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Just getting into cells is not enough: mechanisms underlying 4-(N)-stearoyl gemcitabine solid lipid nanoparticle's ability to overcome gemcitabine resistance caused by RRM1 overexpression.

ABSTRACT: Gemcitabine is a deoxycytidine analog that is widely used in the chemotherapy of many solid tumors. However, acquired tumor cell resistance often limits its use. Previously, we discovered that 4-(N)-stearoyl gemcitabine solid lipid nanoparticles (4-(N)-GemC18-SLNs) can overcome multiple acquired gemcitabine resistance mechanisms, including RRM1 overexpression. The present study was designed to elucidate the mechanisms underlying the 4-(N)-GemC18-SLNs' ability to overcome gemcitabine resistance. The 4-(N)-GemC18 in the 4-(N)-GemC18-SLNs entered tumor cells due to clathrin-mediated endocytosis of the 4-(N)-GemC18-SLNs into the lysosomes of the cells, whereas the 4-(N)-GemC18 alone in solution entered cells by diffusion. We substantiated that it is the way the 4-(N)-GemC18-SLNs deliver the 4-(N)-GemC18 into tumor cells that allows the gemcitabine hydrolyzed from the 4-(N)-GemC18 to be more efficiently converted into its active metabolite, gemcitabine triphosphate (dFdCTP), and thus more potent against gemcitabine-resistant tumor cells than 4-(N)-GemC18 or gemcitabine alone. Moreover, we also showed that the RRM1-overexpressing tumor cells were also cross-resistant to cytarabine, another nucleoside analog commonly used in cancer therapy, and 4-(N)-stearoyl cytarabine carried by solid lipid nanoparticles can also overcome the resistance. Therefore, formulating the long-chain fatty acid amide derivatives of nucleoside analogs into solid lipid nanoparticles may represent a platform technology to increase the antitumor activity of the nucleoside analogs and to overcome tumor cell resistance to them.

SUBMITTER: Wonganan P

PROVIDER: S-EPMC3683387 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Just getting into cells is not enough: mechanisms underlying 4-(N)-stearoyl gemcitabine solid lipid nanoparticle's ability to overcome gemcitabine resistance caused by RRM1 overexpression.

Wonganan Piyanuch P Lansakara-P Dharmika S P DS Zhu Saijie S Holzer Melisande M Sandoval Michael A MA Warthaka Mangalika M Cui Zhengrong Z

Journal of controlled release : official journal of the Controlled Release Society 20130406 1-2

Gemcitabine is a deoxycytidine analog that is widely used in the chemotherapy of many solid tumors. However, acquired tumor cell resistance often limits its use. Previously, we discovered that 4-(N)-stearoyl gemcitabine solid lipid nanoparticles (4-(N)-GemC18-SLNs) can overcome multiple acquired gemcitabine resistance mechanisms, including RRM1 overexpression. The present study was designed to elucidate the mechanisms underlying the 4-(N)-GemC18-SLNs' ability to overcome gemcitabine resistance. ...[more]

PMID: 23570983

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Project description:BackgroundThe gold standard measurement for recording sleep is polysomnography performed in a hospital environment for 1 night. This requires individuals to sleep with a device and several sensors attached to their face, scalp, and body, which is both cumbersome and expensive. Self-trackers, such as wearable sensors (eg, smartwatch) and nearable sensors (eg, sleep mattress), can measure a broad range of physiological parameters related to free-living sleep conditions; however, the optimal duration of such a self-tracker measurement is not known. For such free-living sleep studies with actigraphy, 3 to 14 days of data collection are typically used.ObjectiveThe primary goal of this study is to investigate if 3 to 14 days of sleep data collection is sufficient while using self-trackers. The secondary goal is to investigate whether there is a relationship among sleep quality, physical activity, and heart rate. Specifically, we study whether individuals who exhibit similar activity can be clustered together and to what extent the sleep patterns of individuals in relation to seasonality vary.MethodsData on sleep, physical activity, and heart rate were collected over 6 months from 54 individuals aged 52 to 86 years. The Withings Aura sleep mattress (nearable; Withings Inc) and Withings Steel HR smartwatch (wearable; Withings Inc) were used. At the individual level, we investigated the consistency of various physical activities and sleep metrics over different time spans to illustrate how sensor data from self-trackers can be used to illuminate trends. We used exploratory data analysis and unsupervised machine learning at both the cohort and individual levels.ResultsSignificant variability in standard metrics of sleep quality was found between different periods throughout the study. We showed specifically that to obtain more robust individual assessments of sleep and physical activity patterns through self-trackers, an evaluation period of >3 to 14 days is necessary. In addition, we found seasonal patterns in sleep data related to the changing of the clock for daylight saving time.ConclusionsWe demonstrate that >2 months' worth of self-tracking data are needed to provide a representative summary of daily activity and sleep patterns. By doing so, we challenge the current standard of 3 to 14 days for sleep quality assessment and call for the rethinking of standards when collecting data for research purposes. Seasonal patterns and daylight saving time clock change are also important aspects that need to be taken into consideration when choosing a period for collecting data and designing studies on sleep. Furthermore, we suggest using self-trackers (wearable and nearable ones) to support longer-term evaluations of sleep and physical activity for research purposes and, possibly, clinical purposes in the future.

Dataset Information

Just getting into cells is not enough: mechanisms underlying 4-(N)-stearoyl gemcitabine solid lipid nanoparticle's ability to overcome gemcitabine resistance caused by RRM1 overexpression.

Publications

Just getting into cells is not enough: mechanisms underlying 4-(N)-stearoyl gemcitabine solid lipid nanoparticle's ability to overcome gemcitabine resistance caused by RRM1 overexpression.

Similar Datasets

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