Abstract
Background: Oncology nutrition presents unique challenges for food technologists, including cancer cachexia, taste disorders (dysgeusia), and altered tumor metabolism, characterized by the Warburg effect – the preferential use of glycolysis. Glycolysis-restricted Foods for Special Medical Purposes (FSMP), based on high-energy lipids, offer a promising metabolic support strategy, but their development requires advanced formulation solutions.
Objective: The aim of this review article is a systematic analysis and synthesis of available scientific evidence regarding technologies and ingredients that can be applied in the design of foods, dietary supplements, and FSMP with zero or extremely low glycolytic load for oncology patients. The review focuses on five key areas: (1) lipid bases and ketogenic substrates, (2) bioactive glycolysis modulators, (3) metabolism-supporting ingredients, (4) taste masking technologies in the context of dysgeusia, and (5) strategies for ensuring thermal and oxidative stability during pasteurization.
Methods: A review of scientific and technical literature was conducted, analyzing 525 sources. After a selection process, 50 key ingredients and technologies were subjected to detailed analysis regarding their mechanism of action, typical usage levels, level of scientific evidence, and formulation challenges.
Results: A wide spectrum of ingredients was identified and characterized. Lipid bases, such as medium-chain triglycerides (MCT), structured lipids (MLM), and omega-3 fatty acids (EPA/DHA), form the energetic foundation. Exogenous ketogenic substrates, including ketone salts and esters, can directly support ketosis. Bioactive polyphenols (curcumin, EGCG, resveratrol) show potential for modulating glycolytic pathways in vitro. Strategies for managing dysgeusia were discussed, including zinc supplementation, complexation with cyclodextrins, and the use of bitterness blockers. Encapsulation technologies (e.g., spray drying, coacervation, liposomes) and antioxidant systems (tocopherols, rosemary extract) were also analyzed as crucial for protecting sensitive lipids during thermal processing.
Conclusions: Effective development of glycolysis-restricted FSMP requires an integrated approach, combining the selection of appropriate energy substrates with advanced sensory and stabilizing technologies. Although solid mechanistic and preclinical foundations exist for many ingredients, there is a lack of randomized controlled clinical trials (RCTs) evaluating complete, zero-carbohydrate FSMP formulas in the oncology patient population. Further research is crucial to confirm the clinical efficacy and optimize these advanced nutritional products.
Keywords: foods for special medical purposes (FSMP); oncology nutrition; cachexia; dysgeusia; Warburg effect; ketogenic diet; medium-chain triglycerides (MCT); omega-3; encapsulation; taste masking; thermal stability; polyphenols.
1. Introduction
Nutritional interventions in oncology are an integral part of comprehensive patient care, aiming not only to prevent and treat malnutrition but also to modulate the body's metabolic response to disease and therapy. One of the fundamental discoveries in cancer biology, with profound implications for nutritional strategies, is the Warburg effect. Described almost a century ago, this phenomenon involves the preferential use of aerobic glycolysis by cancer cells for energy production, even in the presence of ample oxygen. This metabolic adaptation provides cancer cells not only with ATP but also with intermediates necessary for macromolecule biosynthesis, supporting their uncontrolled proliferation. This justifies the search for nutritional strategies based on restricting glycolytic substrates, such as glucose, in favor of alternative energy sources, mainly lipids and ketone bodies [1].
Oncology patients face many nutritional challenges that drastically affect their quality of life and prognosis. A key problem is cancer cachexia, a complex metabolic syndrome characterized by progressive loss of muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support. It is estimated to affect 40-80% of patients with advanced cancer and is the direct cause of death in at least 20% of them [2]. Cachexia is driven by systemic inflammation and metabolic disorders that lead to a negative energy and protein balance. Simultaneously, a very common and burdensome problem is taste disorders (dysgeusia) induced by chemotherapy and radiotherapy, occurring in 73-93% of patients [3]. A metallic taste, food aversion, or impaired perception of sweetness lead to a decrease in appetite, reduced food intake, and deepening malnutrition.
Currently available Foods for Special Medical Purposes (FSMP) for oncology patients, although often high-energy and high-protein, largely rely on carbohydrates as the main energy source. This may be suboptimal in the context of tumor metabolism and does not fully address the specific needs of patients with cachexia or dysgeusia. Consequently, there is growing interest in designing a new generation of FSMP, whose formulation core is glycolysis restriction. Such a strategy assumes the delivery of calories mainly in the form of lipids, which not only bypass the glycolytic pathway but can also induce a state of nutritional ketosis, providing ketone bodies as an alternative fuel for healthy cells, and potentially an ineffective one for many types of cancer cells.
