This study revealed significant differences in the relative estimated PK parameters of the plasma, SC, peri-, and intratumoral zones. Additionally, this study demonstrated that the coadministration of MTX with CsA can enhance the intratumoral exposure levels of the drug, whereas coadministration of MTX with probenecid alone, or with a combination of probenecid and CsA, increases intratumoral half-life.
ABSTRACT-Purpose. Efflux and influx proteins play a major role in chemo-resistance by affecting the net cellular uptake of anti-cancer drugs. Hence, alteration of the efflux and influx protein expression may result in variations of chemotherapeutics uptake and consequently cell death rate. The present study investigated the effects of pre-treatment of capan-2 pancreatic cancer cells with calcitriol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) or silibinin on the induction of three major efflux proteins and the main gemcitabine influx protein. The influence of the pre-treatments on the net cellular uptake of gemcitabine, total ATPase activity, and cell death rate were also evaluated. Methods. Capan-2 pancreatic cancer cells were pre-treated for 24 h with calcitriol, BHT, BHA, or silibinin, followed by gemcitabine treatment. The concentration of gemcitabine was quantified using ultra-performance liquid chromatography (UPLC). Real-time polymerase chain reaction (RT-PCR) was utilized in order to investigate the expression of the mRNAs. The expression of the proteins was assessed using western blotting. Measurement of the ATPase activity was conducted utilizing a colorimetric method and viability of the cells was determined using a luminescent cell viability assay. Results. Protein expression studies showed that BHT, silibinin, and BHA increased expression of the efflux proteins and decreased the overall uptake of gemcitabine, whereas calcitriol significantly inhibited expression of the efflux proteins and increased gemcitabine uptake. Expression of specific mRNAs correlated reasonably well with the levels of corresponding proteins. Additionally, the expression of efflux proteins and ATPase activity were well correlated, signifying that the induced efflux proteins are functionally active. Moreover, pre-treatment with calcitriol resulted in a significant increase in cell death with gemcitabine treatment, whereas, BHA significantly reduced the cell death rate. On the other hand, pre-treatment with BHT and silibinin had no significant effect on the cell death rate. Conclusions. Pre-treatment of the pancreatic cancer cells with calcitriol significantly increased gemcitabine cellular uptake and consequently decreased cell viability after treatment with gemcitabine, whereas BHA significantly reduced gemcitabine uptake and decreased cell death rate, which were at least partially attributed to the alteration of expression of efflux and influx proteins.
The objective of this work was to develop uniformly distributed poly(ethylene glycol) grafted poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles of mean size range approximately 100-200 nm using ethyl acetate as the solvent. In the multiple emulsion solvent evaporation method a high pressure microfluidization process was adopted to produce the W/O/W multiple emulsion. Non-toxic ethyl acetate was used to solubilize PEG-PLGA. The mean size of nanoparticles obtained was less than 180 nm. The particle size and size distribution were dependent on the microfluidization conditions applied. Mean particle size steadily increased from 121 nm at three passes to 172 nm at 20 passes of the microfluidizer, indicating that over-processing may be detrimental to PEG-PLGA nanoparticles prepared using this technique. There was no significant alteration of the PEG-PLGA matrix, as evidenced from the differential scanning calorimetric studies.
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