Development and evaluation of PLGA-S S-PEG micelles coencapsulating curcumin difluorinated and paclitaxel for synergistic therapeutic efficacy

Solid tumors like pancreatic tumor has unique property of forming a dense desmoplastic layer around the tumor cells making it difficult for the drug to transport across this layer. Multi drug resistance is also one of the major limitation of chemotherapy. Therefore the aim of this project was to make PLGA-SS-PEG micelles encapsulating CDF and paclitaxel for synergistic cancer therapy. CDF was found to have 16-fold better half-life when compared to curcumin maintaining equivalent bioactivity. Since CDF has chemosensitizing property we tested this by incorporating CDF and paclitaxel in same formulation and tested their synergy on BXPC3 pancreatic cancer cell line and SKOV3 ovarian cancer cell line that is paclitaxel resistant. Here we utilized a number of techniques including incorporation of PEG surface molecules thereby avoiding uptake by monophagocytic system and cysteine protease liable conjugation of PEG to the micelles making CDF and paclitaxel release specific to tumor tissue by enhanced permeation and retention effect. All the micelle formulations were below 200 nm size range. Our drug release study proved that these micelles undergo a fast sheddable process upon encountering the reduction sensitive condition like higher glutathione (GSH) levels. Cell cytotoxicity studies revealed the copolymer has good biocompatibility and self-assembled micelles showed drug loading of around 9 % for both the drugs and they released the drug quantitatively in response to the level of GSH. The synergistic effect was studied by Chou-Talalay method. There was a time and concentration dependent cell killing. Maximum synergy was observed at 72 h time point for BXPC3 cells and SKOV3 cells at 72 h time point with PLGA-S-S-PEG micelles coencapsulating both CDF and paclitaxel. The micelle formulation has higher synergy than compared to free drug combination in both cell lines at 72 hour time point. Overall IC50 values of both CDF and paclitaxel were reduced when used in combination. Based on the results of our study it indicates that these micelles have a potential promote tumor penetration because of smaller size, prolonged circulation and EPR effect and release the drug specifically in tumor cells upon exposure to highly reductive environment. Since these micelles incorporated two drugs they will be efficient for chemotherapy in multi drug resistant tumors.