Caffeic Acid Phenethyl Ester-Incorporated Radio-Sensitive Nanoparticles of Phenylboronic Acid Pinacol Ester-Conjugated Hyaluronic Acid for Application in Radioprotection

Abstract

We synthesized phenylboronic acid pinacol ester (PBPE)-conjugated hyaluronic acid (HA) via thiobis(ethylamine) (TbEA) linkage (abbreviated as HAsPBPE conjugates) to fabricate the radiosensitive delivery of caffeic acid phenetyl ester (CAPE) and for application in radioprotection. PBPE was primarily conjugated with TbEA and then PBPE-TbEA conjugates were conjugated again with hyaluronic acid using carbodiimide chemistry. CAPE-incorporated nanoparticles of HAsPBPE were fabricated by the nanoprecipitation method and then the organic solvent was removed by dialysis. CAPE-incorporated HAsPBPE nanoparticles have a small particle size of about 80 or 100 nm and they have a spherical shape. When CAPE-incorporated HAsPBPE nanoparticles were irradiated, nanoparticles became swelled or disintegrated and their morphologies were changed. Furthermore, the CAPE release rate from HAsPBPE nanoparticles were increased according to the radiation dose, indicating that CAPE-incorporated HAsPBPE nanoparticles have radio-sensitivity. CAPE and CAPE-incorporated HAsPBPE nanoparticles appropriately prevented radiation-induced cell death and suppressed intracellular accumulation of reactive oxygen species (ROS). CAPE and CAPE-incorporated HAsPBPE nanoparticles efficiently improved survivability of mice from radiation-induced death and reduced apoptotic cell death. We suggest that HAsPBPE nanoparticles are promising candidates for the radio-sensitive delivery of CAPE.

Nuclear and Radiological Emergencies: Biological Effects, Countermeasures and Biodosimetry

“…Nevertheless, their low bioavailability due to poor absorption, rapid metabolism, and/or rapid systemic elimination, can compromise their efficacy. Thus, new pharmaceutical formulations (nanoparticles, vesicles, cocrystals…) are being implemented and tested to facilitate oral administration and/or increase their effectiveness (see, e.g., , accessed on 21 January 2022) [ 149 , 150 , 151 ].…”

“…The cytoprotective effects of gallic acid are also due to its ability to enhance DNA repair, chelate metal ions, through the attenuation of MAPK and NF-κB/AP-1 signaling pathways, and reduce the release of inflammatory cytokines and adhesion molecules involved in leukocyte infiltration [ 156 ]. Caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) act as free radical scavengers, compete with oxygen for IR-induced electrons, have antioxidant effects [ 151 , 157 , 158 ], decrease lipid peroxidation and increase antioxidant defenses in the heart and lung tissue of irradiated mice [ 159 ]. Treatment with CAPE prior to irradiation of rats effectively ameliorated intestinal [ 160 ], and hepatic [ 161 ] injuries.…”

“…Moreover, nanoparticles can be modified to respond to different stimuli, such as pH, temperature, magnetic fields, oxidative stress, irradiation etc., thus facilitating the sustained release of drugs in selected tissues. That is the reason why even though CAPE-nanoparticles showed a similar protective activity compared to CAPE under in vitro conditions, mice treated with nanoparticles had a longer survival after being exposed to IR [ 151 ].…”

Development of nanotechnology-mediated precision radiotherapy for anti-metastasis and radioprotection

“…722–724 Various organic nanocarriers have been used to deliver small molecular radioprotectors, such as WR-1065, curcumin, γ-tocotrienol and baicalein, to specific organs or tissues for higher accumulation and longer retention time. 725–739…”

Caffeic acid phenethyl ester: A review on its pharmacological importance, and its association with free radicals, COVID‐19, and radiotherapy

“…Free radicals formed in RT cause cell death by causing DNA breaks as well as causing many damages to the tissue. Another approach to reduce radiation‐related side effects is the systemic use of radiosensitizing or radioprotectant agents that protect normal tissue against radiation but do not have a protective effect on the tumor (Choi et al, 2021; Taysi et al, 2022).…”