In vitro and in vivo anti-tumor activities of a gemcitabine derivative carried by nanoparticles

Abstract

Gemcitabine (Gemzar®) is the first line treatment for pancreatic cancer and often used in combination therapy for non-small cell lung, ovarian, and metastatic breast cancers. Although extremely toxic to a variety of tumor cells in culture, the clinical outcome of gemcitabine treatment still needs improvement. In the present study, a new gemcitabine nanoparticle formulation was developed by incorporating a previously reported stearic acid amide derivative of gemcitabine into nanoparticles prepared from lecithin/glyceryl monostearate-in-water emulsions. The stearoyl gemcitabine nanoparticles were cytotoxic to tumor cells in culture, although it took a longer time for the gemcitabine in the nanoparticles to kill tumor cells than for free gemcitabine. In mice with pre-established model mouse or human tumors, the stearoyl gemcitabine nanoparticles were significantly more effective than free gemcitabine in controlling the tumor growth. PEGylation of the gemcitabine nanoparticles with polyethylene glycol (2000) prolonged the circulation of the nanoparticles in blood and increased the accumulation of the nanoparticles in tumor tissues (> 6-fold), but the PEGylated and un-PEGylated gemcitabine nanoparticles showed similar anti-tumor activity in mice. Nevertheless, the nanoparticle formulation was critical for the stearoyl gemcitabine to show a strong anti-tumor activity. It is concluded that for the gemcitabine derivate-containing nanoparticles, cytotoxicity data in culture may not be used to predict their in vivo anti-tumor activity, and this novel gemcitabine nanoparticle formulation has the potential to improve the clinical outcome of gemcitabine treatment.

Gemcitabine versus Modified Gemcitabine: A Review of Several Promising Chemical Modifications

“…90 Tokunaga Y et al The feasibility of adding GemC18 into other particles to overcome gemcitabine resistance in cancer cells has been evaluated recently in different studies. [93][94][95] GemC18 was incorporated into lipid nanoparticles (NPs) engineered from lecithin/glycerol monostearate-in-water emulsions. 93 In vitro studies were performed with a deficient hENT1 cell line (CCRF-CEM-AraC-8C).…”

“…[93][94][95] GemC18 was incorporated into lipid nanoparticles (NPs) engineered from lecithin/glycerol monostearate-in-water emulsions. 93 In vitro studies were performed with a deficient hENT1 cell line (CCRF-CEM-AraC-8C). 94 Native gemcitabine was not able to enter the cells efficiently, but the GemC18-NPs were able to efficiently deliver the stearoyl gemcitabine into cells by endocytosis and caused apoptosis via caspase-3 activation.…”

“…96 PEGylated nanoparticles were also formulated and evaluated in vitro and in vivo with a pancreatic cancer cell line, BxPc-3. 93 In vitro, GemC18-NPs and PEG-GemC18- In a recent study, the active targeting of nanoparticles has been tested to increase the antitumour effect of the particles. For this, the epithelial growth factor (EGF) was conjugated to the particle surface to target the epidermal growth factor receptor (EGFR).…”

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

“…[177][178][179][180] For example, it was shown that conjugation of a fatty acid, such as stearic acid, to gemcitabine at the 4-N position decreases the sensitivity of the later to deaminase. 181,182 In addition, gemcitabine-fatty acid conjugates formulated into nanoparticles also become less sensitive to deamination, as they are no longer good substrates of CDAs. 182 Meng et al developed a MSNP for co-delivery of gemcitabine and paclitaxel to take advantage of paclitaxel's ability to inhibit CDA expression to increase tumor response to gemcitabine.…”

The in vitro and in vivo anti-tumor effects of MTX-Fe3O4-PLLA-PEG-PLLA microspheres prepared by suspension-enhanced dispersion by supercritical CO2

“…However, the evaluation at a cellular level is not comprehensive. For the sake of harvesting more reliable results, evaluating the effectiveness of the formulations at omnidirectional levels is necessary [18,19]. At a cellular level, evaluation has mainly involved the detection of cell apoptosis by various methods with integrated advantages [20,21].…”