The aim of this review article is a comprehensive analysis of ingredients and technologies that can be used to create advanced, evidence-based FSMP formulations with glycolysis restriction. This review includes a detailed discussion of lipid bases and ketogenic substrates, bioactive glycolysis modulators, as well as key supporting technologies, such as advanced taste-masking methods to manage dysgeusia and encapsulation techniques to ensure thermal and oxidative stability of sensitive ingredients during pasteurization processes.
2. Lipid bases for FSMP with zero glycolytic load
The foundation for formulating glycolysis-restricted FSMP is the selection of an appropriate lipid base, which must meet several key criteria: provide high energy density, be characterized by unique metabolic properties supporting ketogenesis, and demonstrate stability during processing.
Medium-chain triglycerides (MCT)
Medium-chain triglycerides (MCT), consisting mainly of fatty acids with 8 (caprylic acid, C8) and 10 (capric acid, C10) carbon atoms, are a fundamental component in this category [4, 5]. Their unique metabolism involves faster digestion and direct absorption into the portal vein, bypassing the lymphatic system, which distinguishes them from long-chain triglycerides (LCT) [4, 6, 7]. In the liver, medium-chain fatty acids (MCFA) penetrate mitochondria independently of the carnitine transport system, where they undergo rapid beta-oxidation [5, 8]. Under conditions of limited glucose supply, the resulting acetyl-CoA is efficiently redirected to the ketogenesis pathway, leading to an increase in blood ketone body concentration [4, 5, 7]. Clinical studies confirm that MCT supplementation effectively raises beta-hydroxybutyrate (BOHB) levels [7]. Dosing in studies ranges from 3 g/day in enteral nutrition [4] to three times 30 ml of MCT oil daily [7]. It is recommended to start with lower doses (approx. 5 g) and gradually increase them to avoid gastrointestinal discomforts such as diarrhea or cramps [9, 10]. An important formulation aspect is osmolality control, which should not exceed 400 mOsm/kg [6]. Emulsification of MCT can improve tolerance and potentially increase the ketogenic effect [9, 10].
Free fatty acids C8 and C10 (MCFA)
Free fatty acids C8 and C10 (MCFA) also play an important role. Caprylic acid (C8) is considered the most ketogenic component of MCT, showing several times stronger action compared to C10 [10]. This mechanism is partly related to its ability to penetrate the inner mitochondrial membrane independently of carnitine palmitoyltransferase-I (CPT-I) [10]. Preclinical studies suggest that MCFA, including caprylic acid, may exhibit direct anticancer properties, e.g., by inhibiting glycolysis in cancer cells [1, 11].
Long-chain triglycerides (LCT)
Long-chain triglycerides (LCT), especially those rich in oleic acid (MUFA), such as high-oleic sunflower oil or olive oil, are a valuable addition to the lipid base. They are characterized by greater oxidative stability compared to oils rich in polyunsaturated fatty acids (PUFA), which is crucial during pasteurization [12, 13]. Oleic acid is metabolically neutral in terms of the eicosanoid pathway and is not a precursor to pro-inflammatory mediators, unlike omega-6 acids [14]. Lipid emulsions based on olive oil (e.g., 80% olive, 20% soybean oil) showed lower pro-inflammatory potential and less oxidative stress in clinical studies compared to standard MCT/LCT emulsions [12, 14, 15].
Structured lipids (SL)
Structured lipids (SL), especially MLM (medium-long-medium) type, are an advanced technology involving enzymatic interesterification, resulting in MCFA being placed in sn-1 and sn-3 positions of the glycerol molecule, and LCFA in the sn-2 position [16–18]. Such a structure ensures both rapid and stable energy delivery. MCFA are rapidly released by lipase, providing energy, while LCFA in the form of 2-monoglyceride (2-MAG) is efficiently absorbed [17, 18]. Compared to physical mixtures of MCT and LCT, MLM lipids avoid the rapid release of MCFA, which can reduce the metabolic burden on the liver [16]. However, their low oxidative stability should be kept in mind, requiring the addition of antioxidants to the formulation [16, 17, 19].
Omega-3 polyunsaturated fatty acids (PUFA)
Omega-3 polyunsaturated fatty acids (PUFA), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), derived from fish oil or microalgae oil, are key ingredients with immunomodulatory and anti-inflammatory effects [2, 20, 21]. Their mechanism of action includes inhibiting the production of pro-inflammatory eicosanoids derived from arachidonic acid (omega-6) and the synthesis of anti-inflammatory resolvins [20, 22, 23]. In oncology, EPA is particularly studied in the context of preventing and treating cachexia, showing the ability to protect muscle mass [2]. Typical doses in clinical studies range from 300 mg to 5 g of EPA+DHA daily [24]. The main formulation challenge is their exceptional susceptibility to oxidation, which generates undesirable tastes and odors [2, 22].
