Cancer is among the leading causes of morbidity and mortality worldwide. Many of the chemotherapeutic agents used in cancer treatment exhibit cell toxicity and display teratogenic effect on nontumor cells. Therefore, the search for alternative compounds which are effective against tumor cells but reduce toxicity against nontumor ones is of great importance in the progress or development of cancer treatments. In this sense, scientific knowledge about relevant aspects of nutrition intimately involved in the development and progression of cancer progresses rapidly. Phytochemicals, considered as bioactive ingredients present in plant products, have shown promising effects as potential therapeutic/preventive agents on cancer in several
The conventional treatments against cancer are nowadays replaced by new approaches such as hormone therapy, biological therapy, and stem cell transplantation. In addition to these proposals, new chemical compounds are tested, focusing on founding antitumoral agents with high specificity response and low toxic side effects and warding off resistance development. In this sense, phytochemicals (Phy) have received increasing attention due to their high potency and low toxicity compared with common chemotherapeutic agents [
However, despite their promising benefits
Therefore, to increase the Phy applicability, developing formulation strategies that overcome limited oral bioavailability of Phy is needed. In this sense, the association of Phy to delivery systems or carriers composed of diverse materials has been proposed [
In these frameworks, the present work summarizes the existing dietary Phy with promising anticarcinogenic properties and Phy-based therapies that are being currently evaluated
In the last years, several studies have amply demonstrated that tumor development could be highly associated with diet habits [
According to their chemical structure, Phy can be mainly classified into four groups: polyphenols, terpenes, organosulfur compounds, and phytosterols. The following provides a description of Phy belonging to the mentioned structural categories that have shown potential anticancer properties in
Antitumor benefits of polyphenols have been widely described. Polyphenols constitute one of the major constituents of plants and are abundant in our diet. The occurrence in plant matrix is very variable, going from simple phenolic molecules to complex associations (highly polymerized compounds). They are usually classified into different groups according to their structure and number of rings, highlighting phenolic acids, flavonoids, stilbenes, and curcuminoids, which are described below and compiled in Table
Polyphenols studied in experimental
Polyphenols | Phytochemical | Main source | Cancer targets |
Clinical trials | References cancer targets/clinical trials | Chemical structure |
---|---|---|---|---|---|---|
Phenolic acids | Ellagic acid | Pomegranate, berries, grapes |
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Prostate |
[ |
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Bladder | ||||||
Breast | ||||||
Colon | ||||||
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Flavonoids | (−)-Epigallocatechin-3-gallate (EGCG) | Green tea |
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Prostate |
[ |
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Laryngeal carcinoma | ||||||
Non-small cell lung | ||||||
Colon | ||||||
Pancreas | ||||||
Genistein | Soybean |
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Prostate | [ |
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Bone | |||||
Breast | Endometrial | |||||
Cervical | Breast | |||||
Colon | Bladder | |||||
Luteolin | Cabbages, celery, broccoli, onion leaves, parsley |
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— | [ |
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Prostate | ||||||
Breast | ||||||
Thyroid | ||||||
Colorectal | ||||||
Cervical | ||||||
Lung | ||||||
Silymarin | Thistle |
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Upper gastrointestinal |
[ |
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Breast | ||||||
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Colon | ||||||
Lung | ||||||
Bladder | ||||||
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Prostate | ||||||
Quercetin | Capers, lovage leaves, apple | Pancreas | Large bowel | [ |
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Ovary | |||||
Cervical | Pancreas | |||||
Colon | Prostate | |||||
Prostate | Thrombotic | |||||
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Colorectal | |||||
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Stilbenes | Resveratrol | Grape, berries |
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[ |
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Colorectal | |||||
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Colon | |||||
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Gastrointestinal tumors | |||||
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Curcuminoids | Curcumin |
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Pancreas |
[ |
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Breast | ||||||
Cervical | ||||||
Colorectal |
Clinical trials carried out considering phytochemicals as dietary complements or drugs (therapy) in cancer patients.
