# Curcumin Innovative Delivery Forms: Paving the Yellow Brick Road' of Antitumoral Phytotherapy
## 4 Innovative Curcumin Formulations and High-Performance Delivery Forms
### Transdermal Administration  
#### 4.4.1 Curcumin Topical Formulations with Liposomes, Microemulsions, and Polymeric Nanoparticles  
The delivery of curcumin across the skin is of enormous interest not only to the cosmetic industry, due to its anti-inflammatory and rejuvenating properties [201], but also in skin cancer prevention, as demonstrated by various studies with skin cancer models [202; 203; 204; 205; 206]. In transdermal delivery formulations of curcumin, the liposome strategy is fine-tuned to afford liposome variants such as the \"ethosomes\", containing ethanol to convey flexibility and to act as permeability enhancer [207; 208], the propylene glycol liposomes (PegLs), also quite flexible but without the volatility issues associated with ethanol [209] and the \"invasomes\", containing a small number of terpen (0.5 to 1.5%). terpen are known to increase diffusivity and partitioning into the skin by disturbing its lipid bilayers [210]. A study comparing PegLs, ethosomes and plain liposomes for curcumin delivery to the skin showed that the PegLs were the best formulation, with superior results in the curcumin loading ability (ca. 93%), the transdermal delivery ratio and curcumin local action, followed by ethosomes and lastly by plain liposomes [211]. Curcumin invasomes were prepared using different terpen (limonene, fenchone, or neradinol) and HPBCD, to assure a high loading (90%) and tested with an ex vivo skin model (from rat abdominal skin), showing that limonene was the most adequate enhancer for the permeation of curcumin [211]. Formulations containing high amounts of terpenes formed microemulsions due to the oils nature of these compounds. The performance of curcumin microemulsions having 5% or more of limonene, 1,2-cineole or \(\alpha\)-terpineol was studied on skin excised from neonate pigs [212]. Once more, limonene proved to be the most adequate penetration enhancer for curcumin.  
Another strategy for increasing skin permeability of liposomes is to coat their surface with cell-penetrating peptides (CPPs) by means of a conjugation reaction. CPPs are short peptides, generally not exceeding 30 residues, having both the capacity to ubiquitously cross cellular membranes and very limited toxicity. In comparison with permeation of pure curcumin, CPP-coated liposomes carrying curcumin were able to increase the permeation efficacy by 7-fold, whereas the same liposomes without coating only afforded a 2-fold increase. Distribution and deposition of curcumin following its release from the carriers on mouse skin was also studied. CPP-coated liposomes afforded the highest curcumin content in both dermis and epidermis layers (7.0 and 3.5 ug respectively), followed by conventional liposomes and curcumin solution only (Figure 3). The liposomes coated with CPP are thus a good solution for delivering curcumin in high amounts and helping it reach the deep layers of the skin [213].  
Curcumin nanogels for transdermal delivery are also reported. Developed from chitin particles with an average size of 70-80 nm, nanogels offer a good transdermal delivery capacity and the promise of a simple topic formulation for the treatment of melanoma [214]. In vitro studies have demonstrated specific inhibition of the growth of human melanoma cells (A375) with low activity against the non-tumoral human dermal fibroblast cell line (HDF).