# Curcumin Innovative Delivery Forms: Paving the Yellow Brick Road' of Antitumoral Phytotherapy
## 4 Innovative Curcumin Formulations and High-Performance Delivery Forms
### Curcumin Prodrugs and Metal Complexes
[(bpy-9)Zn(curcumin)]BF\({}_{4}\), a cationic derivative, was also very active against the SH-SYSY neuroblastoma cell line [243]. A palladium analogue, [(bpy-9)Zn(curcumin)]CF\({}_{3}\)SO\({}_{3}\), was tested successfully on prostate cancer cells (LNCaP, PC3, and DU145) having IC\({}_{50}\) values in the 20-24 uM range [248]. Curcumin palladium complexes bearing cyclohexane-diamine derivatives as the spectator ligand were developed for colon cancer treatment, having IC\({}_{50}\) values in the 10-34 uM range against the cell lines DLD-1, HT-29 and CRL-1790 [250]. Curcumin ruthenium(II) organometallic complexes obtained from precursors that share a common \"piano-stool\" geometry are represented in Figure 4 [251; 252; 253]. The arena that comprises the \"top\" of the piano stool was either a hexamethylbenzene or a \(p\)-cymene. Curcumin coordinated at the positions of two of the legs and the third leg was a chloride, in some instances replaced by 1,3,5-triaza-7-phospho-adamantane (PTA) for higher aqueous solubility. The complexes with PTA displayed the most promising activities, being able to inhibit the growth of breast cancer A2780 cells (both cisplatin-sensitive and cisplatin-resistant lines) at sub-micromolar concentrations [251]. Their IC\({}_{50}\) on these cell lines were 0.4 uM, approximately ten times lower than pure curcumin (IC\({}_{50}\) = 4.3 uM). Safety was evaluated on a healthy embryonic kidney cell line, HEK293. Ru(hexamethylbenzene)(curcumin)(PTA) had an IC\({}_{50}\) value of 4.3 uM against this cell line while for Ru(\(p\)-cymene)(curcumin)(PTA) IC\({}_{50}\) was 9.1 uM [251]. The activity of Ru(\(p\)-cymene)(curcumin)Cl was inferior or equal to that of curcumin on the tested cancer cell lines [252]. Analogues of curcumin arene complexes can be obtained by replacing the arena with the heterocyclic moiety of 1,4,7-tritiacyclononane (abbreviated as [9]ansS\({}_{3}\)), to afford complexes with higher polarity and thus better compatibility with aqueous media. The complex [Ruthenium(II) (curcumin([9]aneS\({}_{3}\))DMSO)Cl was reported as a strong DNA-binding agent, with higher affinity than pure curcumin [254]. Cytotoxicity against the PC-3 prostate cancer cell line was, however, not observed at concentrations as high as 80 mM. This suggests that cell-penetrating abilities of the complex need to be ameliorated. Two ruthenium polypyridyl complexes with curcumin, with the formulae [Ruthenium(II) (curcumin)(bpy)(N,N\"-Lig)]Cl, where N,N'-Lig = 2,2'bipyridine (bpy) or dppn (benzo-[i]dipyridylo [3,2-a:2',3'-c]phenazine), were recently reported [255]. Despite being cationic, the complexes were lipophylic, with log \(p\) values of 0.75 for the one with two bipyridines and 1.06 for the one with dppn. The in vitro inhibitory activity was evaluated on the A549 human non-small-cell lung cancer line, the MCF-7 human breast adenocarcinoma cell line and the SGC7901 human gastric cancer cell line, with the dppn-bearing complex having exhibited higher activity: IC\({}_{50}\) values were within the 2.1 \(\pm\) 0.2 to 2.7 \(\pm\) 0.2 uM range. Compared to curcumin and cisplatin, which inhibited the same cell lines with IC\({}_{50}\) values of 11.4 \(\pm\) 0.3 to 15.4 \(\pm\) 1.0, the complex is quite more potent. Additional biomolecular studies on the A549 line have shown that the mode of action of the complexes involves apoptosis. Figure 4: Synthesis and structure Ru(II) arene curcumin complexes, with R = hexamethylbenzene or \(p\)-cymene, and X = Cl or 1,3,5-triaza-7-phospho-adamantane (PTA).