The Therapeutic Potential of Novel Carnosine Formulations: Perspectives for Drug Development
Abstract
:1. Introduction
2. Carnosine Structure, Biological Activities, Administration Routes, and Metabolism
3. Drug Delivery Systems
3.1. Vesicular Systems: From Liposomes to Polymerosomes
3.2. Metallic Nanoparticles
3.3. Derivative Conjugates
4. Increasing Carnosine Bioavailability through DDS and/or Chemical Modifications
4.1. Vesicular Systems
4.2. Nanoparticles
4.3. Derivatives/Conjugates
5. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Advantages | Limitations | ||
---|---|---|---|
Vesicular Systems | Liposome | Made of natural ingredients; Biodegradable and biocompatible; Similarity to biomembrane. | Physical instability during storage; Susceptible to oxidation; Rigid liposomes remain confined to the stratum corneum. |
Elastic Liposome | Highly deforming ability and flexibility ensure deeper skin penetration and biomembrane crossing ability. | On prolonged storage, due to increased elasticity and flexibility, it tends to be less stable and lose the entrapped drug, which complicates the scaling process. | |
Niosome | Chemical stability. | Lower biocompatibility. | |
Phytosome | Enhancement of pharmacokinetic and pharmacodynamic properties of herbal-originated polyphenolic compounds; Improves skin absorption of phytoconstituents; | Despite the easy scale-up production of phytosomes, the high pH sensitivity of some components could limit the large-scale synthesis of such formulations and should be considered during the manufacturing. | |
Better stability of incorporated compounds owing to the chemical interaction. | |||
Polymerosome | More stable than liposomes; Allows greater control of chemical and structural properties; Can be used to obtain controlled release kinetics by stimuli-response triggers. | In case of charged polymers, the self-assembled polymersome could induce stronger immune response and therefore be less tolerable for medical applications. | |
Metallic NPs | Multiple shapes; Conductivity; Localized surface plasmon resonance; Ability to direct uptake through external magnetic stimulation. | Chemical contaminants from synthesis can cause toxicity issues. | |
Drug-conjugate derivatives | Increased compound half-life; Increased target specificity; Increase drug stability. | Modification can reduce the potency, especially for small peptides and proteins; Any covalent modification of peptides or proteins presents a potential risk of increased immunogenicity. |
Formulation Name | Basic Description | Mode of Action | Ref. |
---|---|---|---|
Nanoliposomes | Carnosine incorporated into nanoliposomes could represent an innovative approach to overcoming the issues related to the direct application of this antioxidant peptide in food. |
| [113] |
Liposomes | Liposomes are nanosized vesicles with a spherical shape that can be produced starting from natural or synthetic phospholipids. Encapsulation of antioxidants into liposomes has been shown to improve their therapeutic potential against oxidant-induced tissue injuries, facilitating intracellular delivery and extending the retention time of incorporated agents inside the cell. |
| [114] |
Elastic liposomes | EL encapsulated with carnosine represent a promising strategy to enhance the transport into the brain, protecting the dipeptide against enzymatic hydrolysis. |
| [115] |
Niosome derivatized with lipoyl-carnosine | Niosomes are nanovesicles coupled to specific ligands selectively recognized by transporters expressed on the BBB that could promote the delivery of drugs (e.g., carnosine) at brain level. |
| [25] |
Niosome | Carnosine-encapsulated niosomes represent a powerful drug delivery tool allowing it to reach specific organs such as the brain. |
| [116,117] |
Proniosome | Proniosomes are non-hydrated niosomes, which, upon hydration, form niosomes characterized by physical stability that overcome some problems presented by other vesicular systems, such as leaking, fusion, and aggregation. |
| [117] |
Polymerosome | Polymersomes are synthetic vesicles formed through the self-assembly of amphiphilic co-polymers in aqueous conditions. Carnosine encapsulated in polymersomes could exert an enhanced neuroprotective potential. |