Avocado oil and flaxseed oil
Avocado oil and flaxseed oil are alternative, plant-based lipid sources. Avocado oil is rich in oleic acid (~70-75%) and natural antioxidants (tocopherols, phytosterols), which provides it with high thermal stability (smoke point >250°C) [25]. Flaxseed oil is the richest plant source of alpha-linolenic acid (ALA), a precursor to EPA and DHA [26–28]. ALA exhibits anti-inflammatory effects, competing with linoleic acid in metabolic pathways [26, 27, 29]. However, it is extremely sensitive to oxidation and requires storage at low temperatures and protection from light [27, 28].
Phospholipids
Phospholipids (lecithin, krill phospholipids), mainly phosphatidylcholine (PC), play a dual role: as a structural component of cell membranes and as a natural emulsifier [30, 31]. They provide bioavailable choline and facilitate fat digestion and absorption by participating in micelle formation [31, 32]. It has been shown that EPA and DHA delivered in phospholipid form (e.g., from krill oil) have higher bioavailability compared to triglyceride or ethyl ester forms [31].
3. Exogenous ketogenic substrates
To rapidly and effectively induce a state of nutritional ketosis, regardless of dietary restrictions, exogenous sources of ketone bodies have been developed. These are valuable additions to FSMP formulations, allowing for an increase in blood beta-hydroxybutyrate (BHB) levels, which can be metabolically beneficial for oncology patients [33]. These compounds allow bypassing endogenous hepatic ketogenesis, providing a ready energy substrate for the brain and muscles [34, 35].
BHB mineral salts
BHB mineral salts are the most common form of exogenous ketones. These are compounds in which the BHB molecule is ionically bonded to minerals such as sodium, potassium, calcium, or magnesium [34–36]. This form improves the stability, water solubility, and bioavailability of BHB [35]. Kinetic studies in healthy volunteers have shown that BHB salt intake at a dose of 0.5 g/kg body weight leads to a significant increase in D-betaHB concentration in the blood [37]. Therapeutic doses in clinical studies range from 6-12 g BHB daily up to 30-50 g/day depending on the intervention goal [38, 39]. The main challenge associated with BHB salts is their taste – often described as sour, salty, or even soapy – which is a significant barrier to patient acceptance, especially those with dysgeusia [37]. Furthermore, high doses can lead to gastrointestinal discomforts and introduce a significant mineral load, which can affect acid-base and electrolyte balance and requires monitoring [37].
Ketone esters (KE)
Ketone esters (KE) are another generation of ketogenic substrates, characterized by higher efficiency in raising blood BHB levels. These are compounds in which ketone body molecules (e.g., acetoacetate or BHB) are linked by an ester bond to an alcohol, most commonly (R,S)-1,3-butanediol [40, 41]. After consumption, esters are hydrolyzed in the intestines by esterases, releasing ketone bodies and butanediol, which is then metabolized in the liver to BHB [42–44]. Clinical studies have shown that ketone esters can raise blood BHB levels to therapeutic values (2-5 mM) while simultaneously lowering glucose levels [45]. Example doses used in human studies are 12.5 g to 50 g of ester per serving [39, 43]. Like salts, ketone esters are characterized by a very unpleasant, bitter taste, which is a serious formulation challenge [40, 42, 44]. In studies, attempts have been made to mask the taste, e.g., by adding stevia, and also by serving the product in the form of a chilled, flavored drink (e.g., chocolate or tropical) [39, 40, 43, 44]. Nevertheless, reported side effects such as nausea, dizziness, and gastrointestinal discomfort remain a problem [33, 42, 44].
D-BHB monoesters
D-BHB monoesters, such as the monoester of (R)-1,3-butanediol and D-beta-hydroxybutyrate, are a newer form that delivers the biologically active D-BHB isomer, which can lead to a faster and more effective increase in its plasma concentration compared to racemic mixtures [46].
1-Monocaprin
1-Monocaprin (medium-chain monoacylglycerol) is a monoglyceride of capric acid (C10) [47]. Although not a direct precursor of ketone bodies like salts or esters, it is a source of MCFA, which are substrates for ketogenesis. Medium-chain monoglycerides (MCM) are being studied for their impact on metabolic health [48]. 1-monocaprin is a solid compound with a melting point of approximately 53°C, which must be considered in thermal processes [49]. It can act as a co-surfactant, facilitating the formation of stable microemulsions or emulsions in aqueous formulations, which can improve lipid dispersion and absorption in the gastrointestinal tract [50, 51].
4. Bioactive glycolysis modulators permissible in food/FSMP/supplements
Beyond the restriction of exogenous glycolytic substrates, the strategy for formulating FSMP for oncology patients can be enriched with bioactive compounds of natural origin that demonstrate the ability to modulate key metabolic pathways in cancer cells. Many plant polyphenols, approved for use in food and dietary supplements, have been studied for their ability to inhibit glycolysis, often through direct or indirect inhibition of enzymes such as hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), or pyruvate kinase M2 (PKM2).
