Historically a component of Indian Ayurvedic medicine since 1900 BC, turmeric has been widely used to treat a wide variety of ailments. The biological activities of turmeric are attributed to the active component, curcumin. Therapeutic indications of curcumin include antibacterial, anti-inflammatory, hypolipidemic, hepatoprotective, powerful antioxidant, antiangiogenic, anticancer and many more. Curcumin today occupies a unique global niche as "A Wonder Molecule".

Delivery of curcumin in therapeutically relevant concentration poses serious challenges. Poor bioavailability of the drug is complicated by a number of features like low solubility, poor absorption, high first-pass, high rate of intestinal metabolism and rapid elimination. While chemical modification of curcumin has been attempted and includes organo-metallo chelates, pro drugs, DNA conjugates and curcumin polymers (polycurcumin); these studies are still in their early stages. Aggressive research in delivery strategies for curcumin has become an important part of pharmaceutical development.

Complexes of curcumin with proteins, polysaccharides, cyclodextrins and cyclodextrin derivatives and solid dispersions in polyvinyl pyrrolidone K30, etc have shown marked improvement in solubility and pharmacokinetic behaviour. The limitation was degradation of curcumin during processing. Complexes of curcumin with phospholipids (Meriva) showed three-fivefold enhancement in bioavailability, while co-administration of curcumin with piperine, revealed an increase in bioavailability to 154% in rats and almost 2000% in humans. Curcumin dispersed in turmeric oil (Biocurcumax®-BCM-95) has shown even better bioenhancement. CURCU-GELTM Softsules containing BCM-95® is currently under phase II clinical trials, for oral pre malignant lesions/cervical cancer.

Nano Drug Delivery Systems (DDS) of curcumin have been extensively evaluated for various applications. In this article we highlight the various nano delivery approaches and the therapeutic implications therein.

Nano drug delivery systems
NanoDDS have been evaluated for enhancing bioavailability, controlled release, stabilization and protection, and targeted delivery, in cancer and other conditions. The range of nanoDDS for delivery of curcumin is discussed below.

Polymeric nanoparticles
The first report of curcumin as polymeric nanoparticles was Nanocurcumin - micellar aggregates of cross-linked and random copolymers of N-isopropylacrylamide, with N-vinyl-2-pyrrolidone and poly(ethyleneglycol)monoacrylate(<100 nm).Nanocurcumin enabled ready aqueous dispersion and significant inhibition of primary tumour growth in xenograft models of human pancreatic cancer in athymic mice. Combination of parenteral NanoCurc with gemcitabine resulted additive therapeutic effect in vivo.

Biodegradable nanospheres of curcumin using poly (d,l-lactide)(PLLA), poly (lactide-co-glycolide)(PLGA) revealed significant increase in bioavailability compared to plain curcumin with piperine. Poly(butyl)cyanoacrylate nanoparticles(PBCA-NP) coated with poloxamer 188 containing curcuminoids resulted in improved solubility, enhanced photostability, controlled drug release, and decreased RES uptake. Further studies as stealth system for passive targeting of malignant tissues through EPR effect is in progress. Nanoparticles with other biocompatible polymers-alginate, chitosan and pluronic, carboxymethyl chitosan derivatives and silk fibroin-chitosan have also been evaluated. Inorganic mesoporous silica particles to encapsulate curcumin as a molecular tracker, a drug carrier and a controlled drug release system have also been explored.

Solid lipid nanoparticles (SLN)
SLN offer an additional advantage over polymeric nanoparticles of being biodegradable and GRAS approved. Solvent free large-scale production is yet another advantage. SLN of curcumin revealed enhanced stability. SLN of curcumin in GMS or triglycerides revealed increased photostability and decreased sensitivity to oxygen in presence of lipophilic derivatives of a- and ?-cyclodextrin. SLN of curcumin have been studied for tolerability and to optimize dose-plasma concentration relationship in late-stage osteosarcoma patients.

Micelles
Polymeric micelles exhibit low toxicity and high stability and a small size (<100 nm), ideal for passive targeting of solid tumours. The absorption rates of plain curcumin and micellar curcumin formulation with phospholipids and bile salt showed marginal increase of 47% and 56% in the everted rat intestinal sac model. However, polymeric micelles afforded a 60-fold increase in half-life compared to that of plain curcumin in rats. Other micellar systems evaluated were the natural nanostructure of milk casein, series of water-soluble methoxy poly(ethylene glycol) (MePEO) with palmitic acid as well as with polycaprolactone (PCL) block lengths. The half-life of micellar curcumin in MePEO-b-PCL was increased 162-fold with a 13 × 105-fold increase in curcumin solubility.

Liposomes
Curcumin being hydrophobic, is a good candidate for liposome incorporation in the lipid layer of the liposomes. Liposomal curcumin revealed higher/comparable stability in PBS and in human blood after 30 min of incubation. Amphoteric, cationic and anionic liposomes of curcumin have been explored for topical application. Liposomal curcumin exhibited comparable antitumor and antiangiogenic effect than oxaliplatin in colorectal cancer in rats. In addition, at a 4:1 ratio with oxaliplatin, synergistic effects were obtained. Liposomal curcumin has shown similar or even stronger immunosuppression efficacy on concanavalin-A stimulated human lymphocyte, splenocyte and LCL proliferation and enhanced anti-EBV lymphoma cell line efficacy.

