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Yakugaku Zasshi : Journal of the... 2020The first-pass hydrolysis of oral ester-type prodrugs in the liver and intestine is mediated mainly by hCE1 and hCE2 of the respective predominant carboxylesterase (CES)... (Review)
Review
The first-pass hydrolysis of oral ester-type prodrugs in the liver and intestine is mediated mainly by hCE1 and hCE2 of the respective predominant carboxylesterase (CES) isozymes. In order to provide high blood concentrations of the parent drugs, it is preferable that prodrugs are absorbed as an intact ester in the intestine, then rapidly converted to active parent drugs by hCE1 in the liver. In the present study, we designed a prodrug of fexofenadine (FXD) as a model parent drug that is resistant to hCE2 but hydrolyzed by hCE1, utilizing the differences in catalytic characteristics of hCE1 and hCE2. In order to precisely predict the intestinal absorption of an FXD prodrug candidate, we developed a novel high-throughput system by modifying Caco-2 cells. Further, we evaluated species differences and aging effects in the intestinal and hepatic hydrolysis of prodrugs to improve the estimation of in vivo first-pass hydrolysis of ester-type prodrugs. Consequently, it was possible to design a hepatotropic prodrug utilizing the differences in tissue distribution and substrate specificity of CESs. In addition, we successfully established three useful in vitro systems for predicting the intestinal absorption of hCE1 substrate using Caco-2 cells. However, some factors involved in estimating the bioavailability of prodrugs in human, such as changes in recognition of drug transporters by esterification, and species differences of the first-pass hydrolysis, should be comprehensively considered in prodrug development.
Topics: Administration, Oral; Biological Availability; Carboxylic Ester Hydrolases; Esters; Humans; Hydrolysis; Intestinal Absorption; Isoenzymes; Liver; Prodrugs; Species Specificity
PubMed: 32115554
DOI: 10.1248/yakushi.19-00225 -
Molecules (Basel, Switzerland) Jun 2023The construction of duocarmycin-like compounds is often associated with lengthy synthetic routes. Presented herein is the development of a short and convenient synthesis...
The construction of duocarmycin-like compounds is often associated with lengthy synthetic routes. Presented herein is the development of a short and convenient synthesis of a type of duocarmycin prodrug. The 1,2,3,6-tetrahydropyrrolo[3,2-]indole-containing core is here constructed from commercially available Boc-5-bromoindole in four steps and 23% overall yield, utilizing a Buchwald-Hartwig amination followed by a sodium hydride-induced regioselective bromination. In addition, protocols for selective mono- and di-halogenations of positions 3 and 4 were also developed, which could be useful for further exploration of this scaffold.
Topics: Duocarmycins; Prodrugs; Amination
PubMed: 37375372
DOI: 10.3390/molecules28124818 -
Journal of Nanobiotechnology Jan 2022A widely established prodrug strategy can effectively optimize the unappealing properties of therapeutic agents in cancer treatment. Among them, lipidic prodrugs... (Review)
Review
A widely established prodrug strategy can effectively optimize the unappealing properties of therapeutic agents in cancer treatment. Among them, lipidic prodrugs extremely uplift the physicochemical properties, site-specificity, and antitumor activities of therapeutic agents while reducing systemic toxicity. Although great perspectives have been summarized in the progress of prodrug-based nanoplatforms, no attention has been paid to emphasizing the rational design of small-molecule lipidic prodrugs (SLPs). With the aim of outlining the prospect of the SLPs approach, the review will first provide an overview of conjugation strategies that are amenable to SLPs fabrication. Then, the rational design of SLPs in response to the physiological barriers of chemotherapeutic agents is highlighted. Finally, their biomedical applications are also emphasized with special functions, followed by a brief introduction of the promising opportunities and potential challenges of SLPs-based drug delivery systems (DDSs) in clinical application.
Topics: Antineoplastic Agents; Drug Delivery Systems; Lipids; Nanomedicine; Prodrugs
PubMed: 35073914
DOI: 10.1186/s12951-022-01257-4 -
Radiotherapy and Oncology : Journal of... Sep 2023Tumour hypoxia is an established radioresistance factor. A novel hypoxia-activated prodrug CP-506 has been proven to selectively target hypoxic tumour cells and to cause... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND PURPOSE
Tumour hypoxia is an established radioresistance factor. A novel hypoxia-activated prodrug CP-506 has been proven to selectively target hypoxic tumour cells and to cause anti-tumour activity. The current study investigates whether CP-506 improves outcome of radiotherapy in vivo.
