NANOTECHNOLOGY APPROACHES TO ENHANCE THE BIOAVAILABILITY OF CURCUMIN

NANOTECHNOLOGY APPROACHES TO ENHANCE THE BIOAVAILABILITY OF CURCUMIN

Today curcumin has been widely acknowledged globally as a "wonder drug of the future" because of its great potential abilities to prevent and treat a wide spectrum of incurable and chronic diseases. In addition, it has been proved to be remarkably safe in animal studies and in phase I clinical trials even at high doses (up to 12g/day). However, the major problem limiting the exploitation of its potentially valuable therapeutic effects is its low bioavailability).

In practice, only very low or undetectable levels of curcumin can be achieved in blood by oral administration of curcumin. The low bioavailability of curcumin has been attributed to its very low aqueous solubility, tendency to degrade in the gastroinenstinal tract in the physiological environment, high rate of metabolism, and rapid systemic elimination. The low bioavailability of curcumin has so far limited its medical use. It has been suggested that a person is required to consume large doses (about 12-20g/day) of curcumin in order to achieve its therapeutic effects on the human body). That means one has to swallow 24 to 40 curcumin capsules of 500mg each. These doses are considered to be too high, and therefore, not feasible to be incorporated in clinical trials due to unbearable after-taste to the palate, possibility of giving rise to nauseatic feeling and perceived toxicity issues.

Therefore, to achieve the maximum response of this potentially useful chemopreventive agent, a number of approaches such as the use of adjuvants like piperine, synthetic analogues, chelating of curcumin with metals, combination with other dietary agents etc. have been investigated. Nanotechnology-based novel strategies are being aggressively explored worldwide to enhance curcumin's bioavailability and reduce perceived toxicity as they offer several other additional benefits such as improved cellular uptake, enhanced dissolution rates, excellent blood stability, controlled release functions, multifunctional design, enhancement in its pharmacological activities (e.g. antioxidant and antihepatoma activities) etc.

A 2010 article on polymer nanoparticle curcumin) has been ranked as one of the top ten most accessed articles (48029 accesses) for all time by the Journal of Nanobiotechnology. This clearly demonstrates the emerging importance of this field (nanotechnology-based drug delivery of curcumin based systems).

In this pioneering work, researchers from Johns Hopkins University School of Medicine and the University of Delhi have jointly developed a polymer nanoparticle-encapsulated form of curcumin, "nanocurcumin, they have coated ordinary hydrophobic curcumin particles with hydrophilic polymer (N-isopropylacrylamide with N-vinyl-2-pyrrolidonne and poly(ethylene glycol) monoacryalate) nanoparticles. This nanocurcumin is soluble in water and can be readily absorbed into the bloodstream. It has already been tested in vitro on pancreatic cancer cells and it was shown to have equal or better effects than free curcumin on the human cancer cells, such as inhibition of NF-kB and downregulation of IL-6. Nanocurcumin was also given to mice, and did not show any evidence of undesirable effects.

In addition to polymer-encapsulated curcumin, other nanobased drug delivery systems being employed for curcumin include curcumin nanocrystals, curcumin nanoparticles, nanoemulsions, nanoliposome-encapsulated curcumin, curcumin-loaded polymeric micelles, cyclodextrin/curcumin selfassembly, curcumin nanosuspension, solid-lipid nanoparticles etc.

Recent R&D Activities and Breakthroughs in Nano Curcumin

In view of the enormous potential of curcumin in the prevention and therapy of a wide spectrum of diseases, in recent years, intense R&D activities have been undertaken throughout the world in various establishments. The selected examples below highlight some of the ongoing R&D activities on nanotechnology-based curcumin across the globe.

Theracurcumin – A new curcumin formulation with markedly improved absorptivity)

Japanese researchers have recently developed a new form of nanoparticle curcumin (Theracurcumin) containing 10% curcumin, 2% other curcuminoids and balance glycerin, gum ghatti and water. Its oral intake in rat model as well as humans shows 30 fold improvement in bioavailability as compared to conventional curcumin. It shows excellent safety profile even at high dose levels. Theracurcumin can be used as a promising tool to evaluate the anti-cancer potential of curcumin in clinical trials.

