Preparation Of A Solid Dispersion Of Curcumin Derivative C086and Study Of Its Antitumor Activities

Object To improve the solubility of curcumin derivative C086by preparing a suitablesolid dispersion(SD) and study the pharmacokinetic of C086SD in mice andits antitumor activities in vitro and in vivo.Methods1. Using polyvinylpyrrolidone (PVPk30) as the carrier,C086SD was prepared bysolvent evaporation method.Its physicochemical properties were investigated.2. Mice were respectively intravenously and intragastrically administrated C086SDsolution at the dose of100mg/kg and the blood drug concentrations changing overthe time were studied.3. MTT assay was used for detecting the effects of proliferation inhibition of C086SDon K562,HL60,HCT116,SW620,HepG2,NCI-H1975tumor cell lines.4. Western blot was used to detect the related proteins level of PI3K-Akt,Ras-Raf-MAPK and apoptosis pathway in SW620after expoxing to C086SD for24h.5. SW620human colon cancer xenograft tumor model was established in nude miceto evaluate the antitumor activity of C086SD in vivo.6. Western blot was used to analyze the related protein level of Akt, P-Akt, Erk, P-Erkin SW620nude mice xenograft tumor.Results1. The solubility of C086was significantly improved by the solid dispersion in whichC086existed as amorphous or molecucar state.The in vitro dissolution rates ofC086from all solid dispersions were larger than the pure drug and higer carrier-C086ratio led to faster drug dissolution.2. C086SD were administrated at the dose of100mg/kg. For the intragastricaladministration group,the blood drug concentrations were almost close to or belowthe lowest limit of quantification so that we can not obtain complete concentration-time cure. For the intravenous administration group, the pharmacokinetic was inaccordance with open bicameral model.the distribution and elimination half timewere5.445min and49.57min. 3. C086crude drug and C086SD could inhibit the growth activity of different tumorcell lines with a concentration-dependent maner, and the effect of crude drug ismore powerfull than SD.4. C086SD can inhibit the proliferation of SW620and induce its apoptosis throughdownregulating the related proteins of PI3K/Akt,Ras/Raf/MAPK and apoptosispathway.5. Results using a SW620tumor xenograft model in nude mice showed that100mg/kg/d and200mg/kg/d C086SD alone administrated intragastrically respectivelyobtain tumor volume inhibition rates of52.69%,67.66%without loss of bodyweight,while100mg/kg/d alone administrated intravenously C086SD only reachedan inhibition rate of22.69%.6. Western blot results showed that the protein levels of Akt,P-Akt,P-Erk in theSW620colon cell xenograft tumor in nude mice redused after being treated byC086SD intragastrtrically administrated.Conclusions1. The solubility of C086was significantly increased after being prepared to soliddispersion and the dissolution in vivro was fast.2. C086SD had a low bioavailability because of poor absorption or quick metabolismafter intragastrical administration and it was rapidly distributed and eliminated afterintravenous administration.3. C086SD can inhibit the proliferations of different tumor cell lines.The effect ofgrowth inhibition of C086SD on SW620was in connection with the blocking ofPI3K/Akt,Ras/Raf/MAPK survival signal pathway and the activation of apoptosispathway.4. C086SD had a significant inhibition on the growth of SW620nude mice tumorxenograft tumor after intragastrical administration, while it showed poor tumorinhibition rate after iv a same dose with intragastrical administration. The revitaliteof C086in intestinal was considered to explain the difference of antitumor effect.