Since low oxygen(hypoxia) occurs during stroke our non-existent stroke leaders should be creating followup research for stroke survivors. But with NO LEADERSHIP, nothing will occur.
Preparation and Characterization of Mitochondrial-Targeted Nitronyl Nitroxide Loaded PLGA Nanoparticles for Brain Injury Induced by Hypobaric Hypoxia in Mice
Authors Da Q , Xu M, Tian Y , Ma H, Wang H, Jing L
Received 19 November 2024
Accepted for publication 25 March 2025
Published 1 April 2025 Volume 2025:20 Pages 3999—4020
DOI https://doi.org/10.2147/IJN.S507315
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Dong Wang
Qingyue Da,1,2 Min Xu,3,4 Yiting Tian,2 Huiping Ma,2 Haibo Wang,3 Linlin Jing1,2
1Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China; 2Department
of Pharmacy, The 940th Hospital of Joint Logistics Support Force of
PLA, Lanzhou, Gansu, 730050, People’s Republic of China; 3Department of Chemistry, School of Pharmacy, The Air Force Medical University, Xi’an, 710032, People’s Republic of China; 4The
Third Stationed Outpatient Department, General Hospital of Central
Theater Command, Wuhan, 430070, People’s Republic of China
Correspondence:
Linlin Jing, Department of Pharmacy, The First Affiliated Hospital of
Xi’an Jiaotong University, No. 277 Yanta West Road, Yanta District,
Xi’an, Shaanxi, 710061, People’s Republic of China, Tel
+86-029-85323537, Email jinglinlin@xjtufh.edu.cn Haibo Wang, Department
of Chemistry, School of Pharmacy, The Air Force Medical University, No.
169, Changle West Road, Xi’an, Shaanxi, 710032, People’s Republic of
China, Tel +86-029-84774473, Email haibo7691@fmmu.edu.cn
Background:
Oxidative stress is considered an important mechanism of acute
high-altitude brain injury. Imidazole nitronyl nitroxide radicals are a
class of stable organic radical scavengers that contain single electrons
in their molecules. Therefore, in order to search for compounds with
low toxicity and better effect against high-altitude brain injury, the
preparation methods of PLGA nanoparticles (TPP-C6-HPN@PLGA-NPs)
loaded with a synthesized mitochondria targeting imidazole nitronyl
nitroxide were emphasized and investigated. Furthermore, its protective
effect on brain injury caused by low-pressure hypoxia (HH) in mice was
evaluated.
Methods: Nanoparticles were prepared by
emulsion solvent evaporation method, and the preparation method was
optimized by Box Behnken design based on particle size, encapsulation
efficiency (EE) and drug loading (DL). Physical characterization and
release studies of the optimized NPs were conducted. The high altitude
brain injury mice model was selected to evaluate the therapeutic effect
of TPP-C6-HPN@PLGA-NPs in vivo. The histological and biochemical tests were conducted in serum and brain of mice exposed to HH condition.
Results:
The nanoparticle size was 120.63 nm, the EE was 89.30%, the DL was
6.82%, the polydispersity index (PDI) was 0.172, and the zeta potential
was − 22.67 mV under optimal preparation process. In addition, TPP-C6-HPN@PLGA-NPs owned good stabilities and sustained drug releases. TPP-C6-HPN@PLGA-NP exhibited lower toxicity than TPP-C6-HPN and was well uptaken by PC12 cells. Histological and biochemical analysis demonstrated that TPP-C6-HPN@PLGA-NPs
significantly reduced HH induced pathological lesions, oxidative
stress, energy dysfunction and inflammation response of brain tissue.
Furthermore, nanoparticles did not show significant toxicity to major
organs such as the liver and kidneys, as well as hematology in mice.
Conclusion: TPP-C6-HPN@PLGA-NPs
exhibits good stability, low hemolysis rate, sustained release, low
toxicity, and long residence time in brain tissue and can be used as a
promising formulation for the proper treatment of HH-induced brain
damage.
Keywords: nitronyl nitroxide, mitochondrial-targeted, PLGA nanoparticles, characterization, high altitude brain injury
Introduction
There is an increasing number of people, approximately 40 million or more, travelling to or visiting high-altitude (HA) areas each year.1–3 In high-altitude areas, the decrease in oxygen partial pressure caused by low air pressure leads to a reduction in the availability of oxygen absorbed by blood and tissues, which poses a significant challenge to people’s health.4 The brain is particularly susceptible to damage due to hypoxia, as an organ with high metabolic and oxygen consumption rates.5 Drugs such as acetazolamide, dexamethasone and edaravone have demonstrated efficacy in ameliorating high-altitude hypoxia-induced brain injury (HHBI).1,6 However, their widespread clinical adoption is significantly constrained by pronounced adverse effects. Therefore, there is currently a substantial lack of effective therapeutic approaches to HHBI.
