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Drug Metabolism and Pharmacokinetics 2011
Topics: Drug Delivery Systems; Drug Design; Drug Discovery; Humans; Prodrugs
PubMed: 21891971
DOI: 10.2133/dmpk.dmpk-11-pf-904 -
Drug Delivery Dec 2021Chemotherapy plays a major role in the treatment of cancer, but it still has great limitations in anti-tumor effect. Carboplatin (CAR) is the first-line drug in the...
Chemotherapy plays a major role in the treatment of cancer, but it still has great limitations in anti-tumor effect. Carboplatin (CAR) is the first-line drug in the treatment of non-small cell lung cancer, but the therapeutic effect is demonstrated weak. Therefore, we modified CAR with hexadecyl chain and polyethylene glycol, so as to realize its liposolubility and PEGylation. The synthesized amphiphilic CAR prodrugs could self-assemble into polymer micelles in water with an average particle size about 11.8 nm and low critical micelles concentration (0.0538 mg·mL). pharmacodynamics and cytotoxicity experiment evidenced that the polymer micelles were equipped with preferable anti-tumor effect, finally attained the aim of elevating anti-tumor effect and prolonging retention time . The self-assembled micelles skillfully solve the shortcomings of weak efficacy of CAR, which provides a powerful platform for the application of chemical drug in oncology.
Topics: Animals; Carboplatin; Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Drug Carriers; Drug Liberation; Female; Mice; Mice, Nude; Micelles; Nanoparticles; Particle Size; Polyethylene Glycols; Prodrugs; Random Allocation; Solubility
PubMed: 34176381
DOI: 10.1080/10717544.2021.1938754 -
Bioconjugate Chemistry Oct 2023A synthetic platform has been developed that provides access to platinum(IV) prodrugs of highly cytotoxic platinum-acridine anticancer agents and allows them to be...
A synthetic platform has been developed that provides access to platinum(IV) prodrugs of highly cytotoxic platinum-acridine anticancer agents and allows them to be incorporated into conjugation-ready prodrug-payloads (PPLs). The PPLs can be conveniently assembled in highly efficient microscale reactions utilizing strain-promoted azide-alkyne cycloaddition chemistry. Model reactions were performed to study the stability of the PPLs in buffers and media and to assess their compatibility with cysteine-maleimide Michael addition chemistry. Amide coupling was a successful strategy to generate a conjugate containing integrin-targeted [RGDfK] peptide. Reactions with ascorbate were performed to mimic the reductive activation of the PPLs and the latter conjugate, and a cyanine (Cy5) fluorophore-labeled PPL was used to probe the reduction of platinum(IV) in cancer cells by confocal microscopy. The PPL concept introduced here should be evaluated for treating solid tumors with PAs using cancer-targeting vehicles, such as antibody-drug conjugates.
Topics: Humans; Prodrugs; Platinum; Acridines; Antineoplastic Agents; Neoplasms
PubMed: 37813818
DOI: 10.1021/acs.bioconjchem.3c00368 -
Chemical Communications (Cambridge,... Sep 2022A new conjugate formulation, SIWV-PB-SN, based on glioblastoma (GBM)-homing SIWV tetrapeptide and an ROS-responsive prodrug is reported. SIWV-PB-SN selectively...
A new conjugate formulation, SIWV-PB-SN, based on glioblastoma (GBM)-homing SIWV tetrapeptide and an ROS-responsive prodrug is reported. SIWV-PB-SN selectively penetrates the GBM cells and releases anti-GBM drug (SN-38) ROS-induced linker cleavage. This study presents a new insight for a more advanced therapeutic approach to overcoming GBM.
