Corresponding author: Yordan Yordanov ( yyordanov@pharmfac.mu-sofia.bg ) Academic editor: Maya Georgieva
© 2019 Yordan Yordanov.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Yordanov Y (2019) Caffeic acid phenethyl ester (CAPE): cornerstone pharmacological studies and drug delivery systems. Pharmacia 66(4): 223-231. https://doi.org/10.3897/pharmacia.66.e38571
|
Propolis is a natural product with a plethora of biological effects, utilized by traditional medicine since antiquity. However, its application as a pharmaceutical is hindered by its variable composition and difficult standardization. CAPE has been shown to be a major component of propolis, with a large contribution to its pharmacological effects, among which the anti-inflammatory, antioxidant and antineoplastic have been attracting most attention. The current review article aims to present the cornerstone pharmacological studies of CAPE throughout the years, following its discovery, which confirmed its primary importance among propolis constituents and opened the path to its intensive research as a potential pharmaceutical. We present the diversity of drug delivery systems of CAPE, which have been developed to improve its efficacy in in vitro and in vivo disease models and discuss their primary promises and weaknesses. The increased interest in recent years over more practical approaches of CAPE research such as its pharmaceutical formulation comes to show that it has a potential to become commercialized as a pharmaceutical.
Caffeic acid phenethyl ester, propolis, pharmacological properties, drug delivery systems
Propolis is well known for its traditional medical use since antiquity, and its pharmacological activities have been extensively studied in the forms of different extracts and preparations. As for its primary biological function – an antiseptic in the beehives, there is evidence that the antimicrobial activity of the complex mixture of plant metabolites has synergistic activity, which is higher than the activity of any single component (
In order to illustrate the popularity and dynamics of CAPE research over the years, we applied a search in Scopus database (
This first period is followed by one of rapidly increasing number of publications, predominantly elucidating the mechanisms behind CAPE’s pharmacological activities and proposing new applications for diseases, known to be affected by these activities. This period after the year 2000 and especially the research on the basic principles behind CAPE’s impressive diversity of biological effects are the subjects of a related article (
Chronology of milestone research publications on the biological activities of CAPE.
Model system | Major effects | Comment | Ref. |
---|---|---|---|
Cell lines (C3H 10T1/2; Ltk-; normal rat 6 cells; CV1; Vero; CREF; wt3A; MCF-7; SK-MEL-28; SK-MEL-170; HT-29; normal 1434 fibroblasts and melanocytes) | In vitro differential cytotoxicity towards transformed cells, compared to normal cells | 2.5 to 50 µg/ml | ( |
Adenovirus-transformed, compared to normal rat cloned rat embryo fibroblast (CREF) cells | In vitro inhibits chemical-viral carcinogenesis | 0.1–5 µg/mL |
( |
5-LOX, isolated from barley; activated human neutrophils | In vitro antioxidant; 5-LOX inhibitor | 10 µM | ( |
Escherichia coli – produced HIV-1 integrase protein | In vitro antiviral; HIV-1 integrase inhibitor | Integration IC50 = 19 µM | ( |
SENCAR mice | In vivo inhibits chemical carcinogenesis, anti-inflammatory | – | ( |
Adenovirus-transformed rat embryo fibroblast cells | In vitro proapoptotic to transformed cells | 1 µg/mL | ( |
U937 cell line | In vitro blocks activation of NF-κB by tumor necrosis factor (TNF) | prevents the translocation of the p65 subunit of NF-κB to the nucleus | ( |
Rabbits | In vivo protective against spinal cord ischemia/reperfusion injury | 10 μmol/kg pretreatment | ( |
In order to choose a pharmaceutical approach, that will allow for the effective utilization of the biological effects of CAPE, an in-depth understanding of its pharmacokinetic behavior is essential. Pharmacokinetic studies show a favorable profile of CAPE with the exception of its poor water solubility, the resolution of which is a task, achievable by applying tailored technological approaches for pharmaceutical formulation. CAPE has been shown to be hydrolyzed to caffeic acid in rat plasma, but not in human plasma, which is explained by
In vivo experiments show that CAPE’s oral bioavailability is limited due to its poor water solubility (0.021 mg/ml) which could be improved by means of pharmaceutical approaches (
Strategies for pharmaceutical formulation of CAPE and their effectiveness on biological model systems. Biologically-relevant effects marked with bullets●. Arrows represent comparisons towards CAPE water dispersion: ↑more pronounced effect; ↓decrease of activity/biomarker; → comparable effectiveness; no arrow after bullet – comparison not applicable due to experimental design specifics. In vitro studies in normal script, in vivo studies represented in bold script, and major experimental design characteristics represented in italic script.
