The Therapeutic Potential of Novel Carnosine Formulations: Perspectives for Drug Development

Abstract

Carnosine (beta-alanyl-L-histidine) is an endogenous dipeptide synthesized via the activity of the ATP-dependent enzyme carnosine synthetase 1 and can be found at a very high concentration in tissues with a high metabolic rate, including muscles (up to 20 mM) and brain (up to 5 mM). Because of its well-demonstrated multimodal pharmacodynamic profile, which includes anti-aggregant, antioxidant, and anti-inflammatory activities, as well as its ability to modulate the energy metabolism status in immune cells, this dipeptide has been investigated in numerous experimental models of diseases, including Alzheimer’s disease, and at a clinical level. The main limit for the therapeutic use of carnosine is related to its rapid hydrolysis exerted by carnosinases, especially at the plasma level, reason why the development of new strategies, including the chemical modification of carnosine or its vehiculation into innovative drug delivery systems (DDS), aiming at increasing its bioavailability and/or at facilitating the site-specific transport to different tissues, is of utmost importance. In the present review, after a description of carnosine structure, biological activities, administration routes, and metabolism, we focused on different DDS, including vesicular systems and metallic nanoparticles, as well as on possible chemical derivatization strategies related to carnosine. In particular, a basic description of the DDS employed or the derivatization/conjugation applied to obtain carnosine formulations, followed by the possible mechanism of action, is given. To the best of our knowledge, this is the first review that includes all the new formulations of carnosine (DDS and derivatives), allowing a decrease or complete prevention of the hydrolysis of this dipeptide exerted by carnosinases, the simultaneous blood–brain barrier crossing, the maintenance or enhancement of carnosine biological activity, and the site-specific transport to different tissues, which then offers perspectives for the development of new drugs.

Exploring the role of antioxidants in sepsis-associated oxidative stress: a comprehensive review

“…Carnosine is found in the human body in relatively high concentrations in excitable tissues (brain and skeletal muscle) but also in lower quantities in other tissues (kidney, gastrointestinal tract, adipose tissue, heart, and liver) ( Cesak et al., 2023 ). Due to its several modes of action, carnosine supplementation has promise as an additional therapy for the treatment of sepsis ( Bonaccorso et al., 2023 ). Carnosine’s antioxidant qualities, anti-inflammatory actions, and capacity to boost cellular energy generation may help alleviate the systemic inflammation, OS, and mitochondrial dysfunction that characterize sepsis ( Caruso et al., 2023 ).…”

State of the Art in the Development of Human Serum Carnosinase Inhibitors

“…However, carnosine showed better activity both in vitro and in vivo [ 126 , 127 , 128 ]. Therefore, a potential strategy to enhance carnosine bioavailability is to transport the molecule by means of drug delivery systems able to prevent the hydrolysis operated by serum carnosinase [ 129 ]. The two main strategies reported in the literature are to include carnosine in metallic nanoparticles [ 130 , 131 , 132 ] or vesicular systems [ 133 , 134 , 135 , 136 ].…”

“…Such compounds have been designed since the modification of the N-terminus amine was described as a modification inducing resistance to carnosinase (see Section 1.5 ), in agreement with the model described in Figure 8 . As recently reviewed, some of these conjugates have been designed as prodrugs able to enhance carnosine bioavailability, so they can be considered carnosine delivery systems [ 129 ].…”

Feature Reviews in Pharmaceutical Technology

“…The discussed technologies, such as liposomes, polymeric micelles, polymeric nanoparticles, and polymer-drug conjugates, are currently in clinical use or clinical trials [10]. Another paper by Bonaccorso et al [11] focuses on the therapeutic potential of formulations for carnosine, which is an endogenous dipeptide with anti-oxidant and ant-inflammatory properties and is found in tissues with a high metabolic rate. Because this dipeptide is rapidly hydrolyzed in plasma, drug modifications and drug delivery systems have been employed to improve its bioavailability as well as to enhance other pharmacological properties, such as blood-brain barrier transport, biological activity, or transport to different tissues [11].…”