For the experimental studies,
Chemical structures were obtained by using ChemDraw Professional 15.0 software.
(i)
(ii)
Within flavonoids, proanthocyanidins are also underlined as effective naturally occurring compounds in grape seeds or pine bark with antitumorigenic effects. They take the form of oligomers or polymers (+) catechin and (−) epicatechin, and the carried-out
(iii)
(iv)
Another important group of phytochemicals is that constituted by terpenoids or terpenes, which is the most abundant and structurally diverse group synthetized by plants. Terpenes show a wide range of physiological functions, many of them related to the plant defense system, and they are often components of essential oils and resins [
Terpenes, organosulfur, and phytosterols commonly studied in cancer therapy.
Family | Phytochemical | Main source | Cancer targets |
Clinical trials | References cancer targets/clinical trials | Chemical structure |
---|---|---|---|---|---|---|
Terpenes | ||||||
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Carotenoids | Lycopene (tetraterpene) | Tomato |
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Prostate | [ |
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Breast | ||||||
Lung | ||||||
Cervical | ||||||
Breast | ||||||
Laryngeal | ||||||
Liver carcinoma | ||||||
Astaxanthin | Green microalgae |
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— | [ |
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Ginger, celery |
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Glioma | [ |
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Non-small cell lung | ||||||
Gastric cancer | ||||||
Prostate | ||||||
Brain | ||||||
Breast | ||||||
Cervical | ||||||
Colon | ||||||
Ovarian | ||||||
Melanoma | ||||||
Glioblastoma | ||||||
Noncarotenoid | Carnosol (diterpene) | Sage |
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— | [ |
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Breast | ||||||
Ovarian | ||||||
Intestinal | ||||||
Melanoma | ||||||
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Organosulfur | ||||||
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Thiosulfinates | Sulforaphane | Brassica vegetables |
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Breast | [ |
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Ovary | ||||||
Mammary | ||||||
Diallyl disulfide | Allyl vegetables |
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— | [ |
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Neuroblastoma | ||||||
Prostate | ||||||
Colon | ||||||
Thyroid | ||||||
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Phytosterols | ||||||
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Phytosterols |
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Vegetal oils |
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— | [ |
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Breast | ||||||
Stomach | ||||||
Prostate | ||||||
Fibrosarcoma |
Clinical trials carried out considering phytochemicals as dietary complements or drugs (therapy) in cancer patients.
For the experimental studies,
Chemical structures were obtained by using ChemDraw Professional 15.0 software.
(i)
(ii)
Organosulfur compounds are Phy with one or more carbon-sulfur bonds in their structure and a thioketal-linked glucose molecule (S-glycosides). They are classified into two groups: glucosinolates and thiosulfinates [
Thiosulfinates (allyl sulfides), such as diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), are mainly present in garlic and onion (Allium family) [
Phytosterols are lipid-like compounds and essential for maintaining permeability and fluidity on cell plant permeability. Vegetable oils are the main source of dietary phytosterols. They occur in various structural forms (as steryl glucosides, acetylated steryl glucosides, esters, or alcohols) [
Within terpenes, triterpenoids (squalene) play a determinant role as they are considered common precursors of steroids, including phytosterols. Triterpenoids exist in free form or combined with sugar into glycosides. The free form shares the same chemical properties as phytosterol so long as they can be dissolved in organic solvents but insoluble in water [
In general,
Although Phy hold part of their biological activity
Oral route is generally considered the easiest and most convenient method for the delivery of drugs and dietary bioactive compounds due to properties such as noninvasiveness, cost-effectiveness, and being less prone to side effects, such as injection-site reactions [
However, as commented above, the suitability of this administration route depends on the oral bioavailability of the active ingredient, which, as summarized in Figure Physicochemical properties of Phy, which determine their water solubility and stability inside the GI tract Physiological barriers, including the chemical (e.g., pH) and biological environment (e.g., microbiota) inside the GI tract, which also have a significant influence on Phy stability during digestion and absorption [ Biochemical barriers (including biodistribution), biological barrier (GI wall permeability), and pharmacokinetics (metabolism and clearance) of the active ingredient Endogenous factors, as the individual age and gender, mucosal mass, gastric emptying, genetics, and diseases [ Amount of coingested compounds or foods
A compound which can exist in a stable form to survive the GI environment and that has optimum physicochemical properties to penetrate the GI wall is most likely to possess acceptable oral bioavailability. Most of Phy, however, have shown physicochemical properties that lead to a poor water solubility and stability in the GI environment and poor permeability. These include complex structure, size, high molecular weight, high lipophilicity, compound H-bonding to solvent, intramolecular H-bonding, intermolecular H-bonding, crystal packing, crystallinity, polymorphic forms, ionic charge status, isoelectric point (pI), and salt form [
Determinant factors of the oral bioavailability of bioactive compounds, including phytochemicals.
