Methotrexate (MTX) is a folic acid antagonist used as an effective drug to treat various kinds of cancers. However, MTX has limited use in cancer chemotherapy due to its adverse effects such as poor bioavailability, low specificity, drug resistance, and dose-dependent side effects. To improve lymphatic delivery and reduce toxicity of MTX, MTX-loaded nanoparticles (NPs) were prepared in the present study. NPs were prepared with double emulsion solvent evaporation method using poly(lactide-co-glycolide) (PLGA). NPs were assessed for size, encapsulation efficiency, morphology, Fourier-transform infrared spectroscopy, X-ray diffraction, and thermal characterization. In vitro release profiles and cytotoxicity of these NPs were also evaluated. Prepared NPs and free MTX were administered orally or intravenously (5 mg/kg as MTX) to rats to evaluate their pharmacokinetic characteristics and lymphatic delivery effects. Mean particle size and encapsulation efficiency of NPs were 163.7 ± 10.25 nm and 93.3 ± 0.5%, respectively. Prepared NPs showed a sustained release profile of MTX in vitro and may be effective to cancer cells. Area under the blood concentration-time curve, total clearance, half-life, and lymphatic targeting efficiency were significantly different (p < 0.05) between prepared NPs and free MTX. These results demonstrate that MTX-loaded PLGA NPs are good candidates for targeted delivery of MTX to the lymphatic system.

Methotrexate, which is widely used in the treatment of cancer and immune-related diseases, has limitations in use because of its low bioavailability, short half-life, and tissue toxicity. Thus, in this study, a nano-sized water-in-oil-in-water (W/O/W) double emulsion containing methotrexate was prepared to enhance its lymphatic delivery and bioavailability. Based on the results from solubility testing and a pseudo-ternary diagram study, olive oil as the oil, Labrasol as a surfactant, and ethanol as a co-surfactant, were selected as the optimal components for the nanoemulsion. The prepared nanoemulsion was evaluated for size, zeta potential, encapsulation efficiency, pH, morphology, and in vitro release profiles. Furthermore, pharmacokinetics and lymphatic targeting efficiency were assessed after oral and intravenous administration of methotrexate-loaded nanoemulsion to rats. Mean droplet size, zeta potential, encapsulation efficiency, and pH of formulated nanoemulsion were 173.77 ± 5.76 nm, −35.63 ± 0.78 mV, 90.37 ± 0.96%, and 4.07 ± 0.03, respectively. In vitro release profile of the formulation indicated a higher dissolution and faster rate of methotrexate than that of free drug. The prepared nanoemulsion showed significant increases in maximum plasma concentration, area under the plasma concentration-time curve, half-life, oral bioavailability, and lymphatic targeting efficiency in both oral and intravenous administration. Therefore, our research proposes a methotrexate-loaded nanoemulsion as a good candidate for enhancing targeted lymphatic delivery of methotrexate.

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With the current advance in nanotechnology, the development has accelerated of a number of nanoparticle-type drugs such as nano-emulsions, lipid emulsions, liposomes, and cell therapeutics. With these developments, attempts are being made to apply these new drugs to healing many intractable diseases related to antibody production, autoimmune disorders, cancer, and organ transplantation in both clinical and nonclinical trials. Drug delivery to the lymphatic system is indispensable for treating these diseases, but the core technologies related to the in vivo distribution characteristics and lymphatic delivery evaluation of these particle-type drugs have not yet been established. Additionally, the core technologies for setting up the pharmacotherapeutic aspects such as their usage and dosages in the development of new drugs do not meet the needs of the market. Therefore, it is necessary to consider dividing these particle-type drugs into soft-lipid nanoparticles that can change size in the process of body distribution and hard-lipid nanoparticles whose surfaces are hardened and whose sizes do not easily change in vivo; these soft- and hard-lipid nanoparticles likely possess different biodistribution characteristics including delivery to the lymphatic system. In this review, we summarize the different types, advantages, limitations, possible remedies, and body distribution characteristics of soft- and hard-lipid nanoparticles based on their administration routes. We also emphasize that it will be necessary to fully understand the differences in distribution between these soft- and hard-lipid nanoparticle-type drugs and to establish pharmacokinetic models for their more ideal lymphatic delivery.

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Hypoxia-induced epithelial-mesenchymal transition (EMT) has been identified as essential for tumor progression and metastasis. The present study examined the effects of an antioxidant, dieckol, on hypoxia-induced EMT in HT29 human colorectal cancer cells. HT29 cells were treated with a hypoxia-inducing agent, CoCl2, and an increase in the levels of intracellular reactive oxygen species (ROS) and various morphological changes, such as loss of cell-cell contact and aggressive cell migration were observed. CoCl2 also induced an increase in the expression of hypoxia-inducible factor 1α (HIF1α) and various mesenchymal-specific markers, including vimentin and snail family transcriptional repressor 1 (Snail1), and a decrease in the expression of E-cadherin, thus suggesting that CoCl2 induced EMT in HT29 cells. Conversely, the CoCl2-induced EMT of HT29 cells was suppressed following treatment with dieckol. In addition, ROS generation, EMT marker protein expression and intracellular localization, cell migration and cell invasion were attenuated following dieckol treatment. The findings of the present study suggested that dieckol may inhibit hypoxia-induced EMT in HT29 cells by regulating the levels of cellular ROS and protein expression levels downstream of the HIF1α signaling pathway. Therefore, dieckol has the potential to become an attractive therapeutic agent for the treatment of colorectal cancer.

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