Introduction: a high degree of molecular heterogeneity thus

Introduction: One fifth of deaths worldwide annually are caused by various cancers with an estimated 1,685,210 cases of cancer diagnosed in the US alone 1. Cancer is a result of successive genetic and epigenetic alterations resulting in apoptosis uncontrolled cell proliferation, metastasis, angiogenesis 2, 3. Several strategies have been employed in recent years to combat cancer evasion, some of them are surgery, hormonal therapy, chemotherapy, and radiation therapy. Chemotherapy which involves usage of cytotoxic antineoplastic drugs (alkylating agents and antimetabolites) has immense side-effects and is largely restricted due to the recurrence of drug resistance (intrinsic and acquired). The acquired resistance is more severe and is caused mainly by mutations during prognosis induced by over-expression of therapeutic targets or stimulation of cancer-promoting pathway 4. Furthermore, tumors do contain a high degree of molecular heterogeneity thus causing more drug resistance 4.Curcumin is a natural phenolic antioxidant 5. Presently, its known that many different plant species synthesize curcumin, but is mostly extracted from the rhizome of Curcuma longa Linn due to its high concentrations which is shown have cardioprotective, neuroprotective and antidiabetic activities 6, 7, 8. Specifically, it has shown to have various pharmacological activities against diseases like type II diabetes, Alzheimer’s disease, atherosclerosis and human immunodeficiency virus (HIV) replication 6, 7, 8. The most promising of all the chronic diseases, the anti-cancer activity of curcumin has been extensively investigated, where cancers of gastrointestinal, melanoma, genito-urinary, breast, and lung have seen some significant improvements 9, 10, 11, 12. Curcumin has been shown to have pleiotropic properties, due to which it has been seen to be most effective against single pathway targeted cancers 13, 14. Apart from pleiotropic properties, it has been shown to have anti-inflammatory activity with a tolerance at 12 g/day dosage 15, 16. Moreover, the importance of it being considered as a possible drug is that it can freely pass through cellular membranes due to its lipophilicity, however it does has a low aqueous solubility making it susceptible to alkaline degradation 17, 18. This may be the reason for its low bioavailability and an increase dose for reaching therapeutic optimal blood concentrations 17, 18, 19, 20. This article tries to summarize the current curcumin research trying to explore it as a possible target in combination with nanoparticles for treating various cancers. Nanocarriers have proven to be an important carriers of therapeutic agents, they can improve the circulation time to enhance permeation and retention effect 21, 22. Various nanocarriers (polymeric micelles, liposomes, conjugates and peptide carriers) have been investigated for drug delivery. While most of them have been tried with curcumin, some have proved to be extremely efficient in solubilization of curcumin and protect against inactivation by hydrolysis. Curcumin loaded liposomes with bovine brain sphingomyelin, cholesterol, 1,2-stearoyl-sn-glyc-Ero-3-phosphoethanolamine and apolipoprotein E (ApoE) peptide has been proven to enhance the transport of curcumin. The lipid recovery was found to be about 90% with a mean liposomes size of 130 nm 23. ApoE-liposomes were seen to enhance the transport of curcumin through RBE4 brain capillary endothelial cells 23.Different biodegradable polymers have also been implemented for preparation of curcumin loaded nanoparticles 24. The most important of which is PLGA (poly(D,L-lactic-co-glycolic) which has been seen to have increased biocompatibility and biodegradability 25, 26, 27. By using curcumin in PLGA nanoparticles by nanoprecipitation, the size of nanoparticles was found to be decreased from 560 to 76 nm with a neutral zeta-potential 28. While it is unknown how can this drastic drop in size and zeta-potential occurs, absence of charge on the particle surfaces might be the reason for it 28. Further, another technique of preparing curcumin loaded PLGA nanospheres using a nanoprecipitation method with polyethylene glycol (PEG)-5000 as stabilizer was tried, which achieved particle size of 81 nm, but still the question of how does this decrease in size and zeta-potential occurs remains unanswered 29. Some groups have also tried to utilize natural polymers loaded curcumin like chitosan/poly(?-caprolactone), where the mean diameter of the nanoparticles was found between 220 and 360 nm with the encapsulation efficiency of 71% 30. Recently, some stable nanoparticles of 200-220 nm which were held together by electrostatic interaction between the two oppositely charged polymers were synthesized with an curcumin encapsulation efficiency and loading capacity were 74 and 5% 31. They used coacervation method with dextran sulfate and chitosan for generating these particles. Newer polymers, polymeric micelles which are composed of amphiphilic co-polymers can form micelles with a size ranging between 20-100 nm, the hydrophobic core of which can accomodate hydrophobic drugs with higher solubilization 32, 33, 34. These micelles can contain a amphiphilic core composed of methoxy poly(ethylene glycol)-b-poly(?-capro-lactone-co-p-dioxanone) or monomethyl poly(ethylene glycol)-poly(?