Nevertheless, there is a study that reveals that once sulfate and glucuronide conjugates of resveratrol are circulating in plasma (with an expected low bioavailability), their subsequent hydrolysis releases free resveratrol which can be captured by those cells with specific membrane receptors, increasing thus its bioavailability in specific tissues [
These conjugations may also depend on factors described in Section
But as they are increasingly consumed due to their potential antitumoral effects, a new variety with genetic variations has been proposed increasing thus the expression of transcription factors involved in glucosinolate biosynthesis. The resulting broccoli could deliver a larger amount of glucoraphanin (active sulforaphane) in plasma and urine [
The development of crystalline solid formulations by modifying physicochemical properties, as salt formation and micronization (particle size reduction), was initially adopted to amend the poor water solubility of Phy [
Over the last years, new formulation strategies to increase the clinical efficacy of poor water-soluble active compounds have been developed. Figure
Types of (nano)carriers used to increase bioefficacy of phytochemicals. Those developed for oral administration of active compounds are in italic characters.
Furthermore, it is worth mentioning that, in recent years, an increased interest has been focused on the incorporation of poorly water-soluble compounds into higher degree of biodegradability and biocompatibility; higher degree of versatility: lipid formulations can be modified in various ways to suit the stability requirements (molecular weight and physicochemical properties) and toxicity and efficacy of the active agent as well as the route of administration and cost; high and enhanced loading capacity; pharmaceutical stability; release of the active compound in controlled and targeted way; simple preparation methods and easy scale production; low risk of side effects (nontoxic).
The present work reviews the novel LBDS (vesicle and lipid particulate systems and emulsions) as recorded in Figure
LBDS can be obtained by blending excipients such as pure triglyceride oils, mixed glycerides, lipophilic surfactants, hydrophilic surfactants, and water-soluble cosolvents, which determine the absorption process [ Screening and preselection of lipid excipients, mainly considering their solubility, dissolution/dispersion properties, digestibility, and absorption. Other factors are irritancy, toxicity, purity, chemical stability (regulatory issues), capsule compatibility, melting point (depending on the fatty acid composition), and cost Identification of the suitable formulation technique for the intended dosage form. Often solid form, developed mainly by adsorption on solid carriers [ Testing the formulation in appropriate animal models to predict the Optimization of the formulation based on the Phy loading and dissolution profile.
The goal of any oral LBDS is to enhance the GI absorption and oral bioavailability of the active compound. Their mode of action involves the alteration of the following physiological effects.
(I) After oral administration of the lipid-Phy formulation and once in the aqueous environment of the stomach, gastric lipase initiates the digestion of formulation lipids. Simultaneously, peristaltic movements of the stomach facilitate dispersion of lipid excipients into small droplets (Figure
Mode of action of lipid-based delivery systems designed for the efficient oral administration of phytochemicals. (A) Allowing paracellular transport by opening tight junction; (B) facilitating transcellular absorption due to increased membrane fluidity; (C) promotion of phagocytosis via specialized microfold cells (M cells) of Peyer’s patches; (D) increased intracellular concentration and residence time by surfactants due to inhibition of P-gp and/or CYP450; (E) lipid stimulation of lipoprotein/chylomicron production.
