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European Journal of Pharmacology May 20229-nitrocamptothecin (9-NC), an active derivative of camptothecin (CPT), demonstrated antitumor effect on experimental tumors in mice by topoisomerase I (Topo I)...
9-Nitro-20(S)-carbonate-camptothecin (NCP4), a novel prodrug of 9-nitrocamptothecin (9-NC), exhibits potent chemotherapeutic efficacy and improved safety against hepatocarcinoma.
9-nitrocamptothecin (9-NC), an active derivative of camptothecin (CPT), demonstrated antitumor effect on experimental tumors in mice by topoisomerase I (Topo I) inhibition. However, under human physiological conditions, the rapid opening of lactone ring of 9-NC resulting in the formation of inactive and high toxic carboxylate limited its clinical efficacy. Therefore, strategies aimed to maintain the active closed-lactone form of 9-NC in the plasma were developed, such as prodrugs. In our study, 9-nitro-20(S)-carbonate-camptothecin (NCP4), a novel prodrug of 9-NC, was designed and synthesized. A preclinical evaluation of the chemotherapeutic potential of NCP4 was performed in vitro and in vivo. In cytotoxicity assay against six human cancer cells, the cytotoxic effect of NCP4 was slightly weaker than 9-NC. In addition, our data showed that 9-NC can be converted from NCP4 in vivo, and that the intracellular conversion of NCP4 to its active metabolites was correlated well with its cytotoxicity, demonstrating that NCP4 could serve as a prodrug of 9-NC. In human hepatoma Bel-7402 xenografts, NCP4 by intravenous injection showed more potent antitumor efficacy than 9-NC. Mechanistically, NCP4 induced cell apoptosis by increasing the expressions of caspase-3 and Bax in tumor tissues. In human hepatoma Hep G2 xenografts, NCP4 by oral administration significantly inhibited tumor growth. Importantly, the toxic effect of NCP4 on mice was much lower than 9-NC, demonstrating improved safety of NCP4. Overall, our study indicated that NCP4 would be a promising anticancer candidate and worthy of further investigation.
Topics: Animals; Antineoplastic Agents; Camptothecin; Carbonates; Carcinoma, Hepatocellular; Humans; Lactones; Liver Neoplasms; Mice; Prodrugs
PubMed: 35305999
DOI: 10.1016/j.ejphar.2022.174898 -
Molecules (Basel, Switzerland) Oct 2021Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and endanger health and economic security around the globe, and...
Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and endanger health and economic security around the globe, and emerging mosquito-borne pathogens have pandemic potential. However, the rapid spread of insecticide resistance threatens our ability to control mosquito vectors. Larvae of were screened with the Medicines for Malaria Venture Pandemic Response Box, an open-source compound library, using INVAPP, an invertebrate automated phenotyping platform suited to high-throughput chemical screening of larval motility. We identified rubitecan (a synthetic derivative of camptothecin) as a hit compound that reduced larval motility. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC of 25.5 ± 5.0 µM and 22.3 ± 5.4 µM, respectively. We extended our investigation to adult mosquitoes and found that camptothecin increased lethality when delivered in a blood meal to adults at 100 µM and 10 µM, and completely blocked egg laying when fed at 100 µM. Camptothecin and its derivatives are inhibitors of topoisomerase I, have known activity against several agricultural pests, and are also approved for the treatment of several cancers. Crucially, they can inhibit Zika virus replication in human cells, so there is potential for dual targeting of both the vector and an important arbovirus that it carries.
Topics: Aedes; Animals; Antiviral Agents; Camptothecin; Drug Discovery; Female; High-Throughput Screening Assays; Humans; Insecticide Resistance; Insecticides; Larva; Mosquito Vectors; Motor Activity; Pandemics; Topoisomerase I Inhibitors; Vector Borne Diseases; Virus Replication; Zika Virus
PubMed: 34684807
DOI: 10.3390/molecules26206226 -
Biochemical and Biophysical Research... Apr 2021In the present study the role of poly(ADP)ribosylation on rubitecan induced caspase dependent cell death was evaluated. We show that Top1 poisoning by rubitecan induces...
In the present study the role of poly(ADP)ribosylation on rubitecan induced caspase dependent cell death was evaluated. We show that Top1 poisoning by rubitecan induces caspase mediated apoptosis which was reduced by PARP inhibitor olaparib in zebrafish embryo. Collectively our data introduces zebrafish as a valuable model for PARP related biomedical research.