MATERIALS AND METHODS
Mice bearing FaDu and UT-SCC-5 xenografts were randomized to receive 5 daily injections of CP-506/vehicle followed by single dose (SD) irradiation. In addition, CP-506 was combined once per week with fractionated irradiation (30 fractions/6 weeks). Animals were followed-up to score all recurrences. In parallel, tumours were harvested to evaluate pimonidazole hypoxia, DNA damage (γH2AX), expression of oxidoreductases.
RESULTS
CP-506 treatment significantly increased local control rate after SD in FaDu, 62% vs. 27% (p = 0.024). In UT-SCC-5, this effect was not curative and only marginally significant. CP-506 induced significant DNA damage in FaDu (p = 0.009) but not in UT- SCC-5. Hypoxic volume (HV) was significantly smaller (p = 0.038) after pretreatment with CP-506 as compared to vehicle in FaDu but not in less responsive UT-SCC-5. Adding CP-506 to fractionated radiotherapy in FaDu did not result in significant benefit.
CONCLUSION
The results support the use of CP-506 in combination with radiation in particular using hypofractionation schedules in hypoxic tumours. The magnitude of effect depends on the tumour model, therefore it is expected that applying appropriate patient stratification strategy will further enhance the benefit of CP-506 treatment for cancer patients. A phase I-IIA clinical trial of CP-506 in monotherapy or in combination with carboplatin or a checkpoint inhibitor has been approved (NCT04954599).
Topics: Humans; Animals; Mice; Carcinoma, Squamous Cell; Prodrugs; Dose Fractionation, Radiation; Hypoxia; Probability
PubMed: 37315579
DOI: 10.1016/j.radonc.2023.109738 -
Drug Discoveries & Therapeutics Dec 2022Gemcitabine is widely used in the clinic as a first-line antitumor agent. However, intrinsic and acquired resistance hinders its wide clinical application. In this...
Gemcitabine is widely used in the clinic as a first-line antitumor agent. However, intrinsic and acquired resistance hinders its wide clinical application. In this study, a gemcitabine prodrug nominated as WRQ-2 was designed and synthesized by conjugating gemcitabine with the indole-3-methanol analogue OSU-A9 through a carbamate linkage. WRQ-2 exhibited high cytotoxicity against six cancer cell lines (HeLa, A549, MDA-MB-231, HuH-7, MGC-803, and HCT-116) with IC values in low micromolar range. WRQ-2 reversed the resistance of HeLa cells to gemcitabine caused by hENT1 inhibition. Compared to gemcitabine, WRQ-2 induced a higher degree of DNA damage and apoptosis in the presence of hENT1 inhibitor. Our study suggests that compound WRQ-2 is a potential gemcitabine prodrug and worth of further antitumor activity investigation.
Topics: Humans; Gemcitabine; Prodrugs; Deoxycytidine; HeLa Cells; Cell Line, Tumor; Pancreatic Neoplasms
PubMed: 36529509
DOI: 10.5582/ddt.2022.01077 -
International Journal of Molecular... Feb 2022Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to...
Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). We aimed to develop the prodrug approach that can allow such site-specific drug delivery. Currently, using cyclosporine as a drug of choice in IBD is limited to the most severe cases due to substantial systemic toxicities and narrow therapeutic index of this drug. Previously, we synthesized a series of a phospholipid-linker-cyclosporine (PLC) prodrugs designed to exploit the overexpression of phospholipase A (PLA) in the inflamed intestinal tissues, as the prodrug-activating enzyme. Nevertheless, the extent and rate of prodrug activation differed significantly. In this study we applied in-vitro and modern in-silico tools based on molecular dynamics (MD) simulation, to gain insight into the dynamics and mechanisms of the PLC prodrug activation. We aimed to elucidate the reason for the significant activation change between different linker lengths in our prodrug design. Our work reveals that the PLC conjugate with the 12-carbon linker length yields the optimal prodrug activation by PLA in comparison to shorter linker length (6-carbons). This optimized length efficiently allows cyclosporine to be released from the prodrug to the active pocket of PLA. This newly developed mechanistic approach, presented in this study, can be applied for future prodrug optimization to accomplish optimal prodrug activation and drug targeting in various conditions that include overexpression of PLA.
