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Chemical Society Reviews Nov 2022In this review glycosidase activated prodrugs that target cancer cells are discussed. Glycosylated prodrugs undergo enzymatic bioconversion, cleaving the prodrug to... (Review)
Review
In this review glycosidase activated prodrugs that target cancer cells are discussed. Glycosylated prodrugs undergo enzymatic bioconversion, cleaving the prodrug to release the anticancer drug at the desired site of action, hence minimising the toxic side effects associated with many current anticancer drugs. In addition, the presence of the carbohydrate moiety increases the aqueous solubility of the drugs, allowing for a more effective treatment. In the past decade, significant advancements have been made in this field that have led to the development of many novel carbohydrate-based prodrugs - ranging from simple glycoconjugates to complex self-assemblies and materials, which are discussed in detail herein.
Topics: Humans; Prodrugs; Glycoside Hydrolases; Neoplasms; Solubility; Antineoplastic Agents; Carbohydrates
PubMed: 36349720
DOI: 10.1039/d2cs00379a -
British Journal of Cancer May 2016Tumour hypoxia has been pursued as a cancer drug target for over 30 years, most notably using bioreductive (hypoxia-activated) prodrugs that target antineoplastic... (Review)
Review
Tumour hypoxia has been pursued as a cancer drug target for over 30 years, most notably using bioreductive (hypoxia-activated) prodrugs that target antineoplastic agents to low-oxygen tumour compartments. Despite compelling evidence linking hypoxia with treatment resistance and adverse prognosis, a number of such prodrugs have recently failed to demonstrate efficacy in pivotal clinical trials; an outcome that demands reflection on the discovery and development of these compounds. In this review, we discuss a clear disconnect between the pathobiology of tumour hypoxia, the pharmacology of hypoxia-activated prodrugs and the manner in which they have been taken into clinical development. Hypoxia-activated prodrugs have been evaluated in the manner of broad-spectrum cytotoxic agents, yet a growing body of evidence suggests that their activity is likely to be dependent on the coincidence of tumour hypoxia, expression of specific prodrug-activating reductases and intrinsic sensitivity of malignant clones to the cytotoxic effector. Hypoxia itself is highly variable between and within individual tumours and is not treatment-limiting in all cancer subtypes. Defining predictive biomarkers for hypoxia-activated prodrugs and overcoming the technical challenges of assaying them in clinical settings will be essential to deploying these agents in the era of personalised cancer medicine.
Topics: Antineoplastic Agents; Cell Hypoxia; Humans; Neoplasms; Oxidoreductases; Precision Medicine; Prodrugs
PubMed: 27070712
DOI: 10.1038/bjc.2016.79 -
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 -
Accounts of Chemical Research Jun 2018Carbon monoxide is widely acknowledged as an important gasotransmitter in the mammalian system with importance on par with that of nitric oxide. It has also been firmly...
Carbon monoxide is widely acknowledged as an important gasotransmitter in the mammalian system with importance on par with that of nitric oxide. It has also been firmly established as a potential therapeutic agent with a wide range of indications including organ transplantation, cancer, bacterial infection, and inflammation-related conditions such as colitis and sepsis. One major issue in developing CO based therapeutics is its delivery in a pharmaceutically acceptable form. Currently, there are generally five forms of deliveries: inhaled CO, photosensitive CO-releasing molecules, encapsulated CO, CO dissolved in drinks, and molecules that would release CO under physiological conditions without the need for light. For over a decade, the last category only included metal-based CO releasing molecules. What had been missing were organic CO prodrugs, which release CO under physiological conditions with tunable rates and in response to various exogenous and endogenous triggers such as water, chemical reagents, esterase, ROS, and changes in pH. This Account describes our work in this area as well as the demonstration for these organic prodrugs to recapitulate CO's pharmacological effects both in vitro and in vivo. Generally, two categories of CO prodrugs have been developed in our lab. Both can be considered as precursors of norbornadien-7-ones, which readily undergo cheletropic reaction under very mild conditions to extrude CO. The first category of CO prodrugs capitalizes on the inter- and intramolecular inverse electron demand Diels-Alder (DA) reaction to trigger CO release under physiological conditions. As for the bimolecular CO prodrugs, we proposed a new concept of "enrichment triggered CO release" by conjugating both components with a mitochondria-targeting moiety to achieve targeted CO delivery with improved biological outcomes in vitro and in vivo. As for the unimolecular CO prodrugs, the release half-lives can be readily tuned from minutes to days by varying the substituents on the dienone ring, the tethering linker, and the alkyne. Some significant structure-release rates relationships (SRRs) have been unveiled. An esterase-activated CO prodrug and a cascade prodrug system for co-delivery of CO and another payload have also been devised using such an intramolecular click and release strategy. The second category of CO prodrugs leverage on an elimination reaction to generate norbornadien-7-ones for CO release from norborn-2-en-7-ones. In the case of pH-sensitive ones, the CO release is triggered by β-elimination, and the release rate can be quantitatively predicted using the Hammett constant of the substituents on the leaving group. The ROS-activated ones take advantage of ROS-induced selenoxide elimination to achieve targeted CO delivery to disease sites with elevated ROS level. We strongly believe that these CO prodrugs could serve as powerful tools for CO-associated biological studies and are promising candidates for ultimate clinical applications.