The mechanism of acute high-altitude brain injury is relatively complex, and the reasons are not fully understood at present. Nevertheless, it is considered to involve many molecular pathways including oxidative stress (OS)7 and inflammation response.8 The state of low-pressure hypoxia can disrupt the balance between the oxidative and antioxidant systems in the brain, leading to an increase in reactive oxygen species (ROS) such as hydroxyl radicals (•OH), superoxide (O2•−), and hydrogen peroxide (H2O2), while endogenous enzyme antioxidants and non-enzyme antioxidants such as superoxide dismutase (SOD) and glutathione (GSH) decrease.9 Mitochondria are subcellular organelles in cells that contain DNA in addition to the nucleus. The mitochondrial respiratory chain is also the main site for ROS production. The low-pressure hypoxic environment leads to excessive production of ROS in mitochondria, causing mitochondrial damage.10
Therefore, the strategy of targeting drug delivery to mitochondria may provide a new therapeutic approach for combating HH-induced damage. So far, covalently linking drugs with lipophilic cations has been an effective method for delivering them specifically to mitochondria, for instance, linking a triphenylphosphonium (TPP) moiety to a central pharmacophore of interest.11 A very successful example is Mito Q, which is covalently bonded to coenzyme Q10 by triphenylphosphate cation (TPP+). Studies have shown that Mito Q can effectively block the production of ROS, prevent mitochondrial oxidative damage, and has a hundred of times stronger effect than untargeted coenzyme Q10.12 A significant challenge in utilizing TPP-conjugated antioxidants for therapeutic purposes lies in their potential mitochondrial toxicity.13 Consequently, during clinical evaluations of these compounds, precise dosage regulation is imperative to maintain MTA (mitochondria-targeted antioxidant) concentrations below levels that could compromise mitochondrial integrity and functionality. Conventional approaches to developing MTAs involved the conjugation of TPP with antioxidant moieties, including phenolic structures and flavonoid derivatives. However, these traditional agents typically exhibit a stoichiometric 1:1 interaction with ROS, necessitating administration of substantial quantities to achieve therapeutic efficacy.
We synthesized 4’-hydroxy-2-substituted phenyl nitro nitrogen oxide (HPN, Figure 1A) previously, which is an imidazole nitrogen oxygen free radical antioxidant. HPN has the ability to mimic SOD activity and react with OH radicals in cyclic and catalytic manners, blocking Fenton reaction and inhibiting ROS attacks on biomolecules and biofilms, thereby reducing cellular oxidative damage.14–16 We found that HPN was able to penetrate the blood–brain barrier and exerted excellent protective effects on HH-induced brain damage.17,18 However, similar to other nitroxyl radicals, HPN has a small molecular weight, high reactivity, and lacks targeting, resulting in a fast clearance rate and short plasma half-life.19 These factors limit its application in the prevention of HHBI.
 |
Figure 1 The chemistry structure of HPN (A) and TPP-C6-HPN (B). |
Nanotechnology has been widely applied in the development of modern medicine and pharmacy. Nanoparticles have significant advantages in achieving targeted drug delivery and sustained release, enhancing drug stability, improving pharmacokinetics, prolonging blood circulation time and reducing the toxic side effects of drugs.20 Due to the excellent biocompatibility, biodegradability, and unique physicochemical properties of poly(D, L-lactide-co-glycolide, PLGA) copolymers, NPs based on PLGA have been used for drug delivery.21,22 PLGA has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for medical use, and is one of the most widely used nanoparticle polymers.23
With the aim of improving protective efficiency of HPN against HH-induced brain damage, we designed and synthesized a new mitochondrial-targeting HPN derivative (TPP-C6-HPN, Figure 1B) using triphenylphosphine cations as carriers. In addition, we used PLGA as a nanocarrier to encapsulate the TPP-C6-HPN to form nanoparticles (TPP-C6-HPN@PLGA-NPs) for improving the stability and circulation time. Furthermore, we studied the protective effect of TPP-C6-HPN@PLGA-NPs on the HH-induced brain injury in vivo. Finally, we also monitored the toxic effects of TPP-C6-HPN@PLGA-NPs on mice.
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