Topics: Animals; Apoptosis; Camptothecin; Caspase 3; DNA Topoisomerases, Type I; Drug Synergism; Phthalazines; Piperazines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Topoisomerase I Inhibitors; Zebrafish
PubMed: 33706100
DOI: 10.1016/j.bbrc.2021.03.005 -
Journal of Biomolecular Structure &... May 2021In December 2019, COVID-19 epidemic was described in Wuhan, China, and the infection has spread widely affecting hundreds of thousands. Herein, an effort was made to...
In December 2019, COVID-19 epidemic was described in Wuhan, China, and the infection has spread widely affecting hundreds of thousands. Herein, an effort was made to identify commercially available drugs in order to repurpose them against coronavirus by the means of structure-based virtual screening. In addition, ZINC15 library was used to identify novel leads against main proteases. Human TMPRSS2 3D structure was first generated using homology modeling approach. Our molecular docking study showed four potential inhibitors against Mpro enzyme, two available drugs (Talampicillin and Lurasidone) and two novel drug-like compounds (ZINC000000702323 and ZINC000012481889). Moreover, four promising inhibitors were identified against TMPRSS2; Rubitecan and Loprazolam drugs, and compounds ZINC000015988935 and ZINC000103558522. ADMET profile showed that the hits from our study are safe and drug-like compounds. Furthermore, molecular dynamic (MD) simulation and binding free energy calculation using the MM-PBSA method was performed to calculate the interaction energy of the top-ranked drugs.Communicated by Ramaswamy H. Sarma.
Topics: COVID-19; Cysteine Endopeptidases; Drug Repositioning; Humans; Molecular Docking Simulation; Peptide Hydrolases; Pharmaceutical Preparations; Protease Inhibitors; SARS-CoV-2; Viral Nonstructural Proteins
PubMed: 32306862
DOI: 10.1080/07391102.2020.1758791 -
Journal of Pharmaceutical and... Feb 20209-Nitrocamptothecin-20-O-propionate (CZ112) and 9-Nitrocamptothecin (9NC) are the bioactive derivatives of camptothecin (CPT), an alkaloid isolated from Camptotheca...
9-Nitrocamptothecin-20-O-propionate (CZ112) and 9-Nitrocamptothecin (9NC) are the bioactive derivatives of camptothecin (CPT), an alkaloid isolated from Camptotheca acuminata, and have been confirmed to possess high anti-cancer properties. In the present study, 9NC was identified as the major metabolite of CZ112 in rat plasma through HPLC/photodiode array detection (PDA) and liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. A highly sensitive LC-MS/MS method was developed and validated for the simultaneous analysis of CZ112 and 9NC in rat plasma, and camptothecin-20-O-acetate (CZ44) was used as an internal standard (IS). The calibration curves were linear (r > 0.999) over concentrations from 2.5 to 320 ng/mL for both CZ112 and 9NC. The method had an accuracy of 96.7-109.6%, and the intra- and inter-day precision (RSD%) were 10.9% or less for CZ112 and 9NC. The stability data showed no significant degradation occurred under the experimental conditions. This method was successfully applied to the pharmacokinetic study of CZ112 and its metabolite 9NC in rat plasma after intravenous and intragastric administration. The oral bioavailability of CZ112 was 6.2 ± 3.3% (n = 6).
Topics: Animals; Antineoplastic Agents; Biological Availability; Camptothecin; Chromatography, Liquid; Male; Prodrugs; Rats; Rats, Wistar; Tandem Mass Spectrometry
PubMed: 31848079
DOI: 10.1016/j.jpba.2019.112963 -
Drug Delivery Nov 2016Although nanocarriers provide promising potential for oral drug delivery, the delivery efficiency remains unsatisfactory and needs to be improved. Size is considered to...
CONTEXT
Although nanocarriers provide promising potential for oral drug delivery, the delivery efficiency remains unsatisfactory and needs to be improved. Size is considered to be the most important characteristic of nanoparticles related to their oral absorption. Borneol has been proved to have the ability to enhance the penetration and transport of many drugs through various physical barriers.
OBJECTIVE
To investigate the effect of the particle size and coadministration of borneol on the pharmacokinetics and bioavailability of entrapped drug in different size poly(lactic-co-glycolic acid) (PLGA) nanoparticles.
MATERIALS AND METHODS
9-Nitrocamptothecin (9-NC)-loaded PLGA nanoparticles with three different range of size (50-100 nm, 100-200 nm, 200-300 nm) were prepared by emulsion solvent-evaporation method. The pharmacokinetic study in rats of these nanoparticles with borneol was carried out.