Pharmaceutical formulation strategy | CAPE preparation |
Physico Chemical outcome |
Biological outcome (experimental system) | Ref. |
COCRYSTAL FORMATION | cocrystals with nicotinamide | ↑ solubility (17.7×) | ●↑oral bioavailability (2.76×) (rats, 100 mg/kg p.o.) | ( |
PRODRUGS | 4-O-β-D-glucopyranoside | ↑ solubility (35×) | ●↓ TNF-α; IL-6; NO (LPS-induced RAW 264.7 macrophages, 5 µM) | ( |
●↓ cytotoxicity (A375; SMMC-7721; SGC-7901 A549 cell lines, 100 µM) | ||||
4-O-α-D-glucopyranoside | ↑ solubility (770×) | ●↓NO equally to CAPE | ( |
|
↑ stability to oxidation and hydrolysis | ●↑Nrf-2 activation | |||
●Intracellular conversion to CAPE (LPS-induced RAW 264.7 macrophages, 15 µM) | ||||
4-Acylated or 3,4-diacylated | ↑lipid solubility | ●↑protection against oxidative stress induced cell injury | ( |
|
●↑blood-brain barrier permeability (PC12 cell line) | ||||
INCLUSION COMPLEXES | hydroxypropyl-β-cyclodextrin | ↑ solubility catechol in CD cavity | – | ( |
MICROEMULSIONS | eugenol/water | ↑ stability droplets 80–250 nm | ●↑cytotoxicity (HCT-116 cell line, 2 µg/ml) | ( |
SPIONs/eugenol/water | ↑ stability droplets 100–900 nm | ●↑cytotoxicity | ( |
|
●↑cytotoxicity upon external magnetic field (HCT-116 cell line, 2 µg/ml) | ||||
peppermint oil/water | ↑ stability droplets size - <20 nm | ●↑cytotoxicity | ( |
|
●↑cellular uptake | ||||
●↓cyclin D expression | ||||
●↑p53 expression (HCT-116, MCF-7 cells, 10 µg/ml) | ||||
LIPOSOMES | EPC-35, cholesterol and PEG2000-DSPE liposomes | ↑ stability Size – 100 nm; incorporation in bilayer | – | ( |
MICELLES | non-ionic surfactant micelles | ↑ stability | ●↓plasma histamine, released due to Cremophor RH40 (50 µg/kg CAPE; 10 mg/kg solubilizer) | ( |
●↑histamine release, compared to solubilizer alone (isolated peritoneal mast cells; 100 µM CAPE, 20 to 2000 µg/ml solubilizer) | ||||
sucrose fatty acid ester micelles | ↑ stability particle size<100 nm | ●→antioxidant (DPPH; ABTS scavanger) | ( |
|
●↑cytotoxicity (HCT-116; MCF-7 cells, 2 µg/ml) | ||||
triblock copolymer micelles (PEO-b-PCL-b-PEO) | ↑ stability size: 39 nm; narrow size distribution; slightly positive zeta-potential | ●↑ protection against oxidative stress induced cell injury (Hep G2, SH-SY5Y cells, 0.1 µg/ml) | ( |
|
COPOLYMER NANOPARTICLES | poly(d,l-lactic-co-glycolic acid) NPs | ↑ stability Size: 206 nm; highly negative zeta potential | ●↑antigenotoxic<ethanol CAPE (Ames test; 14 µg/ml) | ( |
●↑moderate antimicrobial (S. aureus, 31 µg/ml and MRSA, 61 µg/ml) | ||||
●↑antileischmanial on both forms of parasites (Leishmania infantum promastigotes, IC50=32 µg/ml and amastigotes, IC50=8 µg/ml) | ||||
methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) NPs | ↑ stability lyophilized and reconstituted at 20 mg/ml; size<300 nm; delayed release | ●↑antimetastatic (CT-26 Pulmonary Metastasis Model on BALb/C mice, 5 mg/kg i.v.) | ( |
|
●→weak cytotoxicity (RAW264.7 cells, 50 µg/ml) | ||||
●↑growth inhibition (0.5 µg/ml) | ||||
●↓migration (1 µg/ml) | ||||
●→proapoptotic (10 µg/ml)(CT26 cells,) | ||||
PROTEIN NANOPARTICLES | Albumin NPs | ↑ stability 250–300 nm; negative zeta potential | ●↓p65 and HIF-1α (mouse model of DDS-induced colitis, 20 mg/kg i.p.) | ( |
INCORPORATION IN POLYMER FILMS | CAPE NPs, incorporated in methyl cellulose films | NP size: 50−625 nm; film thickness: 45 to 55 µm | ●↓bacterial growth (S. aureus, MIC = 350 µg/mL and E. faecalis MIC = 700 µg/mL) ●→antioxidant (DPPH, FRAP) |
( |
electrospun poly(3-hydroxybutyrate), coated with polyvinylpyrrolidone | ↑solubility (~1.5×) tunable release profile | ●Bactericidal (S. aureus, 200 µg/mL) | ( |
|
↑surface area | ●Bacteriostatic (E. coli, 850 µg/mL) | |||
MATRIX DRUG DELIVERY SYSTEMS | poly(dimethyl siloxane) matrix | sustained release over 4 weeks | concept of intraocular lenses as devices for CAPE-delivery | ( |
Cocrystal formation. The development of cocrystals of a drug is a long-known strategy, which however has been undergoing rapid development throughout the last decade (
Synthesis of prodrugs. The two hydroxyl groups of CAPE’s catechol moiety make it amenable to conjugation with a variety of molecules, forming prodrugs with potentially improved solubility. In the last decade more than 10% of all FDA-approved small-molecule new chemical entities are prodrugs. Prodrugs have little or no pharmacological activity, but undergo enzymatic and chemical changes in the organism, which lead to their conversion to the active parent drugs (