Curcumin
Curcumin, the main polyphenol of turmeric (Curcuma longa), is one of the best-studied compounds in this context [52, 53]. Its anticancer action is multifaceted and includes, among others, inhibition of NF-kappaB and COX-2 signaling pathways, activation of the Nrf2 antioxidant pathway, and direct modulation of metabolism [54, 55]. In vitro studies have shown that curcumin can inhibit key glycolytic enzymes, including HK2 [56]. Clinical evidence from oncology studies, though still in early stages, suggests safety of use even at high doses (up to 8 g/day) [53]. The main challenge is the low bioavailability of curcumin, resulting from its poor water solubility and rapid metabolism [52, 54]. To improve absorption, advanced delivery systems are used, such as phytosomal formulations (complexes with phosphatidylcholine), which have shown a significant increase in bioavailability [53]. Studies have shown that lecithin-curcumin complexes protect the compound from degradation at intestinal pH and elevated temperatures (65°C), which is important in the context of pasteurization [57].
Epigallocatechin-3-gallate (EGCG)
Epigallocatechin-3-gallate (EGCG), the most abundant and active catechin in green tea (Camellia sinensis), also shows potential in modulating the energetic metabolism of cancer cells [58]. EGCG's mechanisms of action include inhibition of glucose transporters (e.g., GLUT1), inhibition of LDHA, and influence on PI3K/Akt/mTOR signaling pathways [59]. EGCG, like curcumin, has antioxidant and anti-inflammatory properties [58, 60]. Doses used in clinical studies are typically 300-800 mg EGCG per day [61]. A problem is the low bioavailability and stability of EGCG, especially in neutral or alkaline pH environments, which leads to rapid degradation [58, 62]. Encapsulation technologies are a promising strategy to improve the stability and delivery of EGCG in food formulations [61, 62]. Caution should be exercised, however, as high doses of EGCG (>=800 mg/day) have been linked to the risk of liver damage [61].
Resveratrol
Resveratrol, a polyphenol found, among others, in grapes, is known for activating sirtuins (e.g., SIRT1) and AMP-activated protein kinase (AMPK), which are key regulators of cellular metabolism [63]. Activation of AMPK by resveratrol can lead to inhibition of anabolic pathways and glycolysis. Preclinical studies suggest that resveratrol can inhibit glycolysis by lowering HIF-1alpha expression [64]. Doses used in human studies range from 500 mg to 5 g per day, with doses above 2.5 g potentially causing gastrointestinal discomfort [65]. Like other polyphenols, resveratrol is characterized by low water solubility and stability, being sensitive to light, oxygen, and pH changes, which requires the use of encapsulation systems to protect it [63, 65].
Quercetin, a flavonoid commonly found in fruits and vegetables, also exhibits anticancer activity by modulating signaling pathways such as PI3K/mTOR and inhibiting the PKM2 enzyme[66]. Its main limitation is very low water solubility (approx. 0.01 mg/mL) and low bioavailability[66, 67]. A solution to this problem are phytosomal formulations (e.g., Quercefit®), in which quercetin is complexed with sunflower lecithin. Such a formulation, as shown in clinical studies, can increase the bioavailability of quercetin up to 20-fold compared to the unmodified form[66, 68]. Dosage in clinical trials using quercetin phytosomes ranged from 500 to 1000 mg per day[66–68].
Genistein, a soy isoflavone, acts as a phytoestrogen, affecting estrogen receptors, but also modulates hormone-independent pathways[69, 70]. Genistein has been shown to limit glucose and glutamine uptake by cancer cells and affect signaling pathways such as PI3K/Akt and HIF-1α[71]. This is another compound with low water solubility, which limits its application[69].
Berberine, an isoquinoline alkaloid, is a potent AMPK activator, leading to inhibition of the mTOR pathway and suppression of cancer cell proliferation[72]. Its bioavailability is extremely low, estimated at less than 1%[73]. For this reason, similar to quercetin and curcumin, phytosomal formulations (e.g., Berbevis®) have been developed, which significantly improve its absorption and tolerance[74, 75]. Berberine doses used in clinical studies typically range from 900-1500 mg per day[75].
Supportive Bioactives: Anticatabolic, Mitochondrial, and Anti-inflammatory
In addition to ingredients directly modulating glycolysis, effective FSMP formulations for oncology patients should include compounds supporting overall metabolic condition, especially in the context of cachexia and high energy demand.
Coenzyme Q10 (CoQ10), in its two forms – oxidized (ubiquinone) and reduced (ubiquinol) – is a key component of the mitochondrial respiratory chain, essential for ATP production[76, 77]. As the only endogenously synthesized fat-soluble antioxidant, it protects cell membranes and lipoproteins from lipid peroxidation[76, 78]. In the context of a high-fat diet, CoQ10 can support the efficiency of energy metabolism in mitochondria. Clinical studies suggest that CoQ10 supplementation, typically at doses of 100-300 mg daily, may provide benefits in conditions of increased oxidative stress[76–78]. Formulation with CoQ10 requires the use of a lipid carrier (e.g., soybean oil), as it is water-insoluble and its crystalline form has significantly lower bioavailability[76, 77].