Topics: Cyclosporine; Humans; Inflammatory Bowel Diseases; Phospholipases A2; Phospholipids; Prodrugs
PubMed: 35269813
DOI: 10.3390/ijms23052673 -
Acta Biomaterialia Mar 2022L-377,202 prodrug consists of doxorubicin (Dox) conjugated to a prostate-specific antigen (PSA) peptide substrate that can be cleaved by enzymatically active PSA at the...
L-377,202 prodrug consists of doxorubicin (Dox) conjugated to a prostate-specific antigen (PSA) peptide substrate that can be cleaved by enzymatically active PSA at the tumor site. Despite the initial promise in phase I trial, further testing of L-377,202 (herein called Dox-PSA) was ceased due to some degree of non-specific activation and toxicity concerns. To improve safety of Dox-PSA, we encapsulated it into low temperature-sensitive liposomes (LTSL) to bypass systemic activation, while maintaining its biological activity upon controlled release in response to mild hyperthermia (HT). A time-dependent accumulation of activated prodrug in the nuclei of PSA-expressing cells exposed to mild HT was observed, showing that Dox-PSA was efficiently released from the LTSL, cleaved by PSA and entering the cell nucleus as free Dox. Furthermore, we have shown that Dox-PSA loading in LTSL can block its biological activity at 37°C, while the combination with mild HT resulted in augmented cytotoxicity in both 2D and 3D PC models compared to the free Dox-PSA. More importantly, Dox-PSA encapsulation in LTSL prolonged its blood circulation and reduced Dox accumulation in the heart of C4-2B tumor-bearing mice over the free Dox-PSA, thus significantly improving Dox-PSA therapeutic window. Finally, Dox-PSA-loaded LTSL combined with HT significantly delayed tumor growth at a similar rate as mice treated with free Dox-PSA in both solid and metastatic PC tumor models. This indicates this strategy could block the systemic cleavage of Dox-PSA without reducing its efficacy in vivo, which could represent a safer option to treat patients with locally advanced PC. STATEMENT OF SIGNIFICANCE: This study investigates a new tactic to tackle non-specific cleavage of doxorubicin PSA-activatable prodrug (L-377,202) to treat advanced prostate cancer. In the present study, we report a nanoparticle-based approach to overcome the non-specific activation of L-377,202 in the systemic circulation. This includes encapsulating Dox-PSA in low temperature-sensitive liposomes to prevent its premature hydrolysis and non-specific cleavage. This class of liposomes offers payload protection against degradation in plasma, improved pharmacokinetics and tumor targeting, and an efficient and controlled drug release triggered by mild hyperthermia (HT) (∼42°C). We believe that this strategy holds great promise in bypassing any systemic toxicity concerns that could arise from the premature activation of the prodrug whilst simultaneously being able to control the spatiotemporal context of Dox-PSA cleavage and metabolism.
Topics: Animals; Cell Line, Tumor; Doxorubicin; Hot Temperature; Humans; Liposomes; Male; Mice; Prodrugs; Prostatic Neoplasms
PubMed: 34954416
DOI: 10.1016/j.actbio.2021.12.019 -
Theranostics 2021Photodynamic therapy (PDT) has emerged as one of the most up-and-coming non-invasive therapeutic modalities for cancer therapy in rencent years. However, its therapeutic...