SMEDDS, Nanoemulsions & Microemulsions
Microemulsions are isotropic, thermodynamically stable transparent (or translucent) systems of oil, water and surfactant, frequently in combination with a cosurfactant formed upon simple mixing with a droplet size usually in the range of 10-100 nm. Self-microemulsifying drug delivery system (SMEDDS) are water free pre-microemulsion concentrate, which form microemulsions on aqueous dilution. Nanoemulsions are kinetically stable emulsions, which do not form spontaneously and require input of energy.

Curcumin-loaded SMEDDS at surfactant concentration >55% enabled incorporation of curcumin upto 21mg/g with enhanced in situ absorption. Nanoemulsion of curcumin using medium chain triacylglycerols and Tween 20 enhanced anti-inflammatory activity compared to negligible effect of curcumin in Tween 20 solution. Paclitaxel and curcumin nanoemulsions could overcome tumourr multidrug resistance and revealed enhanced cytotoxicity in wild-type and resistant cells. This co therapy strategy has significant promise in the clinical management of refractory diseases, especially in ovarian cancer.

Emulsion preconcentrates of curcumin consisting of curcumin, PEG400, Tween-80, and propylene glycol have resulted in a rapid elevation of curcumin blood levels with a 9-fold increase in oral bioavailability. Nanoemulsions however, exhibited much faster elimination of curcumin, compared to the plain drug.

Exosomes
Exosomes are 50-90 nm vesicles secreted by a wide range of mammalian cell types. Exosomes have been used to deliver curcumin for anti-inflammatory activity to activated myeloid cells.

Dendrimers
Some preliminary studies on curcumin with PAMAM dendrimers generations 3.5 and 4.0 have revealed improved water solubility.

Therapeutic applications
Cancer
NanoDDS of curcumin have been evaluated for various types of cancer. Curcumin has been evaluated against human pancreatic carcinoma cell, spleen lymphocyte cells of the EL4 cell line, anti-EBV lymphoma cell line, concanavalin A-stimulated human lymphocyte, ovarian cells lines both wild-type SKOV3 and drug resistant SKOV3TR human adenocarcinoma cells, breast cancer cell lines expressing Her2/neu, head and neck squamous cell carcinoma (HNSCC) cell lines CAL27 and UM-SCC1, prostate cancer cell lines LNCaP and C4-2B cells, colon cancer cell lines Colo20, Caco-2 and HT-29 etc. The good potential seen in vitro in cell lines has also been confirmed in vivo. The increased half-life enabled through the design of nanoDDS facilitates enhanced accumulation in tumours through EPR effect. The prospects of synergistic action of curcumin with other anti cancer drugs, to tackle multiple drug resistance are also promising.

Nanosized vesicles and GMS nanospheres containing l-glutamic acid, N- (3-carboxy-1-oxo propyl)-1,5- dihexadecyl ester and PEG have successfully delivered curcumin to tissues macrophages, pecifically bone marrow and splenic macrophages. Brain targeted curcumin PBCA-NP coated with polysorbate was more bioavailable than the control solution at half dose. Moreover, the mean residence time was 14-fold that of the control solution. In brain too, curcumin uptake was 2.53-fold than that of the control solution. A bioconjugate of curcumin with ß-cyclodextrin, PEG and folic acid for targeting folic acid receptor-overexpressing tumour cells is reported. Transferrin-mediated SLN have been designed for enhanced anticancer activity against MCF-7 breast cancer cells. Cationic nanoparticles of PBCA-NP with chitosan of 200 nm have been studied for the targeting of hepatocellular carcinoma in murine xenograft models. Magnetic iron oxide nanopa ticles of curcumin for site specific targeting have also been studied.

Combination therapy
The additive effect of curcumin in combination with drugs like artemisin has been successful. The nano approaches of curcumin could also be explored for synergy in the therapy of other disorders like Alzheimers, Parkinsons, psoriasis, diabetes, asthma, heart diseases etc.

Cosmetics
Liposomes and SLNs are capable of penetrating through the lipidic stratum corneum, provide occlusion, increase skin hydration with good tolerability and therefore, find use in creams and lotions. Incorporation of curcumin SLNs into topical creams significantly reduced skin wrinkles, improved skin moisture and firmness, elasticity, and viscoelasticity of the skin of the volunteers after application for 3 weeks. Microemulsion systems of curcumin comprising of terpenes and Pelemol with PEG-20 glycerol monooleate for transdermal delivery exhibited higher permeation rates and penetration than plain curcumin.

Stents
Curcumin-loaded PLGA nanoparticles have been coated on stents, alone as well as in combination with rapamycin. Incorporation of curcumin in rapamycin-loaded PLGA coating significantly decreased the platelet adhesion and activation and decreased the fibrinogen adsorption thereby improving the blood compatibility of rapamycin-eluting stents. Thus, the drug eluting stents had the characteristics of both anti-proliferation and anticoagulation. More extensive in vitro studies show that biodegradable PLLA stent grafts loaded with curcumin could reduce the inflammatory responses of platelets and leukocytes.

Conclusion
Curcumin as "A Wonder Molecule" has shown a lot of promise. The gamut of therapeutic activity coupled with its high safety make curcumin a molecule worth trusting. The day is not far when one would see research from the laboratories being translated rapidly to the clinic to exploit this multifaceted drug in therapy.

Anisha D'souza is Senior Research Fellow & Dr. Padma V. Devarajan is Prof. & Head, Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology,Matunga, Mumbai.