L-carnitine and acetyl-L-carnitine (ALCAR) are essential for transporting long-chain fatty acids into the mitochondrial matrix, where they undergo β-oxidation[79, 80]. In a lipid-rich diet, adequate L-carnitine supply is crucial for efficient utilization of fats as an energy source. Carnitine deficiencies are often observed in oncology patients, which can contribute to fatigue and weakness. Clinical studies in oncology have evaluated L-carnitine supplementation at doses ranging from 2 to 6 grams per day for the treatment of fatigue and cachexia[81–84]. The bioavailability of L-carnitine from supplements is relatively low (14-18%) and dose-dependent[84, 85]. Caution should be exercised regarding interactions with certain medications, e.g., antibiotics containing pivalate[79].
Leucine and its metabolite HMB (β-hydroxy-β-methylbutyrate) play a key role in regulating muscle protein metabolism. Leucine is a potent activator of the mTOR signaling pathway, which initiates muscle protein synthesis[86, 87]. HMB exhibits a dual action: it not only stimulates protein synthesis (via mTORC1 activation) but also inhibits their breakdown (proteolysis), mainly by suppressing the ubiquitin-proteasome pathway[86, 88, 89]. This makes HMB a particularly promising ingredient in the fight against sarcopenia and cancer cachexia[88]. Clinical and preclinical studies suggest that HMB is more potent than leucine in inhibiting catabolism[90]. Typical HMB supplementation doses range from 1.5-3 g daily, with doses up to 6 g/day considered safe[86, 88, 91]. HMB is available as a calcium salt (HMB-Ca) or as free acid (HMB-FA), with the acid form potentially characterized by faster absorption[86, 88, 91].
Glycine, the simplest amino acid, traditionally considered non-essential, is gaining importance as a component with anti-inflammatory, immunomodulatory, and cytoprotective properties[92, 93]. It is a precursor to glutathione, a key intracellular antioxidant[94]. Preclinical studies on cancer cachexia models have shown that glycine supplementation protects muscle mass, reduces oxidative stress, and the expression of genes associated with protein breakdown[95]. In clinical studies, doses ranging from 3-5 g daily up to 0.4 g/kg body weight were used[96, 97]. Glycine is well water-soluble and has a sweet taste, which facilitates its inclusion in formulations[93, 94, 98].
Whey Protein Isolate/Hydrolyzate (WPI/WPH) is considered one of the highest quality protein sources in clinical nutrition due to its complete amino acid profile, high content of branched-chain amino acids (BCAA) including leucine, and rapid digestibility[99]. WPI, being practically lactose- and fat-free, is an excellent choice for patients with intolerances[100]. Hydrolyzates (WPH), being "pre-digested" proteins, provide even faster absorption of amino acids and peptides[101, 102]. Whey proteins are also a rich source of cysteine, an amino acid limiting glutathione synthesis, which can support the body's antioxidant system[100, 103, 104]. Clinical studies in oncology have confirmed that WPI supplementation at doses of 20-40 g/day can improve nutritional status, muscle mass and strength, and reduce chemotherapy toxicity[100, 103, 105]. However, caution should be exercised regarding thermal processing, as whey proteins denature at temperatures above approx. 65°C, which can alter their functional properties and texture[87, 101, 102].
Managing Dysgeusia Induced by Oncology Treatment
Taste and smell disorders (dysgeusia) are among the most troublesome side effects of chemotherapy and radiotherapy, significantly reducing quality of life and leading to food aversions and malnutrition. Effective management of these symptoms is a crucial element in designing acceptable and effective FSMP formulations.
Zinc is a micronutrient with a documented role in taste function[106]. Its deficiency can lead to impaired taste perception, and supplementation is one of the best-studied strategies in treating dysgeusia. The mechanism of zinc's action likely involves its role as a cofactor for enzymes critical for the regeneration and function of taste buds[3]. Meta-analyses of clinical studies indicate that zinc supplementation, most often as sulfate, gluconate, or acetate, at doses of 25 to 60 mg Zn²⁺ ions per day, can be effective in alleviating dysgeusia induced by head and neck radiotherapy[107]. Results for post-chemotherapy dysgeusia are less conclusive[107]. Particularly promising is polaprezinc, a chelate of zinc and L-carnosine, which beyond delivering zinc, exhibits a protective effect on the mucous membrane[3]. It is important to remember about zinc bioavailability, which can be limited by phytates present in plant products[108, 109].
