Synthesis of Vorinostat and cholesterol conjugate to enhance the cancer cell uptake selectivity

Idippily, Nethrie D.; Gan, Chunfang; Orefice, Paul; Peterson, Jane A.; Su, Bin

doi:10.1016/j.bmcl.2017.01.025

Cited by 12 publications

(6 citation statements)

References 11 publications

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“…Table 2 , depicted particle size, zeta potential, and EE of plain LDL, 5-FU-LDL, and 5-FUC-LDL. In this study particle size, and zeta potential of LDL nanoparticles were estimated using dynamic light scattering technique after dilution with PBS [ 20 ]. The particle size of LDL is found in the range of 28–48.6 nm.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, the gel was imagined by an electrophoretic imaging system (Aplegen Omega Lum G, USA). The particle size and zeta potential were measured after dilution with phosphate buffer saline (PBS) [ 20 ] by dynamic light scattering technique using a Zeta sizer Nano ZS (Malvern Instruments, UK). Also, the morphology of LDL particles was visualized using a Transmission Electron Microscopy (TEM) to evaluate their size and morphology (JEOL JEM 1011 F, USA).…”

Section: Methodsmentioning

confidence: 99%

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Crosstalk of low density lipoprotein and liposome as a paradigm for targeting of 5-fluorouracil into hepatic cells: cytotoxicity and liver deposition

et al. 2021

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This study aimed to utilize cholesterol conjugation of 5-fluorouracil (5-FUC) and liposomal formulas to enhance the partitioning of 5-FU into low density lipoprotein (LDL) to target hepatocellular carcinoma (HCC). Thus, 5-FU and 5-FUCwere loaded into liposomes. Later, the direct loading and transfer of 5-FU, and 5-FUC from liposomes into LDL were attained. The preparations were characterized in terms of particle size, zeta potential, morphology, entrapment efficiency, and cytotoxicity using the HepG2 cell line. Moreover, the drug deposition into the LDL and liver tissues was investigated. The present results revealed that liposomal preparations have a nanosize range (155 − 194 nm), negative zeta potential (-0.82 to-16 mV), entrapment efficiency of 69% for 5-FU, and 66% for 5-FUC. Moreover, LDL particles have a nanosize range (28-49 nm), negative zeta potential (-17 to −27 mV), and the entrapment efficiency is 11% for 5-FU and 85% for 5-FUC. Furthermore, 5-FUC loaded liposomes displayed a sustained release profile (57%) at 24 h compared to fast release (92%) of 5-FU loaded liposomes. 5-FUC and liposomal formulas enhanced the transfer of 5-FUC into LDL compared to 5-FU. 5-FUC loaded liposomes and LDL have greater cytotoxicity against HepG2 cell lines compared to 5-FU and 5-FUC solutions. Moreover, the deposition of 5-FUC in LDL (26.87ng/mg) and liver tissues (534 ng/gm tissue) was significantly increased 5-FUC liposomes compared to 5-FU (11.7 ng/g tissue) liposomal formulation. In conclusion, 5-FUC is a promising strategy for hepatic targeting of 5-FU through LDL-mediated gateway.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Crosstalk of low density lipoprotein and liposome as a paradigm for targeting of 5-fluorouracil into hepatic cells: cytotoxicity and liver deposition

et al. 2021

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“…Although vorinostat was the first HDACs inhibitor approved by the FDA for the treatment of T-cell lymphoma and has broad activity against a variety of cancers 24 , the efficacy of the single treatment with vorinostat in clinical settings is not high. A variety of combination regimens were tested in clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Vorinostat and quinacrine have synergistic effects in T-cell acute lymphoblastic leukemia through reactive oxygen species increase and mitophagy inhibition