RESULTS
The experiments showed that the encapsulation drug in nanoparticles with size below 200 nm could improve the oral bioavailability of 9-NC. The small size nanoparticles (50-100 nm) had a better improvement efficacy. As for borneol, it played a significant promotion effect only on the small nanoparticles. Moreover, there was no significant influence on the nanoparticles with size more than 100 nm.
DISCUSSION AND CONCLUSION
The study indicated that both entrapping drug in nanoparticles with the size below 100 nm and coadministrating with borneol could enhance the gastrointestinal absorption of water insoluble drug. The combination of the two strategies provides a potential approach to improve the oral bioavailability of drug.
Topics: Administration, Oral; Animals; Biological Availability; Camphanes; Camptothecin; Drug Carriers; Drug Delivery Systems; Emulsions; Intestinal Absorption; Lactic Acid; Male; Nanoparticles; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Sprague-Dawley
PubMed: 27174642
DOI: 10.1080/10717544.2016.1189466 -
International Journal of Pharmaceutics Dec 2015Recrystallization and micronization of 9-nitro-camptothecin (9-NC) has been investigated using the supercritical anti-solvent (SAS) technology in this study. Five...
Recrystallization and micronization of 9-nitro-camptothecin (9-NC) has been investigated using the supercritical anti-solvent (SAS) technology in this study. Five operating factors, i.e., the type of organic solvent, the concentration of 9-NC in the solution, the flow rate of 9-NC solution, the precipitation pressure and the temperature, were optimized using a selected OA16 (4(5)) orthogonal array design and a series of characterizations were performed for all samples. The results showed that the processed 9-NC particles exhibited smaller particle size and narrower particle size distribution as compared with 9-NC raw material (Form I), and the optimum micronization conditions for preparing 9-NC with minimum particle size were determined by variance analysis, where the solvent plays the most important role in the formation and transformation of polymorphs. Three new polymorphic forms (Form II, III and IV) of 9-NC, which present different physicochemical properties, were generated after the SAS process. The predicted structures of the 9-NC crystals, which were consistent with the experiments, were performed from their experimental XRD data by the direct space approach using the Reflex module of Materials Studio. Meanwhile, the optimal sample (Form III) was proved to have higher cytotoxicity against the cancer cells, which suggested the therapeutic efficacy of 9-NC is polymorph-dependent.
Topics: Antineoplastic Agents; Camptothecin; Particle Size; Solvents
PubMed: 26541305
DOI: 10.1016/j.ijpharm.2015.10.079 -
International Journal of Pharmaceutics Jul 2015Encapsulation of hydrophobic drugs in the form of drug-cyclodextrin (CD) complex in liposomes has been applied as a novel strategy to combine the relative advantages of...
Encapsulation of hydrophobic drugs in the form of drug-cyclodextrin (CD) complex in liposomes has been applied as a novel strategy to combine the relative advantages of CDs and liposomes into one system, naming drug-in-CD-in-liposome (DCL). In the present study, soluble 9-NC/hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complexes were prepared using the freeze-drying technique. Then 9-NC inclusion complexes were further encapsulated into liposomes by ethanol injection method and transferrin (Tf) was conjugated to the surface of 9-NC DCL to obtain Tf modified 9-NC DCL (Tf-9-NC-CL). Compared to PEGylated 9-NC DCL (P-9-NC-CL), the lactone stability and vesicle stability of Tf-9-NC-CL were significantly increased. Both 9-NC and HP-β-CD were found to release from the DCL and Tf modification resulted in reduced release of them. The enhanced targeting efficiency of the Tf-modified liposomes was demonstrated by flow cytometry and confocal microscopy. In vivo pharmacokinetics in rats showed improved lactone stability of 9-NC following intravenous injection of Tf-9-NC-CL. The cytotoxicity of Tf-9-NC-CL against tumor cells and normal cells was investigated in vitro and the antitumor efficacy was evaluated in S180 tumor-bearing mice in vivo. Compared with free 9-NC, 9-NC inclusion complexes and P-9-NC-CL, Tf-9-NC-CL demonstrated the strongest cytotoxicity to tumor cells. And the inhibitory rate of tumor (IRT) values were determined to be 43.08%, 56.92%, 67.69% and 80.00% for 9-NC solution, inclusion complexes, P-9-NC-CL and Tf-9-NC-CL, respectively. In conclusion, Tf modification can be useful in increasing vesicle stability, targeting drug delivery efficiency and antitumor efficacy of DCL containing hydrophobic antitumor drugs, such as 9-NC.