Cyclodextrins (CD), especially β-cyclodextrin (β-CD) and its hydroxypropyl derivative (HP-β-CD), are cyclic oligosaccharides with a torus-like structure[110]. They possess a hydrophobic interior and a hydrophilic outer surface, allowing them to form inclusion complexes with hydrophobic molecules, including many bitter drugs and bioactive ingredients[110]. By enclosing a bitter molecule within their cavity, cyclodextrins physically limit its contact with taste receptors on the tongue, effectively masking bitterness[111]. This technology is particularly useful for bitter, lipophilic ingredients, such as some polyphenols. HP-β-CD has GRAS status from the FDA and is approved as an excipient in pharmaceutical products[110, 111]. Cyclodextrins are thermally stable (above 200°C), making them compatible with pasteurization processes[110].
Complex coacervation is a process in which two oppositely charged biopolymers (typically a protein and a polysaccharide, e.g., gelatin and gum arabic or gelatin and carboxymethylcellulose) separate from a solution, forming a concentrated liquid phase (coacervate), which can be used for microencapsulation[112–114]. The formed shell acts as a physical barrier that can protect active ingredients and mask their undesirable taste[112, 114]. The process is dependent on pH, polymer ratio, and ionic strength[112, 113]. Coacervates exhibit good thermal stability, suggesting their suitability for pasteurized products[113, 114].
Liposomes and micelles are lipid-based nanocarrier systems. Liposomes, consisting of one or more phospholipid bilayers, can encapsulate both hydrophilic compounds (in the aqueous core) and hydrophobic compounds (in the bilayer)[115]. Micelles, formed by surfactants, encapsulate hydrophobic compounds in their core. Both systems create a physical barrier that prevents the bitter substance from contacting taste receptors[115]. Coating liposomes with proteins, such as whey protein isolate (WPI), can further increase stability and bitterness masking effectiveness[116].
Menthol and peppermint oil act by activating the cold receptor TRPM8, inducing a cooling sensation in the mouth[117, 118]. This strong sensory impression can effectively mask other unpleasant tastes, including the metallic aftertaste often reported by patients. The effect of menthol is concentration-dependent – low concentrations induce a pleasant coolness, while high concentrations can be irritating[117, 119]. Clinical studies have shown that aromatherapy using peppermint oil can reduce chemotherapy-induced nausea and vomiting, which indirectly improves taste perception[120, 121].
High-intensity sweeteners, such as sucralose, steviol glycosides (e.g., Reb M), and aspartame, allow for the impartation of a sweet taste without providing calories and carbohydrates[122, 123]. Their application is crucial in formulations with glycolysis restriction. Sucralose is thermally stable and stable over a wide pH range, making it a versatile choice[123]. Aspartame is less thermally stable[123]. It should be noted that some of these substances may exhibit a bitter or metallic aftertaste, which may require additional masking.
Bitterness blockers, such as sodium gluconate or AMP (adenosine monophosphate), are compounds that directly interact with bitter taste receptors (T2Rs) or signaling pathways, inhibiting bitterness perception. Sodium salts, including gluconate, have been shown to effectively suppress the bitterness of many compounds[124, 125]. Compounds like GIV3727 act as T2R receptor antagonists, blocking activation by bitter substances[126]. The use of these specific blockers can be an effective strategy, especially for formulations containing very bitter active ingredients or drugs.
Encapsulation Technologies and Thermal Stabilization of Lipids During Pasteurization
High-fat FSMP formulations, especially those enriched with polyunsaturated fatty acids (PUFA) such as omega-3, are exceptionally susceptible to oxidation. Pasteurization processes (HTST, UHT), essential for ensuring microbiological safety, can accelerate lipid degradation due to high temperature. Therefore, the application of encapsulation technologies and appropriate antioxidant systems is crucial.
Spray drying is one of the most commonly used microencapsulation methods in the food industry. It involves the atomization of an emulsion (oil phase containing the active ingredient in an aqueous phase with a wall material) into a stream of hot air[127, 128]. Rapid evaporation of water (within seconds) leads to the formation of a powder in which oil droplets are enclosed within the wall matrix[128, 129]. Proteins (e.g., whey protein isolate (WPI)), polysaccharides (gum arabic, OSA-modified starches), or their combinations are used as wall materials (matrices)[129]. Although the process is rapid, high inlet air temperature and the presence of oxygen can promote oxidation. This can be counteracted by using nitrogen instead of air or by adding antioxidants to the emulsion before drying[128].
Spray congealing / spray chilling is a technology in which a melted lipid carrier (solid fat at room temperature) containing a dissolved or dispersed active ingredient is sprayed into a cooling chamber[130, 131]. Droplets solidify upon contact with cold air, forming solid lipid microparticles (SLM)[132]. The advantage of this method is milder temperature conditions compared to spray drying, which is beneficial for thermolabile ingredients[130]. Fats with a melting point above 45°C are used as carriers to ensure particle stability[132]. This technology allows for controlled release and taste masking[130, 131].