(II) Once in the small intestine, lipid excipients stimulate bile flow and pancreatic juices excretion [
(III) Formation of colloidal systems (vesicles, micelles, and mixed micelles) that significantly enhances the intestinal absorption of lipid digestion products and Phy as follows:
(i) Changing Phy uptake by interacting with transport processes of enterocyte. These include mucoadhesion (interaction with mucin to increase membrane fluidity), paracellular transport by modulating tight junctions, and promotion of receptor-mediated transport processes (endocytosis, transcytosis, and phagocytosis) via M cells of Peyer’s patches and other mucosa-associated lymphoid tissues (MALT) (Figure
(ii) Inhibiting efflux transporter P-glycoprotein (P-gp) and metabolism by cytochrome P450 (CYP450) or cytochrome 3A (CYP-3A) isozymes (Figure
(iii) Enhancing Phy transport to the systemic circulation via intestinal lymphatic system [
All of this leads to an enhanced absorption, oral bioavailability, and bioefficacy of Phy, which should allow applying an accurate oral dosage to obtain reproducible results in clinical assays (reduced inter- and intrasubject variability) and enhance, thus, the clinical use of Phy therapy.
(IV) In addition of increasing water solubility, absorption, and oral bioavailability, lipid-based delivery systems have been shown to reduce the effect of coingested food on pharmacokinetics of the bioactive molecule [ increase Phy pharmaceutical stability and lengthen its systemic circulation time [ release Phy slowly over an extended duration (days or months) after a single administration (sustained release) [ enhance penetration into tumoral matrices, promoting more reliable Phy access, and enhance blood-brain barrier permeability [ modulate the biodistribution of incorporated molecules, which leads to targeted effects and, hence, reduced side effects [ overcome multidrug resistance [ enhance efficiency of codelivery of active ingredients and therapeutic agents [
As indicated in Figure
Liposomes are highly biocompatible and possess self-assembly capacity. They are considered pharmacologically inactive with minimal toxicity [ improving their water solubility and stability; avoiding their early precipitation and intestinal and hepatic degradation; leading to drug concentration in tumoral tissues. This is because liposomes are preferentially delivered and passively accumulate here due to the high interstitial pressure, enhanced vascular permeability and retention, and the lack of functional lymphatic drainage of solid tumors (passive targeting effect) [ minimizing side effects.
However, conventional liposomes show some disadvantages that limit their applicability. These include poor stability in the systemic circulation and high recognition by reticuloendothelial system (RES), which leads to short circulation time (short shelf life) and low encapsulation efficacy expulsion of loaded molecules by intermembrane transfer [
Over the last years, structural and physicochemical properties of liposomes have been modified to develop different types of liposomal delivery systems, called nanostructured liposomes, which do not show the drawbacks of the conventional ones [
Schematic representation of the different types of liposomal drug delivery systems: (A) conventional liposome; (B) PEGylated liposome; (C) ligand-targeted liposome; (D) theranostic liposome (reprinted from Frontiers in Pharmacology, 6, article 286, 1–12. Advances and Challenges of Liposome Assisted Drug Delivery, by Sercombe et al. [
The stability
Nanostructured liposomes have been adopted in recent years for the efficient oral delivery of several Phy with poor water solubility and stability in the gastric environment (Table
Moreover, brucine, an alkaloid isolated from
Silybin was the first bioactive compound marketed as Phytosome formulation. Phospholipid complexation significantly increased the water solubility and liver protection of silybin, which resulted in an increase of its oral bioavailability and pharmacological activity [
Generally, there are two types of lipid nanoparticles (LNPs), solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) [
LNPs are composed of a lipid solid matrix lipid and surfactants that provide stability [
Structure of solid lipid nanoparticles (SLNs) versus nanostructured lipid carriers (NLCs).