-caprolactone) (MPEGePCL) formed by solid dispersion or one-step solid dispersion methods 35. Such micelles can have a mean diameter of 27 nm with a encapsulation efficiency and drug loading capacity of 99 and 15%. The conjugation of polymers with curcumin and its solubility have been tried to improve with natural and synthetic hydrophilic polymers and some specific amino acids (proline, glycine, leucine, isoleucine, alanine, phenylalanine, phenyl glycine, valine, serine and cysteine) 36. The solubility with such combinations have been found to be increased to 10 mg/ml 36. Furthermore, coupling curcumin with different carboxylic ester conjugates have shown to increase the half-life of free curcumin and a better stability 37. Certain micelles like beta casein (amphiphilic polypeptide) with a molecular mass of 24,650 Da have shown to increase the solubility of nanoparticles to 2500 fold 38. Other biological micelles like cross-linked human serum albumin (HSA) have also been shown to have good biocompatibility drug delivery action and an increased solubility 39, 40. Some groups have utilized rather unconventional products to improve curcumin solubility. Certain cyclic oligosaccharides like cyclodextrins have also been shown to have a lipophilic cavity, that can solubilize hydrophobic drugs and curcumin 41, 42. Another oligosaccharide, 2-hydroxypropyl-g-cyclodextrin (HPgCD) has been complexed to curcumin by a pH shift method and has shown to be an efficient carrier 43. A b-cyclodextrin (b-CD)-curcumin inclusion complex self assembled into nanoparticles with a size of 250 nm. This complex was noted to retain more that 70% of the loaded curcumin, demonstrating a good compatibility of curcumin and its carrier 44. Solid dispersion of dissolving drug in an amorphous or semi-crystalline form is a newer technique of solvent evaporation, that can enhance the solubility and dissolution rate of poorly water-soluble drugs 45. An example of this technique is dissolving HP-b-CD and curcumin in methanol and converting it into an amorphous co-precipitate, which has been shown to enhance hydration and dissolution 46. This technique have been shown to decrease the curcumin concentration up to 90% forming supersaturated curcumin solutions 46.Various groups have performed in-vivo studies of curcumin nanoformulations in different diseases. Table 1 summarizes some recent clinical trials which have used curcumin as a anti-cancer agent. The concentration time curves were found to be larger with curcumin nanoformulations compared to free form curcumin. An oral dose of 1 g/kg of a curcumin nano-emulsion causes an increase in the maximum concentration (Cmax) of more than 40 fold in mice compared to a free suspension of curcumin in 1% methylcellulose 47. Overall, curcumin loaded PEG nanoparticles were found to have a better pharmacokinetics in rats when compared to only curcumin dispersion with a 50 mg/kg dosage 48. Furthermore, a higher curcumin concentration in lung, brain and kidney and lower concentration in spleen and liver with curcumin loaded micelles was seen 49. These micelles could thus permeate the blood brain barrier and can accumulate in the brain owing to their small size and a neutral charge. The mean residence time of the curcumin nanosuspension has been found to be 194 min with a size of 210 nm with a dosage of 15 mg/kg in rabbits and 20 mg/kg in mice 50. While the  residence time of just 16 min in only curcumin treatment was seen, which is approximately a factor 11 higher after nano-encapusulation. Curcumin-loaded lipid nanocapsules administered intraperitoneally at 1.5 mg/kg/day for 14 days significantly decreased tumor growth of gliomas when compared to free curcumin dissolved in DMSO at 50 mg/kg/day dosage 51. Moreover, only curcumin-PEG combination resulted in various side effects in mice like uterine hypertrophy, folliculogenesis, and spermatogenesis of male mice 52. Interestingly, only curcumin in its free form and as nanoformulations has been found to be  benefits for patients with colorectal cancer, pancreatic cancer and breast cancer with no dose-limiting toxicity of curcumin at higher dosages 53, 54, 55. Another group found a Cmax value of 13 ng/ml in healthy volunteers after oral administration of curcumin nano-colloidal dispersion at a single oral dose of 30 mg which was way higher than orally administered same dose curcumin without toxicity 56. Thus, intestine cells showed a strongly absorption of nano-colloidal curcumin and can be effectively used to treat intestinal diseases.Discussion and Conclusions:Summarizing all the above preclinical and clinical studies of curcumin have shown its possible usage as a chemotherapeutic agent. It can inhibit proliferation and inhibition of growth of various cancer cell lines specifically leukemia, breast, colon, hepatocellular, and ovarian carcinomas. Some cancer cells shows resistance attributing to high expression of Hsp70 which can protect cells from apoptosis 57. Another advantage of using curcumin over present anti-cancer drugs is overcoming the possibility of multidrug resistance (MDR) with doxorubicin, paclitaxel, docetaxel gemcitabine and cisplatin by cancer cells. One study have shown that combination of curcumin and gemcitabine has significantly down-regulated the expression of the cell proliferation marker Ki-67 in tumor tissues 58. Combination of curcumin-PCDT and paclitaxel-PCDT have also seen to produce apoptosis and necrosis in the cancer cell lines, where the IC50 value of the combination of paclitaxel-PCDT and curcumin-PCDT was seen to be lower than that with just paclitaxel-PCDT alone 59. A cost-benefit ratio of nanoformulations and free curcumin needs to be analyzed. Curcumin polymers obtained from one-step polycondensation technique has improved hydrophobicity and release due to hydrolysis of the carbonate bonds between PEG and curcumin producing a sustained release over 80 days. This technique can be useful as a cancer suppressor 60. Thus, curcumin can definitely be a useful chemotherapeutic option in treatment of cancer cells, whose maximum potentials will be unravelled in future.

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