# 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  
Curcumin metabolization occurs, as described in Section 2.2.1, mainly by conjugation at its phenolic hydroxyl groups. This way, curcumin is often functionalized at these two positions to form derivatives with improved physico-chemical, biological, and pharmacokinetic properties [228; 229]. A useful strategy is to design curcumin prodrugs that are able to prevent metabolization. This is achieved by protecting the hydroxyls with functional groups such as amino acids, small carboxylic acids [230; 231; 232] and even nucleotides [233]. The prodrugs curcumin maleoyl valinate and curcumin maleoyl glycinate were tested against human bladder cancer EJ cells, having shown dose- and time-dependent inhibition [231]. The toxic side effects on healthy human renal proximal cells (HKC) were considerably lower in comparison with pure curcumin. succinate prodrugs of curcumin with good cytotoxicity against colon adenocarcinoma (Caco-2 cell line) were also reported, with highlight to curcumin diethyl disuccinate, having an IC\({}_{50}\) of 1.9 uM [232]. Conjugation of curcumin with an oligonucleotide chain complementary to a sequence of telomerase RNA allows targeting this specific cellular function [234]. Human prostrate tumor cells (DU145) were transfected with this 5\({}^{\prime}\)-\(O\)-curcumin DNA prodrug but the antiproliferative action was very slow (20% cell survival after 75 days). Another class or curcumin prodrugs comprises nanocarriers. These are obtained by functionalizing the phenolic hydroxyls with oligomers or polymers using linkers that are hydrolyzed in vivo by enzymes or pH [235; 236; 237]. The prodrugs aggregate into nanoparticles, forming a carrier system. Curcumin oligo(ethylene glycol) nanoparticles were shown to reduce the size of intraperitoneal SKOV-3 tumors and subcutaneous (mammary fat pad) MDA-MB-468 tumors in xenografted mice [235]. Additionally, nanocarriers made of biocompatible aluminosilicate clays were reported [238]. These materials are named halloysite nanotubes due to their hollow tubular structure. Curcumin is linked to them by a cysteamine arm, hydrolysate at the disulfide bond. This carrier system can thus be considered a prodrug. In vitro studies with two hepatic carcinoma cell lines showed good cytotoxic activity. At 48 h and using a dose of 50 uM, cell viability rates were low, 22% and 16% for Hep3B and HA22T/VGH, respectively, and at the dose of 100 uM zero viability for the Hep3B line was observed (also after 48 h). Curcumin coordination to a metal center brings advantages to the solubility and stability (both redox and to light). This is very helpful for the biological activity, and positive results have been reported in a varied range of actions, not only with antitumor compounds, but also with reports of better antioxidant and anti-inflammatory agents and even of new complexes to be used in the treatment of [PERSON]'s disease [239]. The preparation of metal complexes with curcumin typically involves deprotonating curcumin in a first step to form a stable enol form [240]; then, an appropriate molar ratio of curcuminate is made react with a metal precursor. Suitable precursors include halogenates of zinc(II) [241; 242; 243; 244], calcium(II) [244] and iron(III) [244; 245], acetates of copper(II) [246; 247], palladium(II) [248] and nickel(II), or vanadyl bis(acetylacetonate), VO(acac)\({}_{2}\)[249]. The VO(curcuminate)\({}_{2}\) complex was very successful in inhibiting mouse lymphoma cells (L1210), with an IC\({}_{50}\) of ca. 15 uM. It was, however, also toxic towards rat smooth muscle cells (CRL-1444), with an IC\({}_{50}\) of 2.9 uM [249]. Curcumin zinc complexes with dinonyl-2,2\({}^{\prime}\)-bipyridine (bpy-9) and 4\(A^{\prime}\)-bis(hydroxymethyl)-2,2\({}^{\prime}\)-bipyridine as the spectator ligands presented good inhibitory action on the prostate cancer cell lines DU145, PC3, and LNCaPP, and the neuroblastoma SHSY-5Y and SD LAN-5 lines, with IC\({}_{50}\) values in the 12-37 uM range at 72 h [242].