In the last years, a great attention has been paid to LNPs as an interesting and cost-effective alternative to polymeric nanoparticles, liposomes, and emulsions. LNPs are cheaper and safer than polymeric carriers, as their production is an organic solvent-free process [
Table
Several Phy have been also loaded into NLCs in studies focused on improving water solubility, enhancing GI absorption and oral bioavailability, controlling release, increasing stability, and lengthening circulation time by reducing the recognition by the reticuloendothelial system (RES) (Table
MEs are constituted by an oil phase, an aqueous phase, a surfactant, and, probably, a cosurfactant [
Like other promising carriers, MEs have been shown to improve oral delivery of bioactive compound by (i) enhancing stability and permeability, (ii) allowing a controlled and sustained release, and (iii) improving GI absorption and oral bioavailability via the lymphatic transport pathway [
Despite their numerous advantages, MEs present some limitations. They are sensitive to changes of environmental conditions, such as temperature, ionic strength, and composition (adding/removing molecules to/from the aqueous continuous phase), which may compromise their stability. In addition, MEs formation requires the use of relatively large amounts of synthetic surfactants to achieve an efficient loading capacity, especially when using triglycerides as dispersed oil phase [
Nanoemulsions (NEs), often also called miniemulsions, are systems with droplet-like structure. They are formed by an oil phase, an aqueous phase, and a mixture of surfactants and cosurfactants stabilizing droplets, whose average size is significantly (10-fold or so) smaller than that of droplets present in conventional emulsions [
Application of MEs and NEs as carriers for the efficient oral administration of Phy is shown in Table
Unlike all the previously described lipid formulations, these systems have a unique property: they remain in a preformulation state until ingestion. Upon dilution in aqueous physiological fluids of GI tract and with the gentle agitation provided by peristaltic movements, SEDSs are able to spread readily and self-emulsify spontaneously, forming fine o/w emulsions (50 nm > droplet size > 250 nm), that keep the active agent in solubilized form [
The reduction in emulsion particle size of these formulations once in the GI tract increases the surface area of particles, which, in turn, provides higher interfacial surface area and a very low interfacial tension. This provides SEDSs with a high capacity to solubilize the loaded Phy in the GI tract and to enhance its release and absorption and oral bioavailability [
Besides improving oral bioavailability of poor water-soluble Phy, SEDSs show multiple advantages. Among them are the following: Formulation surfactants increasing the intestinal permeability, which decreases surface tension and facilitates formulation contact with intestinal mucus [ SEDSs protecting loaded Phy against enzymatic degradation and avoid its first-pass hepatic metabolism SEDSs providing higher loading capacity than conventional lipid solutions Thermodynamic stability Ease of manufacture and scale-up. These advantages make SEDS unique when compared to other drug delivery systems like solid dispersions, liposomes, nanoparticles, and so forth [ Ease of administration and versatility of dosage form, in either liquid or solid form. Liquid dosage forms can be administered in soft or hard gelatin capsules but these have shown some drawbacks, such as high production costs, low drug compatibility and stability, drug leakage and precipitation, capsule ageing, and need of a large quantity of surfactants (30–60%), which can induce GI irritation. These disadvantages are overcome by formulating SEDS as solid forms by extrusion/spheronization methods [
The delivery of poorly water-soluble Phy using SEDSs has been extensively studied during the past decade and many of these studies are summarized in Table
Combined cancer therapy consisting in (i) the combined application of some of the most common types of cancer treatment, including surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy or (ii) the coadministration of different chemotherapy drugs, is often more effective. The rationale for combination chemotherapy is to use drugs that work by different mechanisms, thereby decreasing the likelihood that resistant cancer cells will develop. Moreover, when drugs with different effects are combined, each drug can be used at its optimal dose, without intolerable side effects [
Following the same rationale, it is believed that codelivery of antitumor drugs and plant bioactive compounds could improve therapeutic effects by targeting diverse molecular targets, reducing toxicity, overcoming drug resistance, and facilitating the use of lower and safer doses [
Phytochemicals combined with first-line antitumor drugs and their study in clinical trials. Nanocarriers used to enhance bioefficacy of codelivery are also shown.
