Abstract
Paclitaxel is effective against a wide range of cancers which are considered to be refractory to conventional therapy. It is hydrophobic and thus its solubility in an aqueous medium is poor. Therefore, several approaches have been investigated to enhance the therapeutic potential of paclitaxel in order to overcome the associated problems. Cisplatin has been broadly used anticancer agent for treatment of various types of cancer. However, the efficacy of this chemotherapeutic drug is weak by drug resistance in the advanced stage of the cancer. On the other hand, cisplatin in combination with other agents would be useful for effective treatment of cancer. Curcumin is the yellow pigment found in the Indian spice curry and extensively used in human diet. It has broad biological and pharmacological functions, and it is a candidate to design potential therapeutic strategies for treatment of cancer. In the present study, novel drug delivery formulations were designed in order to enhance therapeutic activity of well-known chemotherapic molecules paclitaxel, cisplatin and curcumin. Further, combination effect curcumin with toxic anticancer molecules paclitaxel and cisplatin was also investigated. Firstly, the novel L-glutamic acid derivative of β-cyclodextrin (CD-Glu) was designed and paclitaxel complex of CD-Glu was investigated to improve its water-solubility, stability and bioactivity for therapeutic applications. The new paclitaxel/CD-Glu complexation was tested on four cancer models; ovarian, lung, prostate and breast cancers. Cell viability, Annexin V apoptotic and colony formation assays showed that CD-Glu encapsulation significantly enhances the cytotoxicity of paclitaxel. Secondly, a novel drug nano-carrier system was formulated by encapsulating curcumin and paclitaxel in poly(β-cyclodextrintriazine) (PCDT) for the therapy of four cancer models; ovarian, lung, prostate and breast cancers. Cell viability, colony formation and Annexin V apoptotic studies revealed improved curcumin cytotoxicity upon complexation. Moreover, a synergism was found between curcumin and paclitaxel, particularly when complexed with PCDT on A2780, SKOV-3 and H1299 cancer cell lines. Finally, a novel oleic acid coupled poloxamer (POA) hydrogel is synthesized to enhance chemotherapeutic effects of curcumin and cisplatin. Cell viability, colony formation and Annexin V apoptosis assays revealed that amphiphilic and thermosensitive POA hydrogel robustly augments the cytotoxicity of cisplatin in three cancer models; ovarian, lung and prostate cancer. In addition, a synergism was determined between cisplatin and curcumin, in particular when formulated with POA hydrogel on A2780 and H1299 cell lines.