| [118] |
Phytosome | Carnosine loaded into lipid-based phytosomes represent an alternative for the prodrug N-acetyl-carnosine as a novel delivery system to the lens. |
| [119] |
Nanophytosome | Nanophytosomes represent one of the novel nanocarriers that could provide potent applications in both food and pharmaceutical fields. A novel nanophytosomal formulation obtained by physical mixture of two compounds, carnosine and Aloe vera, has shown a synergic effect in counteracting cell toxicity. |
| [120] |
Formulation Name | Basic Description | Mode of Action | Ref. |
---|---|---|---|
Fe3O4 | Carnosine-coated Fe3O4 NPs have been prepared via co-precipitation of Fe3O4 in the presence of carnosine. They are commonly used because of their superparamagnetic properties allowing potential applications in many fields. |
| [122] |
Fe3O4 NPs/poly(lactic-co-glycolic acid) (PLGA) polymer-loaded dexamethasone functionalized with carnosine | PLGA functionalized Fe3O4 NPs with carnosine peptide composite loaded with dexamethasone represent suitable drug delivery carriers for biomedical applications able to improve the therapeutic efficiency of carnosine. |
| [123] |
Magnetic | Carnosine-coated MNPs were developed to enhance the chemotherapeutic activity of this dipeptide. |
| [121] |
| [124] | ||
AuNPs/biotin | A new carnosine derivative with biotin was synthesized and structurally characterized. The binding affinity of the new molecular entity to avidin and streptavidin was exploited to functionalize avidin- and streptavidin-AuNPs with the carnosine–biotin conjugate. |
| [125] |
AuNPs/N-acetyl-carnosine | NPs loaded with N-acetyl-carnosine were synthesized, characterized, and tested for cataract treatment. The AuNPs were biofabricated and characterized by using Coccinia grandis bark extract. |
| [126] |
Poly (lactic-co-glycolic acid) microbeads | The Fe3O4 NPs have been encapsulated, along with carnosine, inside porous poly(lactic-co-glycolic acid) microbeads. These new drug-delivery vesicles have the potential to pave the way towards the safe and triggered release of onsite drug delivery as part of a theragnostic treatment for cancer. |
| [127] |
Formulation Name | Basic Description | Mode of Action | Ref. |
---|---|---|---|
Derivatized with β-cyclodextrins | β-cyclodextrin is a heptasaccharide derived from glucose. Ciclodextrins are particularly used in pharmaceutical science for their ability to include and/or stabilize drugs. Glycoconjugate derivatives obtained by functionalization with carnosine in different positions of the sugar or the cyclodextrin are widely used because of their decreased susceptibility to degradation by carnosinases. |
| [131,132,133] |
| [134] | ||
N-acetylcarnosine | N-acetyl-carnosine is obtained by the addition of an acetyl group to carnosine structure, which makes the dipeptide more resistant to the degradation exerted by carnosinases. |
| [135] |
| [136] | ||
| [137] | ||
| [110] | ||
Derivatized by acylation with palmitoyl chain | Palmitic acid is a fatty acid with a 16-carbon chain. This compound is commonly used as a structure-directing agent to induce the fibrillization of carnosine. Its long lipid chains are able to drive self-assembly due to amphiphilicity, showing restricted dynamics and/or crystallization. |
| [138] |
Derivatized by acylation with benzoic acid | Benzoic acid is a compound comprising a benzene ring core carrying a carboxylic acid substituent. N-(4-n-tetradecyloxybenzoyl)-L-carnosine represents a carnosine-based amphiphilic hydrogelator that efficiently gelates water and exhibits salt, pH, and thermoresponsive gelation properties. |
| [139] |
Histidine-based derivatives | Novel histidine-based complexing surfactants containing trifunctional moduli (peptidic/hydrophilic/hydrophobic). It is possible to establish various links between the different parts, allowing the modulation of the lipophilic/hydrophilic balance and obtaining amphiphilic compounds with complexing properties and surfactive or gelator properties. |
| [140] |