Phytochemical | Codelivered antitumor agent |
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Clinical trial | Phase of study | Ref. |
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Ellagic acid | 5-Fluorouracil | Colon | — | — | [ |
Vinorelbine | — | Hormone refractory prostate cancer | Completed | [ | |
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Colon | — | — | [ | |
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(−)-Epigallocatechin-3-gallate (EGCG) | Tamoxifen + sulindac | Lung | — | — | [ |
Sulindac | Intestinal | — | — | [ | |
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Genistein | Tamoxifen | Breast | — | — | [ |
Gemcitabine hydrochloride | Pancreas | Breast | Completed | [ | |
Osteosarcoma | |||||
Decitabine | — | Pediatric solid tumors, leukemia | Recruiting | [ | |
Decitabine | — | Non-small cell lung | Completed | [ | |
Interleukin-2 (high-dose) | — | Kidney cancer | Completed | [ | |
Melanoma | |||||
5-Fluorouracil | Colon | — | — | [ | |
Docetaxel | Prostate | — | — | [ | |
Lung | |||||
Breast | |||||
Pancreas | |||||
Doxorubicin | Prostate | — | — | [ | |
Lung | |||||
Breast | |||||
Pancreas | |||||
Cisplatin | Ovarian | — | — | [ | |
Prostate | |||||
Lung | |||||
Breast | |||||
Pancreas | |||||
Erlotinib | — | Pancreas | Completed | [ | |
Erlotinib + gemcitabine | Pancreas | Pancreas | Completed | [ | |
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Luteolin | Celecoxib | Breast | — | — | [ |
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Quercetin | Docetaxel | Prostate | — | — | [ |
5-Fluorouracil | Esophageal | — | — | [ | |
Colorectal | |||||
Liver | |||||
Sulindac | Colorectal | Colon | Completed | [ | |
Tamoxifen | Breast | — | — | [ | |
Paclitaxel | Liver | — | — | [ | |
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Resveratrol | Rapamycin | Breast | — | — | [ |
Doxorubicin | Breast | — | — | [ | |
Temozolomide | Glioma | — | — | [ | |
5-Fluorouracil | Colon | [ | |||
Mitomycin | Colorectal | — | — | [ | |
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Curcumin | Irinotecan | Colorectal | Colorectal | Active | [ |
Folfox | Colon | Active | [ | ||
Sulindac | Lung | Colorectal | Completed | [ | |
Capecitabine | Rectal | Active | [ | ||
5-Fluorouracil | Colorectal | — | — | [ | |
Dasatinib | Colon | — | — | [ | |
Paclitaxel | Breast | [ | |||
Celecoxib | Colon | [ | |||
Gemcitabine | Lung | — | — | [ | |
Genistein | Prostate | — | — | [ | |
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Lycopene | Docetaxel | Prostate | Adenocarcinoma of the prostate | Active | [ |
Overview of nonlipid formulations, which have been designed to administer phytochemicals by oral route.
