Synthesis and evaluation of fatty acyl ester derivatives of cytarabine as anti-leukemia agents

Chhikara, Bhupender S.; Mandal, Deendayal; Parang, Keykavous

doi:10.1016/j.ejmech.2010.07.024

Cited by 37 publications

(26 citation statements)

References 23 publications

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“…These results show a clear dependence on chemical conformation of cytarabine derivatives for biological activity, and time-dependent cytotoxicity suggests a gradual intracellular release of the active drug. Further in vivo testing of these drugs is required to determine if the lipophilic formulation also increases bioavailability and cellular uptake, and the potential benefit of conjugating the monophosphate form of cytarabine to avoid dependency on dCK activation [74]. …”

Section: Lipid-drug Conjugate Chemistrymentioning

confidence: 99%

Improving nucleoside analogs via lipid conjugation: Is fatter any better?

Alexander¹,

Kucera²,

Pardee³

2016

Critical Reviews in Oncology/Hematology

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In the past few decades, nucleoside analog drugs have been used to treat a large variety of cancers. These antimetabolite drugs mimic nucleosides and interfere with chain lengthening upon incorporation into the DNA or RNA of actively replicating cells. However, efficient delivery of these drugs is limited due to their pharmacokinetic properties, and tumors often develop drug resistance. In addition, nucleoside analogs are generally hydrophilic, resulting in poor bioavailability and impaired blood-brain barrier penetration. Conjugating these drugs to lipids modifies their pharmacokinetic properties and may improve in vivo efficacy. This review will cover recent advances in the field of conjugation of phospholipids to nucleoside analogs. This includes conjugation of myristic acid, 12-thioethyldodecanoic acid, 5-elaidic acid esters, phosphoramidate, and self-emulsifying formulations. Relevant in vitro and in vivo data will be discussed for each drug, as well as any available data from clinical trials.

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Section: Lipid-drug Conjugate Chemistrymentioning

confidence: 99%

Improving nucleoside analogs via lipid conjugation: Is fatter any better?

Alexander¹,

Kucera²,

Pardee³

2016

Critical Reviews in Oncology/Hematology

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“…32 Fatty acyl derivatives of Cyt were developed to improve cellular uptake. 33 Translocator protein (TSPO) ligand-Ara-C conjugation has been reported for the selective delivery of the antineoplastic agent to brain tumors. 34 Amino acid conjugate ValCytarabine and fatty acid derivative CP-4055 provided improved cellular uptake and generated derivatives with a longer duration of action.…”

Section: Introductionmentioning

confidence: 99%

“…Several independent researchers have also tried to address these drawbacks of Cyt by synthesizing its various prodrugs, [26][27][28][29] analogues 30 and conjugates. [31][32][33][34][35][36][37] Phospholipid-Ara-C conjugates were prepared as a prodrug of Cyt and found to be much more effective than Ara-C in vivo. 31 Conjugate of thioether phospholipid with Cyt showed stability in a micellar solution and offered substantial therapeutic benefit to mice with leukemia.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Cytarabine Lipid Drug Conjugate for Treatment of Meningeal Leukemia: Development, Characterization and <I>In</I> <I>Vitro</I> Cell Line Studies

Sharma

Dube²,

Sawant³

2012

Journal of Biomedical Nanotechnology

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Cytarabine (Cyt) used in the treatment of meningeal leukemia is associated with drawbacks like non selectivity to tumor cells, very short half-life and inability to cross blood brain barrier (BBB) due to its hydrophilic nature. Therefore, stable lipid drug conjugate (LDC) of Cyt with stearic acid was prepared. LDC was characterized by NMR, FTIR, DSC and XRD studies. Polysorbate 80 stabilized nanoparticles of this LDC (LDC-NP) were prepared using solvent injection method and characterized for size, zeta potential and loading efficiency. The LDC-NPs were loaded with appreciable amount (considering hydrophilic nature of drug, prior to conjugation) of drug conjugate (58.39 ± 4.69%). The prepared LDC-NPs had smooth surface, particle size of 136.80 ± 3.24 nm, were non-aggregated and had almost spherical and uniform shapes. In vitro release pattern showed initial fast release (14.89±0.056% in 1 h) followed by sustained release up to 72 h (76.26±0.156%). The blank stearic acid nanoparticles showed no significant cytotoxic effect on leukemic EL-4 cells and LDC-NPs were more cytotoxic than Cyt solution at 48 h. The lyophilized LDC-NPs were found to be physically stable with respect to size and zeta potential at refrigerated condition for 90 days. These results suggest that Polysorbate 80 stabilized LDC-NPs can be explored for treatment of meningeal leukemia owing to their ability of providing sustained drug release, stability and improved cytotoxicity in leukemic EL-4 cell line.

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“…The low permeability of cytarabine is due to its low membrane permeability and rapid conversion into inactive metabolite 1-b-D-arabinofuranosyl uracil. [9][10][11][12][13][14] The prodrug strategy for cytarabine involves the chemical modication or introduction of a potentiating group on parent drug. 7 These toxicity and non specic distribution oen results in chemotherapeutic failure.…”

Section: Introductionmentioning

confidence: 99%

Preparation and characterization of solid lipid nanoparticles loaded with cytarabine via a micellar composition for leukemia

Raj

Ram

2016

RSC Adv.

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Cytarabine is an anticancer drug used in hematological malignancies and lymphoma but its short biological half life demands continuous intravenous infusion or time spaced injection. This would lead to patient incompliances and discomfort. Therefore it is imperative to look for novel therapeutic systems with lesser side effects urgently to address the underlying causes of poor treatment outcomes associated with conventional therapy. Hence entrapping of cytarabine in a solid lipid nanoparticle (SLN) based formulation could be a better alternative to sustain release and improve therapeutic activity by maintaining the plasma level. We chose tristearin as solid lipid and formulated it in nanoparticulate form by an ultrasonic emulsification method. SLN formulations were optimized and characterized for various physiochemical parameters like size (below 200 nm), charge, morphology and entrapment efficiency. An in vitro drug release study through a dialysis bag revealed a prolonged release of cytarabine. A cell line study on HL60 cell showed a significantly higher efficacy of cytarabine SLN as compared to cytarabine solution. Well characterized carriers were further subjected to hemolytic toxicity. Results showed no hemolytic toxicity and good stability at ambient temperature.

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Synthesis and evaluation of fatty acyl ester derivatives of cytarabine as anti-leukemia agents

Cited by 37 publications

References 23 publications

Improving nucleoside analogs via lipid conjugation: Is fatter any better?

Improving nucleoside analogs via lipid conjugation: Is fatter any better?

Synthesis of Cytarabine Lipid Drug Conjugate for Treatment of Meningeal Leukemia: Development, Characterization and <I>In</I> <I>Vitro</I> Cell Line Studies

Preparation and characterization of solid lipid nanoparticles loaded with cytarabine via a micellar composition for leukemia

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