Complex coacervation is a process of forming microcapsules by phase separation of two oppositely charged biopolymers, e.g., gelatin and gum arabic[133, 134]. The resulting shell is characterized by good temperature resistance and can effectively protect omega-3-rich oils during UHT pasteurization[133].
Pickering emulsions are stabilized by solid particles (e.g., modified proteins or polysaccharides) that irreversibly adsorb at the oil-water interface, forming a mechanical barrier against coalescence[135–137]. Such a structure provides exceptional stability, also during thermal processing, making them a promising technology for pasteurized lipid emulsions[138].
Multiple W/O/W (water-in-oil-in-water) emulsions are complex systems in which small water droplets are dispersed within larger oil droplets, which in turn are dispersed in an external aqueous phase[139, 140]. Such a structure allows for the encapsulation of both hydrophilic (in the internal aqueous phase) and hydrophobic ingredients. This is a particularly useful technology for masking bitter, water-soluble substances, which can be enclosed in the internal aqueous phase, limiting their contact with taste receptors[141, 142].
Electrospinning and electrospraying are techniques that use a high electric field to create nanofibers or nanoparticles from polymer solutions[143]. They allow for the encapsulation of active ingredients in biopolymer matrices, such as zein or whey proteins, under conditions without elevated temperature, which is ideal for thermolabile substances[144, 145].
A key element in lipid stabilization is the use of antioxidant systems. A mixture of tocopherols (vitamin E) is a basic, fat-soluble antioxidant that interrupts chain reactions of lipid oxidation[146]. Rosemary extract, standardized to carnosic acid and carnosol, is an EU-approved food additive (E392) with strong antioxidant properties in lipid matrices and exhibits thermal stability during pasteurization[147]. Ascorbyl palmitate, as a fat-soluble form of vitamin C (E304), acts synergistically with vitamin E, regenerating it to its active form[148–150]. Other antioxidants, such as astaxanthin or polyphenols from green tea and sage, have also shown effectiveness in protecting PUFA[151–153].
The choice of matrix material for encapsulation is equally important. Whey protein isolate (WPI), gum arabic, zein, chitosan-alginate, and plant protein isolates (pea, soy) offer various functional properties (emulsifying, film-forming, gelling) and can be selected depending on process requirements and the final product[154–163].
Integrated Strategy for FSMP Formulation with Glycolysis Restriction
Designing an effective and acceptable FSMP with glycolysis restriction requires a holistic approach that integrates knowledge from biochemistry, food technology, and nutritional sciences. The goal is to create a product that not only meets specific metabolic objectives but is also stable, safe, and palatable for the patient.
The target macronutrient profile is the foundation of the formulation. Calories should come 100% from lipids and proteins, with zero or trace amounts of digestible carbohydrates. A typical lipid to protein energy ratio can range from 60:15 to 70:20, depending on clinical needs and objectives (e.g., inducing deeper ketosis vs. supporting muscle mass). The target caloric density should be high, in the range of 1.5–2.5 kcal/mL, to allow for the delivery of a large amount of energy in a small volume, which is crucial for patients with anorexia and early satiety.
Osmolality management is critical for gastrointestinal tolerance, especially in liquid oral and enteral formulations. High mineral content (from BHB salts) and hydrolyzed proteins can significantly increase osmolality. The aim should be to achieve values not exceeding 400 mOsm/kg, which often requires careful selection of ingredients and avoiding excessive doses of mineral salts in favor of ketone esters or MCTs[6].
The production process sequence must be carefully planned to protect sensitive ingredients. A typical scheme may look as follows:
- Preparation of the aqueous phase (with dissolved proteins, stabilizers) and the oil phase (with dissolved antioxidants, e.g., tocopherols and rosemary extract).
- Creation of a primary emulsion through high-pressure homogenization (HPH) or microfluidization to obtain small, homogeneous fat droplets.
- Addition of encapsulated active ingredients (e.g., polyphenols in microcapsules) after the high-temperature step to avoid their degradation.
- Pasteurization, preferably HTST (High Temperature Short Time) or UHT (Ultra-High Temperature), to minimize thermal load.
- Addition of thermolabile and taste-masking ingredients (e.g., flavors, menthol, some bitterness blockers) under aseptic conditions after product cooling.
- Maintaining pH in the range of 6.5–7.2 is usually optimal for the stability of protein emulsions and minimization of undesirable chemical interactions.
Stability testing strategies are essential to ensure product quality and safety throughout its shelf life. This includes accelerated (elevated temperature) and real-time tests, monitoring key parameters such as particle size, emulsion stability, degree of lipid oxidation (e.g., peroxide value, TBARS), and active ingredient content.