Inclusion complexes are formed when a host compound with a hydrophilic exterior and lipophilic cavity, surrounds molecules or parts of molecules of proper size, held in place in the cavity only by van der Waals forces (
Microemulsions are thermodynamically stable systems with droplet sizes of about 10 to 100 nm. They can be water-in-oil, oil-in-water or bi-continuous systems, made of water, oil, surfactant and a co-surfactant. Microemulsions are monophasic, transparent and optically isotropic systems. They differ from emulsions by having much lower surface tension values and improved thermodynamic stability (
Liposomes are considered the most-successful drug delivery system with many FDA-approved drug products (
Micelles are dynamic colloidal particles with sizes usually in the range of 5–100 nm in which, unlike liposomes, amphiphilic molecules form monolayers. They consist of core-shell structured aggregates that form when the amphiphilic molecules reach their inherent critical micelle concentration (CMC). The lower the CMC, the more easily micelles are formed. The first study of a CAPE micelle formulation was on non-ionic surfactant dispersions at concentrations close to their CMCs (CMCs in the range of 0.1 mM to 1 mM or 0.01% to 0.05% w/v) and higher, which aimed at studying their histamine-releasing potential (
Copolymer nanoparticles have important advantages, including tunable physicochemical parameters, structural stability, capability to form complex structures by addition of a diverse set of functionalities, slow drug release and potentially - biodegradability (
Protein nanoparticles. Protein nanoparticles allow for the formulation of drug delivery systems with improved biocompatibility, biodegradability, surface modification and cellular uptake. There are several successful protein NP products on the market with undoubtedly the most successful and often pointed out as an example for nanopharmaceutical – Abraxane, which is an albumin-bound paclitaxel (
Incorporation in polymer films has been researched due to CAPE’s antibacterial and antioxidant activities. Such formulations can be applied in food packaging in order to increase the shell life of products at risk of oxidation or bacterial growth or in wound dressings for its antiseptic and anticicatrizing properties.
Matrix drug delivery systems are employed in a variety of pharmaceutical formulations, such as tablets, granules, capsules, films, implants, patches, pellets etc. The matrix is a vehicle, in which the active substance is distributed homogenously or dispersed. These systems have the advantages of being relatively simple and inexpensive for production and allow control of the release profile of the loaded drug (
The listed diversity of drug carriers have been shown to possess the capacity to resolve CAPE’s solubility issue while allowing its release in the organism, which are prerequisites for its successful pharmaceutical application. The biocompatibility of CAPE delivery systems for specific routes of administration ought to be tested in a case specific manner before they are applied clinically, with special attention on the toxicological approach for the complex nanosized drug delivery systems (
Research on CAPE in the decade after its discovery was focused mainly on finding proof that it is a major constituent of propolis, being a contributor to its diverse pharmacological effects. As such knowledge amassed the cornerstone research period was followed by a period of intensified research on its pharmacodynamic principles, which is the subject of a related article on CAPE’s therapeutic potential. In the recent years there has been a growing interest in approaches to overcome a major obstacle towards CAPE’s realization as a drug – its poor aqueous solubility. Formulation approaches of CAPE include diverse strategies to not only make it soluble, but also optimize its pharmacokinetic profile and efficacy in different pathological conditions. The described trends in research publication on different aspects of CAPE is an indication that it has a bright future as a pharmaceutical.