Advanced Drug Delivery Systems of Curcumin for Cancer Chemoprevention
TL;DR: Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been shown to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation.
Abstract: Since ancient times, chemopreventive agents have been used to treat/prevent several diseases including cancer. They are found to elicit a spectrum of potent responses including anti-inflammatory, antioxidant, antiproliferative, anticarcinogenic, and antiangiogenic activity in various cell cultures and some animal studies. Research over the past 4 decades has shown that chemopreventives affect a number of proteins involved in various molecular pathways that regulate inflammatory and carcinogenic responses in a cell. Various enzymes, transcription factors, receptors, and adhesion proteins are also affected by chemopreventives. Although, these natural compounds have shown significant efficacy in cell culture studies, they elicited limited efficacy in various clinical studies. Their introduction into the clinical setting is hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Therefore, to circumvent these limitations and to ease their transition to clinics, alternate strategies should be explored. Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been shown to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation. In this review article, we have attempted to provide a comprehensive outlook for these delivery approaches, using curcumin as a model agent, and discussed future strategies to enable the introduction of these highly potent chemopreventives into a physician9s armamentarium. Cancer Prev Res; 4(8); 1158–71. ©2011 AACR .
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TL;DR: The design and development of nanoparticles, self-assemblies, nanogels, liposomes and complex fabrication for sustained and efficient curcumin delivery and the anticancer applications and clinical benefits of nanocurcumin formulations are focused on.
573 citations
TL;DR: A review of the commonly used biocompatible and biodegradable nanoparticles including liposomes, emulsions, solid lipid nanoparticles, nanostructured lipid carriers, micelles and poly(lactic-co-glycolic acid) nanoparticles is presented in this article.
Abstract: Nanotechnology is an innovative approach that has potential applications in nutraceutical research. Phytochemicals have promising potential for maintaining and promoting health, as well as preventing and potentially treating some diseases. However, the generally low solubility, stability, bioavailability and target specificity, together with the side effects seen when used at high levels, have limited their application. Indeed, nanoparticles can increase solubility and stability of phytochemicals, enhance their absorption, protect them from premature degradation in the body and prolong their circulation time. Moreover, these nanoparticles exhibit high differential uptake efficiency in the target cells (or tissue) over normal cells (or tissue) through preventing them from prematurely interacting with the biological environment, enhanced permeation and retention effect in disease tissues and improving their cellular uptake, resulting in decreased toxicity, In this review, we outline the commonly used biocompatible and biodegradable nanoparticles including liposomes, emulsions, solid lipid nanoparticles, nanostructured lipid carriers, micelles and poly(lactic-co-glycolic acid) nanoparticles. We then summarize studies that have used these nanoparticles as carriers for epigallocatechin gallate, quercetin, resveratrol and curcumin administration to enhance their aqueous solubility, stability, bioavailability, target specificity and bioactivities.
344 citations
Cites background from "Advanced Drug Delivery Systems of C..."
...Despite these advantages, curcumin has poor aqueous solubility, has low bioavailability and is quickly metabolized by hepatic enzymes in humans and research animals [133]....
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TL;DR: This review highlights various hypoxia-targeted and activated design strategies for the formulation of drugs or prodrugs and their mechanism of action for tumour diagnosis and treatment.
Abstract: Hypoxia is a state of low oxygen tension found in numerous solid tumours. It is typically associated with abnormal vasculature, which results in a reduced supply of oxygen and nutrients, as well as impaired delivery of drugs. The hypoxic nature of tumours often leads to the development of localized heterogeneous environments characterized by variable oxygen concentrations, relatively low pH, and increased levels of reactive oxygen species (ROS). The hypoxic heterogeneity promotes tumour invasiveness, metastasis, angiogenesis, and an increase in multidrug-resistant proteins. These factors decrease the therapeutic efficacy of anticancer drugs and can provide a barrier to advancing drug leads beyond the early stages of preclinical development. This review highlights various hypoxia-targeted and activated design strategies for the formulation of drugs or prodrugs and their mechanism of action for tumour diagnosis and treatment.
294 citations
TL;DR: In this paper, a review summarizes the recent advances in application of different oil-in-water emulsion-based approaches, such as, conventional emulsions (surfactants-, protein-and protein-polysaccharide-stabilized emelsions), nano-emulsions, and Pickering emulsion that have been specifically used to deliver curcumin.
Abstract: Background Curcumin has been widely acknowledged for its health-promoting effects. However, its application is often limited by its poor water solubility and biochemical/structural degradation during physiological transit that restricts its bioavailability. Emulsion based approaches have attracted the most research attention to encapsulate curcumin and improve its stability, bioaccessibility and bioavailability. Scope and approach This review summarizes the recent advances in application of different oil-in-water emulsion-based approaches, such as, conventional emulsions (surfactants-, protein- and protein-polysaccharide-stabilized emulsions), nanoemulsions, and Pickering emulsions that have been specifically used to deliver curcumin. Particular emphasis is given to factors affecting curcumin solubility, change in crystalline structure of curcumin upon dispersion and encapsulation efficiency. Changes in the droplet size and emulsion stability during in vitro oral-to-gastrointestinal digestion are discussed, with clear focus on the bioaccessibility of the encapsulated curcumin. Key findings and conclusions Key factors that influence curcumin delivery include emulsion droplet size, oil composition, volume fraction, dispersion conditions of curcumin in the oil phase and the type of interfacial materials. Nanoemulsions have been the preferred choice for delivery of curcumin up to now. Although scarce in literature, emulsions stabilized by edible Pickering particles as shown by recent evidence are effective in protecting curcumin in an in vitro gastrointestinal setting due to their high coalescence stability. Further studies with emulsions stabilized by food-grade particles and accurate tracking of the physiological fate ( in vitro to human trials) of different emulsion-based delivery vehicles are essential for rational designing of curcumin-rich functional foods with high bioaccessibility.