The utilization of formulation synergies is also crucial. For example, combining MCT oil with BHB salts can enhance and stabilize ketosis. Omega-3 fatty acid supplementation combined with curcumin can potentiate anti-inflammatory effects. Zinc, beyond its role in masking dysgeusia, can interact with biopolymers such as gum arabic, affecting the rheological properties of the product.
Regulatory Status of Ingredients and Legal Framework for Oncological FSMPs
The marketing of Food for Special Medical Purposes (FSMP), including products dedicated to oncology patients, is subject to strict legal regulations aimed at ensuring the safety and efficacy of these products. In the European Union, the basic legal framework is set by Regulation (EU) No 609/2013 of the European Parliament and of the Council on food for infants and young children, food for special medical purposes and total diet replacement for weight control.
According to this regulation, FSMP is specially processed or formulated food intended for the dietary management of patients, including infants, under medical supervision. It must be used by patients with a limited, impaired, or disturbed capacity to take, digest, absorb, metabolize, or excrete ordinary foodstuffs or certain nutrients contained therein, or by patients whose medical condition causes particular nutritional requirements. The composition and labeling of FSMP must comply with Commission delegated acts, and their placing on the market requires notification to the competent national authority.
Many ingredients discussed in this review have an established status in the EU and USA. Medium-chain triglycerides (MCTs), omega-3 fatty acids, tocopherols (vitamin E), and rosemary extract (E392) have GRAS (Generally Recognized as Safe) status in the United States and are approved as food additives or ingredients in the EU. Similarly, sweeteners such as sucralose and steviol glycosides are widely approved.
However, some of the more innovative ingredients, such as ketone esters and BHB salts, are subject to the Novel Food procedure in the European Union under Regulation (EU) 2015/2283. This means that before being placed on the market, they must undergo a rigorous safety assessment by the European Food Safety Authority (EFSA). EFSA's scientific opinions are crucial for obtaining authorization.
Claims regarding the properties of FSMP are also strictly regulated. Unlike food supplements, the labeling and presentation of FSMP may include information that the product is intended for the dietary management of a specific disease, disorder, or medical condition. However, they cannot attribute properties of preventing, treating, or curing diseases to the product. Every claim must be supported by robust scientific evidence. The requirements for clinical trials as a basis for registration and substantiation of claims are becoming increasingly stringent, which is crucial for ensuring the credibility and effectiveness of FSMP in oncology nutrition.
10. Conclusions and Research Perspectives
This review systematizes the current state of knowledge regarding ingredients and technologies crucial for the development of Food for Special Medical Purposes (FSMP) with glycolysis restriction in oncology nutrition. The synthesis of evidence indicates that creating an effective and acceptable product requires a multidisciplinary approach, combining advanced formulation science with a deep understanding of tumor pathophysiology and patient needs.
Key findings indicate a wide range of technological tools and ingredients enabling the design of zero-carbohydrate, high-fat formulations. Lipid bases derived from MCTs, structured lipids, and omega-3 fatty acids, combined with exogenous ketogenic substrates, form a robust metabolic foundation. Concurrently, technologies such as microencapsulation and advanced antioxidant systems are essential to protect these sensitive ingredients during pasteurization, ensuring their stability and functionality. Equally crucial is the integration of dysgeusia management strategies, from zinc supplementation to the use of bitterness blockers and sensory modifiers, which directly impacts patient compliance.
Despite promising mechanistic foundations and numerous preclinical studies, a major gap in the evidence is the lack of randomized controlled trials (RCTs) evaluating complete FSMP formulations with glycolysis restriction in the oncology patient population. Most existing studies focus on single ingredients rather than the synergistic action of the finished product. Furthermore, data on the long-term bioavailability and stability of bioactive polyphenols under industrial production and storage conditions for pasteurized FSMP are limited. There is also a need to define and validate biomarkers (e.g., degree of ketosis, inflammatory markers) that could serve as endpoints in studies on formulation efficacy.
Research priorities should therefore focus on:
- Conducting well-designed RCTs evaluating the impact of complete, zero-carbohydrate FSMP on clinical parameters such as nutritional status, muscle mass and strength, quality of life, treatment tolerance, and metabolic markers in oncology patients.
- Research on the stability and interactions of ingredients in complex food matrices throughout the entire product lifecycle, from production to consumption.
- Development and validation of standardized methods for sensory evaluation and product acceptance by patients with dysgeusia.
In summary, the clinical potential of glycolysis-restricted FSMP in oncology is significant. Further development in this field, based on rigorous research and technological innovations, can lead to the creation of a new generation of nutritional support better adapted to the unique metabolic and sensory needs of cancer patients.
Evidence Base
This review article is based on the analysis of 525 scientific and internet sources. The initial selection included 480 scientific papers. After applying inclusion criteria, 237 papers underwent detailed analysis. Based on this, 50 key ingredients and technologies were identified and thoroughly characterized. In the final version of the article, 293 unique sources were cited to support the presented theses and conclusions.