Curcumin nanoparticles with enhanced antioxidant and antihepatoma activities)

Curcumin-based nanoscale particle system (CURN) was developed by following a nanoprecipitation route with polyvinylpyrrolidone (PVP) as a hydrophilic carrier. The physiochemical properties including water solubility and drug release were improved by the reduction of particle size and formation of an amorphous phase with hydrogen bonding. In vitro studies clearly demonstrated that nanosized curcumin shows superior antioxidant and antihepatoma activities as compared to conventional curcumin.

Curcumin nanoparticles with highly potent antimicrobial properties)

Water-soluble curcumin nanoparticles (2-40 nm) were prepared by wet milling method. These nanocurcumin showed marked improvement in their antibacterial and antifungal activities as compared to that of curcumin in DMSO. The antibacterial activity of nanocurcumin particles was attributed to their ability to penetrate inside the bacterial cell by breaking the cell wall, resulting to cell death.

Chitosan-PVA-Curcumin-Silver nanocomposite antimicrobial films for wound dressing)

Chitosan-PVA-Silver nanocomposite antimicrobial films were fabricated by a chemical method in view of their potential applications in antimicrobial packaging and wound/burn dressing. Incorporation of curcumin into chitosan-PVA-silver nanocomposite films improve their therapeutic efficacy as anti-microbial agent. Curcumin-encapsulated chitosan-PVA-silver nanocomposite films show enormous growth inhibition of E-coli in comparison with curcumin or chitosan-PVA-silver nanoparticles film alone.

Curcumin/MPEG-PCL micelles for colon cancer therapy)

Curcumin encapsulated into monomethoxy poly(ethylene glycol)-poly( -caprolactone) (MPEG-PCL) biodegradable micelles were prepared by a nano-precipitation technique. These curcumin-loaded micelles are an intravenously injectable formulation of curcumin. They were shown to supress the growth of colon carcinoma by inhibiting angiogenesis and killing the cancer cells.

Curcumin loaded PBCN nanoparticles for enhanced transport of curcumin to brain)

Polybutylcyanoacrylate nanoparticles (PBCN) loaded with curcumin were synthesized by modified anionic polymerization technique. Curcumin loaded PBCN shows enhanced transport of curcumin to the brain and has excellent potential to cross the blood-brain barrier. This novel delivery system will find applications for blocking brain tumor formation and curing Alzheimer's disease.

Curcumin loaded Lipo-PEG-PEI complex with enhanced antitumor effects on curcumin-sensitive/curcumin resistant cells)

A cationic liposome containing PEI and PEG as a carrier complex (LPPC) was developed to encapsulate curcumin for the treatment of cancer. It was found that curcumin/LPPC exhibits enhanced cytotoxicity and is able to rapidly penetrate curcumin-sensitive and resistant cells. It was observed that curcumin/LPPC is able to inhibit the colon/melanoma tumor growth in mice.

Nanoemulsion formulation and coadministration of Paclitaxel and curcumin to overcome multidrug resistance in tumour cells

Intracellular co-administration of Paclitaxel (mitotic inhibitor) and curcumin (NF-kB activity inhibitor) in the form of nanoemulsion exhibits remarkable enhancement in cytotoxicity in wild type (SKV3) and drug resistant (SKOV-3TR) human ovarian adenocarcinoma cells by promoting apoptotic response. This dual strategy shows great promise in the clinical management of refractory diseases (diseases that resist treatment) such as ovarian cancer.

Chemo/radio-sensitization in ovarian cancer cells using nano-curcumin)

Ovarian cancer cells are resistant both to radiation therapy and cisplatin-based drugs used in chemotherapy. Nano-enabled curcumin pretreatment strategy with enhanced efficacy and specificity was employed to induce chemo/radio sensitization in ovarian cancer cells. It was shown that this pretreatment with nano-curcumin improves in vivo therapeutic efficacy of curcumin, and thereby, inhibits the ovarian cancer cell growth.

Coformulation of Doxorubicin (DOX) and curcumin in the clinical management of leukemia)

The coadministration of DOX and curcumin in PLGA nanoparticle formulation can help in enhancing efficacy of DOX, thereby leading to cytotoxicity in erythroleukamia type K562 cells. The synergistic growth inhibition is clinically important and may provide combinatorial strategies in a variety of cancers, especially leukemia.

