Synthesis and activity of a folate peptide camptothecin prodrug

Henne, Walter A.; Doorneweerd, Derek D.; Hilgenbrink, Andrew R.; Kularatne, Sumith A.; Low, Philip S.

doi:10.1016/j.bmcl.2006.07.076

Cited by 142 publications

(120 citation statements)

References 34 publications

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“…Here, while some authors point out the role of GSH for disulfide cleavage and cytosolic release, 8,9,17,[21][22][23][24][25][43][44][45][46] the endosomal/lysosomal reducing activity mediated by PDI 43 or endosomal reductase, 47 could also bring an early download of the therapeutic molecule. In addition, it must be taken into account that carbonate bonds could also be cleaved by unspecific cytosolic carboxylases.…”

Section: Cpt Intracellular Release Mechanismmentioning

confidence: 99%

“…While prodrugs of CPT with cleavable disulfide linkers that release the unaltered drug have been developed, no information was available on its direct attachment to a nanoparticulated transporter. [21][22][23][24][25] We therefore performed a singular synthetic strategy based on the direct incorporation of CPT prodrugs on the nanocarrier. For this purpose, we first synthesized novel (pyridin-2-yldisulfanyl)alkyl carbonate derivatives of CPT, according to Scheme 1 (compounds 4a-c).…”

Section: Synthesis Of Prodrugs and Cpt Nanoplatformmentioning

confidence: 99%

“…In addition, it must be taken into account that carbonate bonds could also be cleaved by unspecific cytosolic carboxylases. 24 To provide further evidence of the suggested GSH-driven mechanism of CPT release the cytotoxic activity of RhB-SiO 2 @MSN-SS-CPT was studied by MTT assay in the presence of a GSH synthesis inhibitor like BSO. 48 BSO was added to a concentration range of 0.1-1 mM 24 h before RhB-SiO 2 @MSN-SS-CPT incorporation to deplete GSH levels in HeLa cells.…”

Section: Cpt Intracellular Release Mechanismmentioning

confidence: 99%

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Glutathione-sensitive nanoplatform for monitored intracellular delivery and controlled release of Camptothecin

et al. 2013

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We report the design, synthesis, characterization and in vitro testing of a novel nanodrug based on a covalent linking model that allows intracellular controlled release of the pharmaceutical payload. A new synthetic strategy is implemented by direct coupling of as-synthesized (pyridin-2-yldisulfanyl)alkyl carbonate derivatives of camptothecin (CPT) with thiol groups of silica hybrid nanoparticles containing a non-porous core and a mesoporous shell. Upon reaction with thiols in physiological conditions, disulfide bridge cleavage occurs, releasing the naked drug after an intramolecular cyclization mechanism.Additional incorporation of a fluorophore into particles core facilitates imaging at the subcellular level for the monitoring of uptake and delivery. Confocal microscopy experiments in HeLa cervix cancer cells confirms that nanoparticles enter the cells by endocytosis but are able to escape from endo-lysosomes and enter the cytosolic compartment to release their cargo. The incorporation to cells of L-buthioninesulfoximine, a glutathione inhibitor allows concluding that the intracellular releasing mechanism is mainly driven by the reducing activity of this tripeptide. This camptothecin nanoplatform shows the same cytotoxic activity than the free drug and is clearly superior to those release systems depending on enzymatic hydrolysis (as determined by calculation of the IC 50 ratios).

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Section: Cpt Intracellular Release Mechanismmentioning

confidence: 99%

Section: Synthesis Of Prodrugs and Cpt Nanoplatformmentioning

confidence: 99%

Section: Cpt Intracellular Release Mechanismmentioning

confidence: 99%

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Glutathione-sensitive nanoplatform for monitored intracellular delivery and controlled release of Camptothecin

et al. 2013

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“…This leads to release of the free CPT drug in endoplasmic reticulum, as well as the production of a red-shifted fluorescence emission at λmax=535 nm. Low et al [152] synthesized a folate-peptide-camptothecin conjugate prodrug with releasable disulfide carbonate linker. The poor water solubility of CPT is a drawback of its therapeutic agent.…”

Section: Non-fluorescent Prodrugs/converted Into Fluorescent Active Dmentioning

confidence: 99%

Fluorescent Dyes Used in Polymer Carriers as Imaging Agents in Anticancer Therapy

Miksa¹

2016

Med chem (Los Angeles)

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This review highlights the role of fluorescent dyes as active "molecular photoswiches" focusing on the application in bioimaging and anticancer therapies in the field of therapeutic delivery. The author describes the development of prodrugs targeted to specific cell types and polymeric nanocarriers (capsules, micelles and silica nanoparticles) used as fluorescent probes which offer advantages in the integration of "smart" features of fluorescent dyes into synthetic materials. The incorporation of biologically responsive components that cleave upon changes in pH or light irradiation is fundamental to the successful design of such carriers with capabilities to load and release therapeutics specifically at a target site.

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“…4A. In the control experiment, Hela cells were pretreated with an excess of thiol-reactive NEM [35] which consumed all of the free thiols within the cells, and then incubated with the sensing nanoparticles after washing three times with PBS. There was hardly any fluorescence, as observed in Fig.…”

Section: Application Of This Sensor In Living Cell Imagingmentioning

confidence: 99%

FITC functionalized magnetic core–shell Fe3O4/Ag hybrid nanoparticle for selective determination of molecular biothiols

Chen

Wang

et al. 2014

Sensors and Actuators B: Chemical

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a b s t r a c tA sensing strategy for chromogenic detection of molecular biothiols has been proposed based on fluorescein isothiocyanate (FITC) functionalized magnetic core-shell Fe 3 O 4 /Ag hybrid nanoparticles. Ag coated magnetic Fe 3 O 4 nanoparticles were initially synthetized. FITC was subsequently conjugated on the surface of core-shell nanoparticles by Ag-SCN linkage and then the fluorescence of FITC was quenched. Upon addition of molecular biothiols, since the Ag S bond is stronger than Ag-SCN, a place-displacement between thiols and FITC would occur and thereby the fluorescence of FITC would recover. Thus, a fluorescence "off-on" probe was attained by virtue of biothiols, so after magnetic separation, the fluorescence signal change of FITC in clear solution could be employed for quantitative determination of typical molecular biothiols such as glutathione (GSH) and cysteine (Cys). High sensitivity was obtained with the detection limits of 10 nM and 20 nM for GSH and Cys, respectively. As well as, the assay strategy presented excellent selectivity toward molecular biothiols against other amino acids. Furthermore, confocal imaging was achieved in living cells, indicating that this fluorescent probe is potentially applicable for imaging molecular thiols in biological systems.

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Synthesis and activity of a folate peptide camptothecin prodrug

Cited by 142 publications

References 34 publications

Glutathione-sensitive nanoplatform for monitored intracellular delivery and controlled release of Camptothecin

Glutathione-sensitive nanoplatform for monitored intracellular delivery and controlled release of Camptothecin

Fluorescent Dyes Used in Polymer Carriers as Imaging Agents in Anticancer Therapy

FITC functionalized magnetic core–shell Fe3O4/Ag hybrid nanoparticle for selective determination of molecular biothiols

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