Enhanced Antitumor Activity of Monophosphate Ester Prodrugs of Gemcitabine: In Vitro and In Vivo Evaluation

Qi, Huixin; Lu, Jia; Li, Jiajun; Xu, Yunting; Wang, Yedong; Zhang, Hongjian

doi:10.1016/j.xphs.2016.02.006

Cited by 17 publications

(11 citation statements)

References 18 publications

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“…Further, poor therapeutic outcomes have also been attributed to the systemic biochemical instability of the drugs [ 14 ]. Metabolism and rapid elimination of Gem significantly affect its bioavailability [ 15 ]. Cytidine deaminase is widely reported to rapidly convert Gem to 2’,2’- difluoro-deoxyuridine (dFdU) especially in the liver and to a lesser extent in plasma [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Smart thermosensitive liposomes for effective solid tumor therapy and in vivo imaging

et al. 2017

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In numerous studies, liposomes have been used to deliver anticancer drugs such as doxorubicin to local heat-triggered tumor. Here, we investigate: (i) the ability of thermosensitive liposomal nanoparticle (TSLnp) as a delivery system to deliver poorly membrane-permeable anticancer drug, gemcitabine (Gem) to solid pancreatic tumor with the aid of local mild hyperthermia and, (ii) the possibility of using gadolinium (Magnevist®) loaded-TSLnps (Gd-TSLnps) to increase magnetic resonance imaging (MRI) contrast in solid tumor. In this study, we developed and tested gemcitabine-loaded thermosensitive liposomal nanoparticles (Gem-TSLnps) and gadolinium-loaded thermosensitive liposomal nanoparticles (Gd-TSLnps) both in in-vitro and in-vivo. The TSLnps exhibited temperature-dependent release of Gem, at 40–42°C, 65% of Gem was released within 10 min, whereas < 23% Gem leakage occurred at 37°C after a period of 2 h. The pharmacokinetic parameters and tissue distribution of both Gem-TSLnps and Gd-TSLnps were significantly greater compared with free Gem and Gd, while Gem-TSLnps plasma clearance was reduced by 17-fold and that of Gd-TSLpns was decreased by 2-fold. Area under the plasma concentration time curve (AUC) of Gem-TSLnps (35.17± 0.04 μghr/mL) was significantly higher than that of free Gem (2.09 ± 0.01 μghr/mL) whereas, AUC of Gd-TSLnps was higher than free Gd by 3.9 fold high. TSLnps showed significant Gem accumulation in heated tumor relative to free Gem. Similar trend of increased Gd-TSLnps accumulation was observed in non-heated tumor compared to that of free Gd; however, no significant difference in MRI contrast enhancement between free Gd and Gd-TSLnps ex-vivo tumor images was observed. Despite Gem-TSLnps dose being half of free Gem dose, antitumor efficacy of Gem-TSLnps was comparable to that of free Gem(Gem-TSLnps 10 mg Gem/kg compared with free Gem 20 mg/kg). Overall, the findings suggest that TSLnps may be used to improve Gem delivery and enhance its antitumor activity. However, the formulation of Gd-TSLnp needs to be fully optimized to significantly enhance MRI contrast in tumor.

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Section: Introductionmentioning

confidence: 99%

Smart thermosensitive liposomes for effective solid tumor therapy and in vivo imaging

et al. 2017

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“…Development of prodrugs follows similar research and regulatory paths to a typical small-molecule new chemical entity, except that a prodrug requires “activation” step(s) to release its active moiety. As described previously, Compound- 3 is a promising gemcitabine prodrug with oral antitumor activity [ 11 ]; subsequent studies have been carried out to support its development. Results from the present study indicated that alkaline phosphatase may be an important enzyme in the activation of Compound- 3 , a monophosphate prodrug of gemcitabine.…”