Topics: Cell Line, Tumor; Glioblastoma; Humans; Irinotecan; Prodrugs; Reactive Oxygen Species
PubMed: 36082694
DOI: 10.1039/d2cc03777g -
Anti-cancer Agents in Medicinal... Aug 2008The main drawback of most cancer chemotherapy is its relatively low ability to target tumour cells versus normal cells. As a consequence, chemotherapy is usually... (Review)
Review
The main drawback of most cancer chemotherapy is its relatively low ability to target tumour cells versus normal cells. As a consequence, chemotherapy is usually connected with severe side effects due to the toxicity of traditional cytostatic agents towards normal tissues. A few years ago, the site-specific activation of non-toxic prodrugs in tumours has been proposed in order to enhance the selectivity for the killing of cancer cells. Within this framework, most of the prodrugs that have been designed were three part compounds comprising trigger, linker and effector units. The main function of the linker is to release the effector unit after selective trigger activation via a spontaneous chemical breakdown. However, its structure also affects significantly many prodrug properties such as stability, pharmacokinetic, organ distribution, bioavailability or trigger activation. This review, focussed on the linker unit, is an update of our previous article published in 2002. It deals with recent advances in the design of prodrug linkers including new delivery systems such as elongated linkers or self-immolative dendrimers.
Topics: Cyclization; Delayed-Action Preparations; Drug Carriers; Drug Design; Humans; Models, Biological; Neoplasms; Prodrugs
PubMed: 18690826
DOI: No ID Found -
Methods in Enzymology 2022As a class of enzymes, esterases have been investigated for decades and have found use in industrial processes, synthetic organic chemistry, and elsewhere. Esters are...
As a class of enzymes, esterases have been investigated for decades and have found use in industrial processes, synthetic organic chemistry, and elsewhere. Esters are functional groups composed of an alcohol moiety and a carboxylic acid moiety. Although much work has explored the influence of the carboxyl moiety of an ester on its susceptibility to esterases, little work has explored the influence of the alcohol moiety. Here, we describe an in vitro methodology to explore the influence of changing the alcohol moiety of an ester on its enzymatic hydrolysis, including strategies for analyzing such data. We then describe leveraging data from these assays to develop targeted antimicrobial prodrugs that activate in certain species due to the discriminatory activity of species-specific esterases. We envisage the potential of genomics and machine learning to further these efforts. Finally, we anticipate the potential future uses of these ideas, including developing targeted anti-cancer compounds.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Esterases; Esters; Hydrolysis; Prodrugs
PubMed: 35331374
DOI: 10.1016/bs.mie.2021.11.008 -
Carbohydrate Polymers Jul 2022Polymer-based prodrug nanocarriers with tumor-targeting and controlled-release properties are in great demand for enhanced cancer treatment. Hyaluronic acid (HA), which...
Polymer-based prodrug nanocarriers with tumor-targeting and controlled-release properties are in great demand for enhanced cancer treatment. Hyaluronic acid (HA), which has excellent biocompatibility and targeting ability for cluster determinant 44 (CD44), has been proposed for delivering drugs that have poor solubility and high toxicity. Herein, podophyllotoxin (PPT) was conjugated to HA via ester and disulfide linkages to construct a pH- and reduction-responsive prodrug (HA-S-S-PPT). The micelles self-assembled from HA-S-S-PPT prodrug efficiently accumulated at tumor site due to HA receptor-mediated endocytosis. HA-S-S-PPT micelles exhibited 33.1% higher cumulative release than HA-NH-CO-PPT micelles (sensitive only to pH) owing to their dual responsiveness to pH and reduction. HA-S-S-PPT micelles achieved excellent antitumor activity in vivo, with the tumor inhibition rate reaching 92%, significantly higher than that of HA-NH-CO-PPT micelles (65%), and negligible systemic toxicity. This controllable-targeting nanoparticle system provides a potential platform for clinical application of PPT.
Topics: Drug Delivery Systems; Humans; Hyaluronic Acid; Hydrogen-Ion Concentration; Micelles; Neoplasms; Podophyllotoxin; Prodrugs
PubMed: 35450654
DOI: 10.1016/j.carbpol.2022.119402 -
Acta Biomaterialia Oct 2022Selective in situ activation of prodrugs or generation of bioactive drugs is an important approach to reducing the side effects of chemotherapy. Herein, a tailored...