Topics: Animals; Carbon Monoxide; Drug Liberation; Gasotransmitters; HeLa Cells; Humans; Mice; Molecular Structure; Norbornanes; Prodrugs; RAW 264.7 Cells; Rats
PubMed: 29762011
DOI: 10.1021/acs.accounts.8b00019 -
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 -
European Journal of Medicinal Chemistry Oct 2017The increasing development of targeted cancer therapy provides extensive possibilities in clinical trials, and numerous strategies have been explored. The prodrug is one... (Review)
Review
The increasing development of targeted cancer therapy provides extensive possibilities in clinical trials, and numerous strategies have been explored. The prodrug is one of the most promising strategies in targeted cancer therapy to improve the selectivity and efficacy of cytotoxic compounds. Compared with normal tissues, cancer cells are characterized by unique aberrant markers, thus inactive prodrugs targeting these markers are excellent therapeutics to release active drugs, killing cancer cells without damaging normal tissues. In this review, we explore an integrated view of potential prodrugs applied in targeted cancer therapy based on aberrant cancer specific markers and some examples are provided for inspiring new ideas of prodrug strategy for cancer cell-specific targeting.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Neoplasms; Prodrugs; Structure-Activity Relationship
PubMed: 28837920
DOI: 10.1016/j.ejmech.2017.08.010 -
Dalton Transactions (Cambridge, England... Aug 2016Anticancer platinum (Pt) complexes have long been considered to be one of the biggest success stories in the history of medicinal inorganic chemistry. Yet there remains... (Review)
Review
Anticancer platinum (Pt) complexes have long been considered to be one of the biggest success stories in the history of medicinal inorganic chemistry. Yet there remains the hunt for the "magic bullet" which can satisfy the requirements of an effective chemotherapeutic drug formulation. Pt(iv) complexes are kinetically more inert than the Pt(ii) congeners and offer the opportunity to append additional functional groups/ligands for prodrug activation, tumor targeting, or drug delivery. The ultimate aim of functionalization is to enhance the tumor selective action and attenuate systemic toxicity of the drugs. Moreover, an increase in cellular accumulation to surmount the resistance of the tumor against the drugs is also of paramount importance in drug development and discovery. In this review, we will address the attempts made in our lab to develop Pt(iv) prodrugs that can be activated and delivered using targeted nanotechnology-based delivery platforms.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Humans; Organoplatinum Compounds; Platinum Compounds; Prodrugs
PubMed: 27493131
DOI: 10.1039/c6dt01738j -
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 -
Nature Reviews. Drug Discovery Aug 2018Prodrugs are molecules with little or no pharmacological activity that are converted to the active parent drug in vivo by enzymatic or chemical reactions or by a... (Review)
Review
Prodrugs are molecules with little or no pharmacological activity that are converted to the active parent drug in vivo by enzymatic or chemical reactions or by a combination of the two. Prodrugs have evolved from being serendipitously discovered or used as a salvage effort to being intentionally designed. Such efforts can avoid drug development challenges that limit formulation options or result in unacceptable biopharmaceutical or pharmacokinetic performance, or poor targeting. In the past 10 years, the US Food and Drug Administration has approved at least 30 prodrugs, which accounts for more than 12% of all approved small-molecule new chemical entities. In this Review, we highlight prodrug design strategies for improved formulation and pharmacokinetic and targeting properties, with a focus on the most recently marketed prodrugs. We also discuss preclinical and clinical challenges and considerations in prodrug design and development.
Topics: Animals; Drug Approval; Drug Design; Drug Development; Humans; Prodrugs; United States; United States Food and Drug Administration
PubMed: 29700501
DOI: 10.1038/nrd.2018.46