Active ingredient | Lipid-based formulation | Effect of formulation | Ref. | |
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Type | Subcategory | |||
Curcumin | PBDS | PLGAa-NPs | Overcome multidrug resistance and increased oral bioavailability |
[ |
Silymarin |
|
[ | ||
Curcumin | Hydroxypropyl cellulose NPs | Temperature-dependent release |
[ | |
Puerarin | Dendrimers | Increased |
[ | |
Curcumin | ||||
Resveratrol | ||||
Genistein | ||||
Podophyllotoxin | ||||
Curcumin | Hyaluronic acid conjugate | Improved water solubility, stability, and antitumoral activity |
[ | |
Alginate conjugate | Higher water solubility, stability, and cytotoxicity |
[ | ||
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Rutin | CD inclusion complexes |
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Improved water solubility and stability, increasing the oral bioavailability and bioefficacy. | [ |
3-EGCG | [ | |||
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Silymarin |
Inorganic nanocarriers | Porous silica nanoparticles (PSN) | Sustained release and enhanced oral bioavailability |
[ |
Silybin meglumine | [ | |||
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Resveratrol | Hybrid nanocarriers | TCCc- liposomes | Improved absorption and oral bioavailability and reduced side effects |
[ |
DQA-PEG1930-DSPEa liposomes | [ | |||
Vincristine | Dextran-sulfate-SLNs | [ | ||
PLGA-PEG-R7a NPs | [ | |||
Tripterine | CPPa-NLCs | [ | ||
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Silymarin | Other novel nanocarriers | Liquid crystalline nanocarrier | Sustained release. |
[ |
Quercetin | Folate-modified lipid nanocapsules | [ | ||
Tetrandrine | Lipid nanocapsules | [ |
b
cTCC: N-trimethyl chitosan chloride-coated.
Overview of lipid-based delivery systems to administer phytochemicals by oral route.
Active ingredient | Lipid-based formulation | Effect of formulation | Ref. |
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Vinorelbine | Liposomes | Reduced side effects and increased circulation half-life. | [ |
Improved therapeutic effect | |||
Gypenoside | Activated |
[ | |
Curcumin | Improved pharmacokinetics and oral bioavailability |
[ | |
3-EGCG | Enhanced |
[ | |
Brucine | Improved absorption and oral bioavailability, enhanced targeting, and reduced side effects |
[ | |
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Quercetin | Phytosome | Enhanced membrane permeability, sustained and controlled release. |
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Kaempferol | [ | ||
Isorhamnetin | |||
Silybin | [ | ||
3-EGCG | [ | ||
Quercetin | [ | ||
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Microemulsions | Increased water solubility and permeability and improved oral bioavailability. | [ |
Hydroxysafflor yellow A | [ | ||
Puerarin | [ | ||
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Baicalin | SEDS | Enhanced stability, oral bioavailability, and targeting effects |
[ |
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Curcumin | SMEDS | Enhanced stability, oral bioavailability, and targeting effects |
[ |
Indirubin | [ | ||
Hydroxysafflor yellow A | [ | ||
Gentiopicrin | [ | ||
Lutein | [ | ||
Apigenin | [ | ||
Nobiletin | [ | ||
Oridonin | [ | ||
Silymarin | [ | ||
Puerarin | [ | ||
Hesperidin | [ | ||
Berberine hydrochloride (BBH) | [ | ||
|
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Morin | SNEDS | Enhanced stability, oral bioavailability, and targeting effects |
[ |
Curcumin | [ | ||
Lutein | [ | ||
Oleanolic acid | [ | ||
Vinpocetine | [ | ||
|
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Puerarin | SLNs | Improved absorption and oral bioavailability and reduced side effects (irritation of GI mucous membrane) |
[ |
Triptolide | [ | ||
Cantharidin | [ | ||
Resveratrol | [ | ||
|
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Silymarin | NLCs | Increased absorption and oral bioavailability |
[ |
Tripterine | [ | ||
Curcumin |
Codelivery strategy is, however, usually limited by low water solubility, poor oral bioavailability, undesirable pharmacokinetic characteristics, and side effects [
In this sense, few Phy described in Table
To overcome limitations in the oral administration of poor water-soluble Phy, parental (intravenous and intraperitoneal) and topical (transdermal, nasal, and ocular) administration routes can be used to increase dose precision and clinical efficacy.
Likewise, in recent years, topical delivery of bioactive compounds has also drawn great attention owing to its advantages over other administration routes and outstanding contribution in improving local action [
On the other hand, and to get over limitations of parenteral and topical administration routes, application of nanocarriers has demonstrated to be also an efficient formulation strategy. Table
Overview of lipid and nonlipid formulations, which have been designed to administer phytochemicals by parental and topical routes.