Selective in situ activation of prodrugs or generation of bioactive drugs is an important approach to reducing the side effects of chemotherapy. Herein, a tailored ROS-activable prodrug nanomedicine (Cu-SK@DTC-PPB) was developed as the prodrug activation nanoamplifier for highly selective antitumor therapy. Cu-SK@DTC-PPB was rationally constructed by the diethyldithiocarbamate (DTC) prodrug DTC-PPB and the nanoscale coordinated framework Cu-SK based on copper and the ROS generator shikonin (SK). Cu, SK and DTC were kept in the inactive state in the fabricated Cu-SK@DTC-PPB. In the presence of ROS within tumors, DTC-PPB can be activated to release less cytotoxic DTC, which can rapidly chelate Cu from the Cu-SK framework to synthesize highly cytotoxic Cu(DTC) and induce SK to release in a cascade. The released SK can generate ROS to increase the intracellular ROS level, further activating DTC-PPB to release more DTC. That is, Cu-SK@DTC-PPB can undergo a self-amplifying positive feedback loop to induce numerous bioactive Cu(DTC) formation and SK release triggered by a small amount of ROS within the tumor microenvironment, which endows the transformation of "less toxic-to-high toxic" and thus significantly improve its selectivity towards tumors. Therefore, this study provides a new strategy of prodrug activation for tumor therapy with high efficiency and low toxicity. STATEMENT OF SIGNIFICANCE: Owing to the striking difference in ROS level between cancer cells and normal cells, ROS-responsive prodrugs are regarded as a promising approach for tumor-specific therapy. However, the stability and responsiveness of prodrugs are hard to balance. Preferable sensitivity may cause premature activation while favorable stability may lead to incomplete prodrug activation and insufficient active drug release. This study provides a tailored ROS-responsive prodrug activation nanoamplifier with favorable stability and effective prodrug activation capacity. The nanoamplifier can undergo a self-amplifying positive feedback loop to achieve numerous bioactive drugs generation in situ under ROS triggers within the tumor microenvironment, showing the enhanced antitumor therapeutic effect. Thus, this study provides a new strategy for prodrug activation and tumor-specific therapy.
Topics: Cell Line, Tumor; Copper; Ditiocarb; Humans; Nanoparticles; Neoplasms; Prodrugs; Reactive Oxygen Species; Tumor Microenvironment
PubMed: 36084924
DOI: 10.1016/j.actbio.2022.08.072 -
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 -
ACS Applied Materials & Interfaces Mar 2023Controlled photoreduction of Pt(IV) prodrugs is a challenging task due to the possibility of targeted light-controlled activation of anticancer agents without affecting...
Controlled photoreduction of Pt(IV) prodrugs is a challenging task due to the possibility of targeted light-controlled activation of anticancer agents without affecting healthy tissues. Also, a conjugation of photosensitizers and clinically used platinum drugs into one Pt(IV) prodrug allows combining photodynamic therapy and chemotherapy approaches into one molecule. Herein, we designed the cisplatin-based Pt(IV) prodrug Riboplatin with tetraacetylriboflavin in the axial position. A novel Pt(IV) prodrug is able to act both as a photodynamic therapy (PDT) agent through the conversion of ground-state O to excited-state O and as an agent of photoactivated chemotherapy (PACT) through releasing of cisplatin under gentle blue light irradiation, without the requirement of a reducing agent. The light-induced behavior of Riboplatin was investigated using an electrochemical sensor in MCF-7 tumor spheroids. Photocontrolled cisplatin release and ROS generation were detected electrochemically in real time. This appears to be the first confirmation of simultaneous photoactivated release of anticancer drug cisplatin and ROS from a dual-action Pt(IV) prodrug observed from the inside of living tumor spheroids.
Topics: Cisplatin; Prodrugs; Reactive Oxygen Species; Antineoplastic Agents; Platinum; Cell Line, Tumor
PubMed: 36854172
DOI: 10.1021/acsami.3c01771