Section: Discussionmentioning

confidence: 99%

“…MS/MS quantitation was conducted using an API 4000 Qtrap mass spectrometer operated in the electrospray ionization positive mode with multiple reaction monitoring (MRM) to detect analytes and internal standards with a dwell time set to 100 milliseconds. The ion transitions monitored were Compound- 3 , 640.5 (M + H) → 246.0; Compound- 2 (internal standard for Compound- 3 ) [ 11 ], 652.5 (M + H) → 344.1; M2, 656.3 (M + H) → 246.0; M3, 654.3 (M + H) → 246.0; M4, 670.3 (M + H) → 246.0; pafuramidine, 365.2 (M + H) →334.2; DB775 (metabolite of pafuramidine formed by CYP4F2) 351.1 (M + H) → 320.1; gemcitabine, 264.2 (M + H) → 112.0; diazepam (internal standard for pafuramidine and gemcitabine), 285.2 (M + H) → 193.2. Mass transition, collision energy and all other parameters were optimized for the best sensitivity.…”

Section: Methodsmentioning

confidence: 99%

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Involvement of CYP4F2 in the Metabolism of a Novel Monophosphate Ester Prodrug of Gemcitabine and Its Interaction Potential In Vitro

Wang

et al. 2018

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Compound-3 is an oral monophosphate prodrug of gemcitabine. Previous data showed that Compound-3 was more potent than gemcitabine and it was orally active in a tumor xenograft model. In the present study, the metabolism of Compound-3 was investigated in several well-known in vitro matrices. While relatively stable in human and rat plasma, Compound-3 demonstrated noticeable metabolism in liver and intestinal microsomes in the presence of NADPH and human hepatocytes. Compound-3 could also be hydrolyzed by alkaline phosphatase, leading to gemcitabine formation. Metabolite identification using accurate mass- and information-based scan techniques revealed that Compound-3 was subjected to sequential metabolism, forming alcohol, aldehyde and carboxylic acid metabolites, respectively. Results from reaction phenotyping studies indicated that cytochrome P450 4F2 (CYP4F2) was a key CYP isozyme involved in Compound-3 metabolism. Interaction assays suggested that CYP4F2 activity could be inhibited by Compound-3 or an antiparasitic prodrug pafuramidine. Because CYP4F2 is a key CYP isozyme involved in the metabolism of eicosanoids and therapeutic drugs, clinical relevance of drug-drug interactions mediated via CYP4F2 inhibition warrants further investigation.

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“…The cells were injected into the fourth, right, inguinal mammary fat pad. Mice were randomly divided into four groups and biweekly intraperitoneal injection of 0.9% saline, methotrexate (50 mg/kg) [ 36 ], gemcitabine (80 mg/kg) [ 37 ], or the combination of methotrexate and gemcitabine began once tumor volume reached ∼50 mm 3 . Tumor volume was measured biweekly using digital calipers (Traceable) and calculated as (width 2 × length)/2 = mm 3 [ 21 , 38 ].…”

Section: Methodsmentioning

confidence: 99%

CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues

et al. 2017

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The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint activated by oncoproteins. Since CKS overexpression and oncoprotein activation/overexpression are often observed in the same tumors, we have hypothesized that CKS-mediated checkpoint override could enhance the ability of premalignant cells experiencing oncoprotein-induced replication stress to expand. This tumor advantage, however, could represent a vulnerability to exploit therapeutically. Here, we first show in vitro that CKS protein overexpression selectively sensitizes tumor-derived cell lines to nucleoside analog-mediated toxicity under replication stress conditions. A treatment combination of the nucleoside analog gemcitabine and an agent that induces replication stress (thymidine or methotrexate) resulted in selective targeting of CKS protein-overexpressing tumor-derived cells while protecting proliferative cells with low CKS protein levels from gemcitabine toxicity. We validated this strategy in vivo and observed that Cks2-overexpressing mammary tumors in nude mice were selectively sensitized to gemcitabine under conditions of methotrexate-induced replication stress. These results suggest that high CKS expression might be useful as a biomarker to identify subgroups of cancer patients who might benefit from the described therapeutic approach.

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Enhanced Antitumor Activity of Monophosphate Ester Prodrugs of Gemcitabine: In Vitro and In Vivo Evaluation

Cited by 17 publications

References 18 publications

Smart thermosensitive liposomes for effective solid tumor therapy and in vivo imaging

Smart thermosensitive liposomes for effective solid tumor therapy and in vivo imaging

Involvement of CYP4F2 in the Metabolism of a Novel Monophosphate Ester Prodrug of Gemcitabine and Its Interaction Potential In Vitro

CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues

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