In addition to the above approaches, a number of other unique nanotech-based techniques including a class of novel multifunctional hybrid nanogels amenable to photothermal therapy), "nanodiscs" with phospholipids bilayers), biocompatible thermoresponsive polymeric nanoparticles loaded with curcumin), yeast cell-encapsulated-curcumin with high stability against heat, light and humidity etc. are being developed) to enhance the bioavailability of curcumin combined with multifunctional attributes.

A number of commercial nanotechnology based curcumin products with enhanced bioavailability have been developed by companies from the USA, India, Japan, and Canada. (These products and their manufacturers are listed in the original article in the July issue of the Nanotech Insights newsletter.)

It is pertinent to note that the above mentioned products based on curcumin are treated as herbal/dietary supplements only and are regulated by the US Food and Drug Administration (FDA), but not as pharmaceutical drugs. They fall under a category called dietary supplements. Manufacturers must follow good manufacturing practices (GMPs) to ensure that supplements are processed consistently and meet quality standards. Once a dietary supplement is on the market, the FDA is responsible for monitoring its safety.

It is interesting to note that Johnson & Johnson has been marketing turmeric band-aids in India), which are being used as a traditional cure for cuts. It would be worthwhile to consider use of curcumin nanoparticles in place of turmeric for band-aids/dressings for cuts, wounds and other infections as they exhibit enhanced antibacterial/anti-infection properties.

Challenges and Future Directions

Curcumin has only recently captured the attention of the scientific community as providing potential health benefits on account of its antitumor, antioxidant, antiarthritic, antiamyloid, anti-ischemic, and anti-inflammatory properties. One of the greatest challenges in developing curcumin for clinical efficacy is its low oral bioavailability.

Curcumin's poor bioavailability within the body can be attributed to its poor absorption and high rate of metabolism in the intenstines and rapid elimination from the body. This has been a major obstacle in preventing its progress from the lab to clinic; therefore, not much progress could be made in conducting clinical trials beyond Phase I. In view of this, curcumin's chemoprevention and therapeutic potential has not been fully exploited for the prevention and treatment of diseases. As has been discussed earlier, nano-enabled drug delivery systems have been developed, which show good promise in overcoming the problem of low bioavailability of curcumin).

In the United States, turmeric (curcumin) is generally recognized as a safe (GRAS) food additive by the FDA. Doctors often prescribe curcumin as a natural, non-toxic remedy that has very few side effects. No serious adverse effects have been reported in humans taking even high doses of curcumin. In a recently conducted Phase I clinical trial) on 24 adults, it was found that single oral dosages up to 12 g could be well tolerated.

However, contrary to the general perception that curcumin is quite safe there is some evidence suggesting that curcumin may cause toxic effects under specific conditions and these have been discussed in a recent review by Burgos-Mor'on et al).These include commonly reported side effects like stomach upset, nausea and diarrhea, an allergic skin reaction and anti-thrombosis activity interfering with blood clot formation. There is some evidence suggesting that high dose administration of curcumin in rodents for long-term duration can be tumourigenic.

Although side effects have been limited in animal and Phase I short-term clinical studies, long-term, large scale and randomized clinical trials on humans are needed to establish the safety of curcumin at antioxidant and antiinflammatory doses. These clinical studies are also necessary to determine the optimal dosage, bioavailability and bioefficacy of curcumin-based drugs.

The major challenge is to develop drugs based on curcumin with scientific evidence acceptable to the global community. An effective drug should exhibit adequate absorption, low toxicity, acceptable distribution, metabolism and excretion, and should be capable of treating the targeted disease with specificity and efficacy. The traditional medicinal system may need to adopt novel strategies such as combinatorial chemistry route combined with nanotechnology to develop curcumin-based drugs having enhanced bioavailability and efficacy. The challenges and technological prospects in realizing nano-curcumin based drugs for the future of medicine and healthcare) will be covered in a forthcoming issue of this newsletter. In the same issue, global scenario based on literature and patent analysis) will also be presented.

Source:nanowerk.com