Synthesis and in vitro assessment of novel water‐soluble dextran‐docetaxel conjugates as potential pH sensitive system for tumor‐targeted delivery

Abstract

Docetaxel is a potent taxane agent mostly used in breast, lung, and prostate cancers. Its low water solubility is the major drawback that leads to use of Tween 80 as surfactant and ethanol as solvent in market formulation. But, these excipients cause severe hypersensitivity reactions. In this study, docetaxel was conjugated to biocompatible polymer, dextran 70 kDa, via a pH sensitive linker to enhance solubility and diminish the need of surfactants. Folic acid was also conjugated to dextran to provide targeted delivery. Synthesized conjugates were examined for solubility, hemo‐compatibility, stability, and cytotoxicity on MCF‐7 and MDA‐MB‐231 cell lines. Results showed about 1200‐fold enhancement in water solubility by dextran and 280‐fold by dextran‐folate conjugation. Conjugates released the drug in a pH‐dependent manner and faster hydrolysis was observed in pH 5.4 than physiological pH 7.4. Docetaxel‐dextran conjugates showed proper hemo‐compatibility and presented greater cytotoxicity than docetaxel solution. Higher cytotoxicity was seen in folate conjugated samples and the final conjugates targeted by folate would be suitable novel substitutions for currently marketed formulation. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 45457.

Targeted co‐delivery of paclitaxel and anti P‐gp shRNA by low molecular weight PEI decorated with L‐3,4‐dihydroxyphenylalanine

“…The results of drug release experiments showed that the release pattern would be associated with pH‐responsive breakage of the ester bond resulting in the release of PTX from the conjugates. The same pattern was also observed in the previous investigations on the conjugation of PTX to dextran 30,49 . In order to compare the dissolution pattern of the free drug (PTX) with the conjugated forms, the free drug was also evaluated at the different pH values.…”

“…Previous studies with docetaxel and cabazitaxel have shown similar peaks for methylene of succinate at 2.7-3.2 ppm. 27,30 In the second and third steps, the LMW PEI was conjugated with PTX-SUC and LD, respectively, and utilized as a targeted carrier for the delivery of PTX.…”

“…The amount of PTX in the conjugate was determined by a previously reported method with minor modification 30 . Briefly, a defined amount of conjugate was dispersed in 2 ml basic solution (pH 9) and stirred for 3 h. Then, 6 ml acetonitrile was added to the mixture and vortexed for 30 min to extract PTX.…”

“…PTX content was determined by the HPLC method as described earlier. Each experiment was carried out in triplicate 30 …”

“…The amount of PTX in the conjugate was determined by a previously reported method with minor modification. 30 Briefly, a defined amount of conjugate was dispersed in 2 ml basic solution (pH 9) and stirred for 3 h. Then, 6 ml acetonitrile was added to the mixture and vortexed for 30 min to extract PTX. Finally, 50 μl of the solution was analyzed by HPLC to determine the concentration of the drug that was conjugated to LMW PEI using the standard curve of PTX.…”