug-based drug delivery strategies in chemotherapy are highlighted.
Topics: Animals; Antineoplastic Agents; Fatty Acids, Unsaturated; Humans; Nanoparticles; Neoplasms; Prodrugs
PubMed: 28844757
DOI: 10.1016/j.jconrel.2017.08.034 -
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 -
Future Medicinal Chemistry Aug 2019Prodrug entrapment into nanocarriers for tumor delivery is a strategy to achieve a valid therapy with high efficiency. The prodrug contains anticancer agents conjugating... (Review)
Review
Prodrug entrapment into nanocarriers for tumor delivery is a strategy to achieve a valid therapy with high efficiency. The prodrug contains anticancer agents conjugating with functional moieties or ligands so that the active component is released after metabolism in the body or tumor. The advantages of nanosystems for loading prodrugs include high loading, increased prodrug stability, improved bioavailability and enhanced targeting to tumor cells. In the present article, we introduce the prodrug delivery approaches according to nanomedicine and the recent advances in prodrug-loaded nanocarriers. First, we discuss the conceptional design of combined prodrugs and nanocarriers in response to the obstruction in anticancer therapy. Then we describe the cases of prodrug-loaded nanoparticles for cancer treatment during the past 5 years.
Topics: Animals; Antineoplastic Agents; Drug Carriers; Drug Delivery Systems; Humans; Nanoconjugates; Nanomedicine; Nanoparticles; Nanotechnology; Neoplasms; Prodrugs; Treatment Outcome
PubMed: 31538520
DOI: 10.4155/fmc-2018-0388 -
Angewandte Chemie (International Ed. in... Dec 2023Enzyme-prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control...
Enzyme-prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control of both the enzyme and its substrate at the target site, preservation of enzyme activity, and in situ substrate depletion due to low prodrug delivery efficiency continue to be great challenges. Here, we propose a novel core-shell reactor partitioning enzyme and prodrug by ZIF-8, which integrates an enzyme with its substrate and increases the drug loading capacity (DLC) using a prodrug as the building ligand to form a Zn-prodrug shell. Cytochrome P450 (CYP450) is immobilized in ZIF-8, and the antitumor drug dacarbazine (DTIC) is coordinated and deposited in its outer layer with a high DLC of 43.6±0.8 %. With this configuration, a much higher prodrug conversion efficiency of CYP450 (36.5±1.5 %) and lower IC value (26.3±2.6 μg/mL) are measured for B16-F10 cells with a higher NADPH concentration than those of L02 cells and HUVECs. With the tumor targeting ability of hyaluronic acid, this core-shell enzyme reactor shows a high tumor suppression rate of 96.6±1.9 % and provides a simple and versatile strategy for enabling in vivo biocatalysis to be more efficient, selective, and safer.
Topics: Humans; Prodrugs; NADP; Antineoplastic Agents; Dacarbazine; Cytochrome P-450 Enzyme System; Neoplasms
PubMed: 37881154
DOI: 10.1002/anie.202314025 -
Molecules (Basel, Switzerland) Oct 2017: Poor pharmacokinetic profiles and resistance are the main two drawbacks from which currently used antiviral agents suffer, thus make them excellent targets for... (Review)
Review
: Poor pharmacokinetic profiles and resistance are the main two drawbacks from which currently used antiviral agents suffer, thus make them excellent targets for research, especially in the presence of viral pandemics such as HIV and hepatitis C. : The strategies employed in the studies covered in this review were sorted by the type of drug synthesized into ester prodrugs, targeted delivery prodrugs, macromolecular prodrugs, other nucleoside conjugates, and non-nucleoside drugs. : Utilizing the ester prodrug approach a novel isopropyl ester prodrug was found to be potent HIV integrase inhibitor. Further, employing the targeted delivery prodrug zanamivir and valine ester prodrug was made and shown a sole delivery of zanamivir. Additionally, VivaGel, a dendrimer macromolecular prodrug, was found to be very efficient and is now undergoing clinical trials. : Of all the strategies employed (ester, targeted delivery, macromolecular, protides and nucleoside analogues, and non-nucleoside analogues prodrugs), the most promising are nucleoside analogues and macromolecular prodrugs. The macromolecular prodrug VivaGel works by two mechanisms: envelope mediated and receptor mediated disruption. Nucleotide analogues have witnessed productive era in the recent past few years. The era of non-interferon based treatment of hepatitis (through direct inhibitors of NS5A) has dawned.
Topics: Antiviral Agents; Cell Differentiation; Humans; Molecular Structure; Nucleosides; Nucleotides; Prodrugs
PubMed: 29035325
DOI: 10.3390/molecules22101736