Lipoilcarnosine | Lipoic acid is an organosulfur compound derived from caprylic acid. Lipoilcarnosine is a conjugated molecule obtained by coupling α-lipoic acid to carnosine. |
| [141] |
Derivatized with trolox | Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) is a water-soluble analog of vitamin E. (S)-trolox-L-carnosine (STC) and (R)-trolox-L-carnosine (RTC) represent novel derivatives of carnosine synthesized by N-acylation of carnosine with (S)- and (R)-trolox, respectively. |
| [142] |
Derivatized with vitamin E-carnosine (VECAR) | VECAR is a novel heterodimer of α-tocopherol (vitamin E) and carnosine that was designed by using 13-carbon phytyl-chain to link carnosine to Trolox at the C2 carbon position, maintaining the antioxidant activities of the two components. |
| [143] |
Derivatized with acetylsalicylic acid | Acetylsalicylic acid is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation and as an antithrombotic. Salicyl-carnosine was synthesized by condensation of acetylsalicylic acid and carnosine. Its properties are particularly promising for the potential development of new anti-inflammatory and antithrombotic drugs. |
| [110] |
Derivatized with trehalose | Trehalose is a sugar consisting of two molecules of glucose. The glyco-conjugate trehalose-carnosine (TrCar), differently from carnosine, is not hydrolyzed by human carnosinases. Particular attention has been paid to the characterization of the Cu2+ binding features of TrCar. |
| [144] |
| [145] | ||
Derivatized with hyaluronic acid | Hyaluronic acid is a linear glycosaminoglycan, an anionic, gel-like polymer, found in the extracellular matrix of epithelial and connective tissues. A derivative obtained from hyaluronic acid and carnosine was considered a pharmacological approach to cure and/or prevent the onset of neurodegenerative disorders. |
| [146] |
Carnosinol | A derivative of carnosine with high oral bioavailability because of its resistance to carnosinases. Carnosinol displayed a suitable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and the greatest potency and selectivity toward α,β-unsaturated aldehydes. |
| [147] |
Amide derivatives | New family of amide derivatives that are not significantly hydrolyzed by carnosinases. In these derivatives, the sugar moiety can act as a recognition element. |
| [108] |
| [148] | ||
Carnosine analogues containing NO-donor substructures | Carnosine analogs containing NO-donor substructures of which the physico-chemical characterization and preliminary pharmacological profile were carried out. These analogs are characterized by higher resistance to carnosinases’ degradation. |
| [149] |
Derivatized with sulfamido pseudopeptides | These compounds, characterized by the presence of a sulfonamido junction, present several interesting aspects which relate to the biological relevance of taurine and the stability toward enzymatic hydrolysis. The high polar character and the sulfur tetrahedral structure make these compounds suitable for the design of tight-binding enzyme inhibitors. |
| [130] |
FL-926-16 | A novel, rationally designed carnosine peptidomimetic with a favorable pharmacokinetic profile, which might be suitable for testing in human subjects. |
| [150] |
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Bonaccorso, A.; Privitera, A.; Grasso, M.; Salamone, S.; Carbone, C.; Pignatello, R.; Musumeci, T.; Caraci, F.; Caruso, G. The Therapeutic Potential of Novel Carnosine Formulations: Perspectives for Drug Development. Pharmaceuticals 2023, 16, 778. https://doi.org/10.3390/ph16060778
Bonaccorso A, Privitera A, Grasso M, Salamone S, Carbone C, Pignatello R, Musumeci T, Caraci F, Caruso G. The Therapeutic Potential of Novel Carnosine Formulations: Perspectives for Drug Development. Pharmaceuticals. 2023; 16(6):778. https://doi.org/10.3390/ph16060778
Chicago/Turabian StyleBonaccorso, Angela, Anna Privitera, Margherita Grasso, Sonya Salamone, Claudia Carbone, Rosario Pignatello, Teresa Musumeci, Filippo Caraci, and Giuseppe Caruso. 2023. "The Therapeutic Potential of Novel Carnosine Formulations: Perspectives for Drug Development" Pharmaceuticals 16, no. 6: 778. https://doi.org/10.3390/ph16060778