et al. 2018

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Despite recent progress in the treatment, the outcome of adult acute T-cell lymphoblastic leukemia (T-ALL) is poor. Development of novel approach to combat this disease is urgently required. Vorinostat, a pan-histone deacetylase (HDAC) inhibitor, exerts promising anticancer activity in a variety of solid and hematologic malignancies. However, the efficacy of vorinostat monotherapy is unsatisfactory. Here, we show that quinacrine (QC), an anti-malaria drug with potent autophagy inhibitory activity, could synergistically enhance vorinostat-induced cell death at a non-toxic concentration. Compared to the single treatment, QC plus vorinostat significantly induced apoptosis, disrupted the mitochondrial transmembrane potential, and decreased Mcl-1 and Bcl-2/Bax ratio. Interestingly, the application of QC plus vorinostat resulted in mitophagy blockade, as reflected by the increase in the K63-linked ubiquitination of mitochondria protein and the formation of mitochondrial aggresomes. QC plus vorinostat markedly increased the reactive oxygen species (ROS) level in cells. Moreover, the ROS scavenger N-acetylcysteine (NAC) abrogated QC plus vorinostat-induced ROS, decreased the ubiquitination of mitochondria proteins, and cell death. Finally, using a xenograft mouse model, we demonstrated that QC plus vorinostat significantly reduced cell proliferation and induced cell death in vivo. Taken together, our results showed that the combination of QC with vorinostat may represent a novel regimen for the treatment of T-cell acute lymphoblastic leukemia, which deserves clinical evaluation in the future.

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“…To that end, we prepared a series of functionalized Pt(IV) prodrug complexes with a therapeutic payload tethered to self-immolative linkers as a proof of concept and investigated their release kinetics (Figure ). Methyl trans -2-hydroxycinnamate (MeHC) and 7-hydroxy-3-methylcoumarin (7-HMC) were chosen as model codrugs as they are privileged scaffolds of natural products with known therapeutic effects against cancer. , Suberoylanilide hydroxamic acid (SAHA) is an FDA-approved histone deacetylase inhibitor (HDACi) , and the combination therapy of SAHA and cDDP has been reported to produce a synergistic effect in inducing cancer cell death. − Because the self-immolative linkers could spontaneously decompose, we developed a synthesis approach that initially masked the trigger group before carrying out functional group transformation for direct coupling with the Pt(IV) scaffold. We investigated their self-immolation kinetics and demonstrated that the unmodified payload could be released upon reduction at the Pt(IV) center.…”

Section: Introductionmentioning

confidence: 99%

“…Methyl trans-2-hydroxycinnamate (MeHC) and 7-hydroxy-3-methylcoumarin (7-HMC) were chosen as model codrugs as they are privileged scaffolds of natural products with known therapeutic effects against cancer. 17,26 Suberoylanilide hydroxamic acid (SAHA) is an FDA-approved histone deacetylase inhibitor (HDACi) 27,28 and the combination therapy of SAHA and cDDP has been reported to produce a synergistic effect in inducing cancer cell death. 29−31 Because the self-immolative linkers could spontaneously decompose, we developed a synthesis approach that initially masked the trigger group before carrying out functional group transformation for direct coupling with the Pt(IV) scaffold.…”

Section: ■ Introductionmentioning

confidence: 99%

Strategy for Traceless Codrug Delivery with Platinum(IV) Prodrug Complexes Using Self-Immolative Linkers

et al. 2021

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A common challenge in Pt(IV) prodrug design is the limited repertoire of linkers available to connect the Pt(IV) scaffold with the bioactive payload. The commonly employed linkers are either too stable, leading to a linker artifact on the payload upon release, or too unstable, leading to premature release. In this study, we report the synthesis of a new class of Pt(IV) prodrugs using masked self-immolative 4-aminobenzyl linkers for controlled and traceless codrug delivery. Upon reduction of self-immolative Pt(IV) prodrugs, the detached axial ligands undergo decarboxylation and 1,6-elimination for payload release. Introduction of self-immolative linkers conferred good aqueous stability to the Pt(IV) codrug complex. Investigation revealed that efficient 1,6-elimination could be attributed to stabilization of the p-aza-quinone-methide intermediate. In particular, the self-immolative Pt(IV) prodrugs with cinnamate and coumarin derivatives were more potent than the coadministration of cisplatin with an unconjugated cinnamate or coumarin payload in vitro.

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Synthesis of Vorinostat and cholesterol conjugate to enhance the cancer cell uptake selectivity

Cited by 12 publications

References 11 publications

Crosstalk of low density lipoprotein and liposome as a paradigm for targeting of 5-fluorouracil into hepatic cells: cytotoxicity and liver deposition

Crosstalk of low density lipoprotein and liposome as a paradigm for targeting of 5-fluorouracil into hepatic cells: cytotoxicity and liver deposition

Vorinostat and quinacrine have synergistic effects in T-cell acute lymphoblastic leukemia through reactive oxygen species increase and mitophagy inhibition

Strategy for Traceless Codrug Delivery with Platinum(IV) Prodrug Complexes Using Self-Immolative Linkers

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