Phytochemical | Lipid-based formulation | Effect of formulation | Admin. route | Ref. | |
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Type | Subcategory | ||||
Curcumin | LBDS | NLCs | Enhanced stability and brain targeting |
Intraperitoneal | [ |
Baicalein | LBDS | Tocol-NLCs | [ | ||
|
NLCs | Less irritating and toxic and enhanced bioavailability and antitumor efficacy |
[ | ||
Bufadienolides | Reduced toxicity and improved pharmacokinetic profile |
Intravenous | [ | ||
Breviscapine | Ionic-complex-based NLCs | Sustained-release and protection against liver enzyme degradation |
[ | ||
Berberine | DQA-PEG2000-DSPE |
Overcome multidrug resistance |
[ | ||
|
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Quercetin | LBDS | MEs | Transdermal | [ | |
Genistein | Increased permeation and skin retention. | [ | |||
Chlorogenic acid | Efficient systemic distribution |
[ | |||
Resveratrol | |||||
Curcumin | PEG |
Increased stability and anti-inflammatory effects |
[ | ||
Bufadienolides | Poloxamer-liposomes | Reduced toxicity and enhanced antitumor efficacy |
[ | ||
Ligustrazine phosp. | Ethosomes | Enhanced skin permeation |
[ | ||
Apigenin | Enhanced anti-inflammatory effects |
[ | |||
Curcumin | NLCs | Enhanced antitumor activity and brain targeting |
Intranasal | [ | |
Tetrandrine | Charged SLNs | Reduced irritation of eye mucous membrane in vivo. | Ocular | [ | |
|
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3-ECGC | Inorganic carriers | Gold NPs | Enhanced efficacy and reduced toxicity |
Intratumoral injection | [ |
|
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Curcumin | PBDS | Dextran sulfate-chitosan NPs | Controlled release and targeted effect against tumor cells |
Intravenous | [ |
Curcumin | Chitosan/PBCA |
|
[ | ||
Trans-resveratrol | Chitosan-NPs | Higher |
[ | ||
Oridonin | Galactosylated chitosan NPs | Enhanced targeting and binding to the specific site of action (liver). | |||
|
|||||
Artemisinin | PBDS | Polymeric micelles |
Achieving site-specific cell targeting and enhancing intracellular drug accumulation. | Intraperitoneal | [ |
Resveratrol | Transferrin modified PEG-PLA |
Cellular uptake, |
[ | ||
Bufalin | Biotinylated chitosan NPs | Enhanced targeting and binding to the specific site of action breast carcinoma. | [ | ||
|
|||||
Quercetin | PBDS | Lecithin-chitosan NPs |
|
Topical | [ |
Phy are molecules obtained from natural plant species and in the last decades have shown their positive benefits in human health, in prevention and treatment.
In the framework of cancer, polyphenols are the most studied group of phytochemicals, in both the
The bioavailability of these compounds still adheres to measure urine levels as a routine parameter, but many authors defend the use of carriers to improve their availability in plasma and in targeted organs. This need is reflected in the development of new delivery mechanisms, where lipid-based delivery systems are part of a strategy to increase the water solubility and stability, prevent the rapid systemic clearance, prevent the intestinal and hepatic metabolism, enhance the bioavailability, and enhance the cancer cell targeting. The importance of measuring tissue levels of the chemopreventive agents would help to better understand the mode of action of the nanoparticles and phytochemicals and to avoid toxicity of both.
All the authors declare that there are no conflicts of interest regarding the publication of this paper.
Lamia Mouhid and Marta Corzo-Martínez contributed equally to the manuscript.
This work has been supported by Ministerio de Economía y Competitividad del Gobierno de España (MINECO, Plan Nacional I+D+i AGL2013-48943-C2-2-R), Gobierno Regional de la Comunidad de Madrid (P2013/ABI-2728, ALIBIRD-CM), and EU Structural Funds. Marta Corzo-Martínez also thanks Ministerio de Economía y Competitividad (Spain) for her Juan de la Cierva contract.