Photodynamic therapy (PDT) has emerged as one of the most up-and-coming non-invasive therapeutic modalities for cancer therapy in rencent years. However, its therapeutic effect was still hampered by the short life span, limited diffusion distance and ineluctable depletion of singlet oxygen (O), as well as the hypoxic microenvironment in the tumor tissue. Such problems have limited the application of PDT and appropriate solutions are highly demand. Herein, a programmatic treatment strategy is proposed for the development of a smart molecular prodrug (), which comprise a two-photon photosensitizer and a hypoxia-activated chemotherapeutic prodrug. A rhodamine dye was designed to connect them and track the drug release by the fluorescent signal generated through azo bond cleavage. The prodrug () can stay on the cell membrane and enrich at the tumor site. Upon light irradiation, the therapeutic effect was enhanced by a stepwise treatment: (i) direct generation of O on the cell membrane induced membrane destruction and promoted the uptake; (ii) deep tumor hypoxia caused by two-photon PDT process further triggered the activation of the chemotherapy prodrug. Both and experiments, have exhabited excellent tumor treatment effect. The innovative treatment strategy provides new strategy for the design of follow-up anticancer drugs.
Topics: Animals; Azo Compounds; Cell Membrane; Female; Fluorescent Dyes; HeLa Cells; Humans; Hypoxia; Mammary Neoplasms, Experimental; Photochemotherapy; Photons; Photosensitizing Agents; Prodrugs; Rhodamines; Singlet Oxygen; Staining and Labeling
PubMed: 33537100
DOI: 10.7150/thno.55014 -
Chemical Society Reviews Jun 2024Polymer prodrugs are based on the covalent linkage of therapeutic molecules to a polymer structure which avoids the problems and limitations commonly encountered with... (Review)
Review
Polymer prodrugs are based on the covalent linkage of therapeutic molecules to a polymer structure which avoids the problems and limitations commonly encountered with traditional drug-loaded nanocarriers in which drugs are just physically entrapped (, burst release, poor drug loadings). In the past few years, reversible-deactivation radical polymerization (RDRP) techniques have been extensively used to design tailor-made polymer prodrug nanocarriers. This synthesis strategy has received a lot of attention due to the possibility of fine tuning their structural parameters (, polymer nature and macromolecular characteristics, linker nature, physico-chemical properties, functionalization, ), to achieve optimized drug delivery and therapeutic efficacy. In particular, adjusting the nature of the drug-polymer linker has enabled the easy synthesis of stimuli-responsive polymer prodrugs for efficient spatiotemporal drug release. In this context, this review article will give an overview of the different stimuli-sensitive polymer prodrug structures designed by RDRP techniques, with a strong focus on the synthesis strategies, the macromolecular architectures and in particular the drug-polymer linker, which governs the drug release kinetics and eventually the therapeutic effect. Their biological evaluations will also be discussed.
Topics: Prodrugs; Polymerization; Drug Carriers; Humans; Polymers; Nanoparticles; Drug Liberation; Free Radicals
PubMed: 38775004
DOI: 10.1039/d2cs01060g -
International Journal of Molecular... Dec 2022Herein, we developed a dual-activated prodrug, BTC, that contains three functional components: a glutathione (GSH)-responsive BODIPY-based photosensitizer with a...
Herein, we developed a dual-activated prodrug, BTC, that contains three functional components: a glutathione (GSH)-responsive BODIPY-based photosensitizer with a photoinduced electron transfer (PET) effect between BODIPY and the 2,4-dinitrobenzenesulfonate (DNBS) group, and an ROS-responsive thioketal linker connecting BODIPY and the chemotherapeutic agent camptothecin (CPT). Interestingly, CPT displayed low toxicity because the active site of CPT was modified by the BODIPY-based macrocycle. Additionally, BTC was encapsulated with the amphiphilic polymer DSPE-mPEG to improve drug solubility and tumor selectivity. The resulting nano-prodrug passively targeted tumor cells through enhanced permeability and retention (EPR) effects, and then the photosensitizing ability of the BODIPY dye was restored by removing the DNBS group with the high concentration of GSH in tumor cells. Light-triggered ROS from activated BODIPY can not only induce apoptosis or necrosis of tumor cells but also sever the thioketal linker to release CPT, achieving the combination treatment of selective photodynamic therapy and chemotherapy. The antitumor activity of the prodrug has been demonstrated in mouse mammary carcinoma 4T1 and human breast cancer MCF-7 cell lines and 4T1 tumor-bearing mice.
Topics: Humans; Mice; Animals; Female; Prodrugs; Breast Neoplasms; Reactive Oxygen Species; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Cell Line, Tumor
PubMed: 36555298
DOI: 10.3390/ijms232415656