Topics: Animals; Antineoplastic Agents; Camptothecin; Cyclodextrins; Drug Carriers; Drug Delivery Systems; Drug Stability; Lactones; Liposomes; Mice; Mice, Inbred ICR; Neoplasms; Rats; Rats, Sprague-Dawley; Transferrin
PubMed: 26004006
DOI: 10.1016/j.ijpharm.2015.05.047 -
International Journal of Pharmaceutics Dec 2014Our study aimed to develop an amorphous 9-nitrocamptothecin solid dispersion (9-NC-SD) using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer...
Our study aimed to develop an amorphous 9-nitrocamptothecin solid dispersion (9-NC-SD) using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus(®)) for improving its oral bioavailability and antitumor efficacy in vivo. Freeze-dried 9-NC-SD with an optimized drug/polymer ratio at 1:15 (w/w) was characterized by powder X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy. The amorphous form of 9-NC was obtained by freeze-drying and the aqueous solubility of 9-NC was increased to 1.42 mg/mL. Upon dilution, 9-NC-SD was proven to form micellar structures with an average size distribution around 58 nm ± 5 nm (PDI=0.107 ± 0.016). Moreover, 9-NC-SD showed significantly increased intracellular uptake efficiency in Caco-2 cells compared to free 9-NC. Furthermore, the AUC0-8h of 9-NC-SD following oral administration showed a 2.68-fold increase in the lactone form of 9-NC compared to that of free 9-NC in Sprague-Dawley rats. The 9-NC-SD did not show obvious inflammatory responses and gastrointestinal toxicity following oral administration as demonstrated by the histological analysis of the rat intestinal sections. Thus, 9-NC-SD represents a promising approach for improving the solubility and oral bioavailability of drugs with poor solubility.
Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Transport; Caco-2 Cells; Camptothecin; Cell Culture Techniques; Drug Carriers; Drug Compounding; Endocytosis; Gastrointestinal Tract; Humans; Male; Mice, Inbred ICR; Molecular Structure; Particle Size; Polyethylene Glycols; Polyvinyls; Rats, Sprague-Dawley; Sarcoma 180; Surface Properties
PubMed: 25445521
DOI: 10.1016/j.ijpharm.2014.10.055 -
Molecules (Basel, Switzerland) Feb 2014Advanced small cell lung cancer (SCLC) has a dismal prognosis. Modulation of the camptothecin topotecan, approved for second-line therapy, may improve response. Our...
Advanced small cell lung cancer (SCLC) has a dismal prognosis. Modulation of the camptothecin topotecan, approved for second-line therapy, may improve response. Our recent finding of synergistic enhancement of the cytotoxic activity of camptothecin (CPT) by cyclin-dependent kinase 4 inhibitors is extended here to a panel of camptothecin analogs comprising 10-hydroxy-CPT (HOCPT), topotecan (TPT; 9-[(dimethylamino)-methyl]-10-hydroxy-CPT), 9-amino-CPT (9AC), 9-nitrocamptothecin (rubitecan), SN38 (7-ethyl-10-hydroxycamptothecin) and 10-hydroxy-9-nitrocamptothecin (CPT109) in combination with PD0332991, CDK4I, roscovitine and olomoucine. SCLC cell lines employed are chemoresistant NCI-H417 and DMS153 and the chemosensitive SCLC26A line established at our institution. The CPT analogs exhibiting highest cytotoxicity towards the three SCLC lines tested were SN38 and 9AC, followed by rubitecan, HOCPT, TPT and CPT109. NCI-H417 and DMS153 revealed an approximately 25-fold and 7-fold higher resistance compared to the chemosensitive SCLC26A cell line. Whereas the CDK4/6 inhibitor PD0332991 proved less effective to chemosensitize SCLC cells to CPT analogs, the CDK inhibitors CDK4I, roscovitine and olomoucine gave comparable chemosensitization effects in combination with 9AC, SN38, rubitecan and to a lesser extent with TPT and CPT109, not directly related with topoisomerase mRNA expression. In conclusion, small chemical modifications of the parent CPT structure result in differing cytotoxicities and chemomodulatory effects in combination with CDKIs of the resulting analogs.
Topics: Antineoplastic Agents; Camptothecin; Cell Line, Tumor; Cyclin-Dependent Kinases; Drug Synergism; Enzyme Inhibitors; Humans; Irinotecan; Small Cell Lung Carcinoma; Topotecan
PubMed: 24549232
DOI: 10.3390/molecules19022077