264 citations
TL;DR: The clinical evidence, current status, and future opportunities of curcumin nanoformulation(s) in the field of medicine are discussed, and a concise summary of the actions required to develop curcuming nanoformulations as pharmaceutical or nutraceutical candidates are presented.
Abstract: Curcumin (diferuloylmethane) is a bioactive and major phenolic component of turmeric derived from the rhizomes of curcuma longa linn For centuries, curcumin has exhibited excellent therapeutic benefits in various diseases Owing to its anti-oxidant and anti-inflammatory properties, curcumin plays a significant beneficial and pleiotropic regulatory role in various pathological conditions including cancer, cardiovascular disease, Alzheimer’s disease, inflammatory disorders, neurological disorders, and so on Despite such phenomenal advances in medicinal applications, the clinical implication of native curcumin is hindered due to low solubility, physico-chemical instability, poor bioavailability, rapid metabolism, and poor pharmacokinetics However, these issues can be overcome by utilizing an efficient delivery system Active scientific research was initiated in 2005 to improve curcumin’s pharmacokinetics, systemic bioavailability, and biological activity by encapsulating or by loading curcumin into nanoform(s) (nanoformulations) A significant number of nanoformulations exist that can be translated toward medicinal use upon successful completion of pre-clinical and human clinical trials Considering this perspective, current review provides an overview of an efficient curcumin nanoformulation for a targeted therapeutic option for various human diseases In this review article, we discuss the clinical evidence, current status, and future opportunities of curcumin nanoformulation(s) in the field of medicine In addition, this review presents a concise summary of the actions required to develop curcumin nanoformulations as pharmaceutical or nutraceutical candidates
258 citations
References
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TL;DR: Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.
Abstract: Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of...
4,275 citations
"Advanced Drug Delivery Systems of C..." refers background in this paper
...Even in clinical studies, high doses of orally administered curcumin (8–12 g daily) resulted in very low curcumin concentrations in the plasma (<1 mg/mL), levels that were not high enough to exert any significant pharmacologic or therapeutic activity (26)....
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TL;DR: Relevant issues for the introduction of SLN to the pharmaceutical market, such as status of excipients, toxicity/tolerability aspects and sterilization and long-term stability including industrial large scale production are discussed.
3,260 citations
"Advanced Drug Delivery Systems of C..." refers background in this paper
...SLNs were first introduced in mid 1990s as novel drug delivery systems (69) capable of protecting the labile drugs from light/pH/heat mediated degradation, controlled release and excellent biocompatibility/toleratability (70)....
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TL;DR: An overview about the selection of the ingredients, different ways of SLN production and SLN applications, and the in vivo fate of the carrier are presented.
2,786 citations
"Advanced Drug Delivery Systems of C..." refers background in this paper
...This drug delivery carrier not only protects the entrapped drug from photochemical or pH-mediated degradation but also enables drug targeting and easy large-scale production (72, 73)....
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Journal Article•
TL;DR: Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis, and Pharmacologically,Curcumin has been found to be safe.
Abstract: Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF- κB, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies. Curcumin, derived from turmeric (vernacular name: Haldi), is a rhizome of the plant Curcuma longa. The medicinal use of this plant has been documented in Ayurveda (the Indian
2,453 citations
"Advanced Drug Delivery Systems of C..." refers background in this paper
...Various cell culture studies have shown that it induces apoptosis in oncogenic cells by inhibiting various intracellular transcription factors and secondary messengers such as NFkB, AP-1, c-Jun, the Jak-STAT pathway and various others (13-15)....
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TL;DR: Delivery may be less efficient in cranial tumors than in subcutaneous tumors, delivery may be reduced during tumor regression induced by hormonal ablation, and permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter.
Abstract: Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100–300 nm in diameter) An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined The microenvironment was modulated: (i) spatially, by growing tumors in subcutaneous or cranial locations and (ii) temporally, by inducing vascular regression in hormone-dependent tumors Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 12 μm This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal Vessels induced in basic fibroblast growth factor-containing gels had a pore cutoff size of 200 nm Albumin permeability was independent of pore cutoff size These results have three major implications for the delivery of therapeutic agents: (i) delivery may be less efficient in cranial tumors than in subcutaneous tumors, (ii) delivery may be reduced during tumor regression induced by hormonal ablation, and (iii) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter
2,340 citations
"Advanced Drug Delivery Systems of C..." refers background in this paper
...In majority of solid tumors, the vascular cutoff pore size ranges between 380 and 780 nm (55, 56), whereas normal vasculature is imperme-...
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