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Lipid Nanocarriers for Oligonucleotide Delivery to the Brain
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Andreia F. Jorge, Santiago Grijalvo, Alberto Pais, Ramón Eritja
The natural isomer of the lipophilic vitamin E, α-tocopherol, has also emerged as a successful vector for siRNA delivery in the mouse liver and brain [116, 117]. HDL plays a key role in mediating the cellular delivery of α-tocopherol in different tissues, including the brain, promoting lipid uptake via scavenger receptor class B, type I (SR-B1) [118, 119]. Therefore, the combination of HDL as a second carrier of the α-tocopherol-siRNA conjugate (Fig. 8.2) enables the specific knockdown of (3-site amyloid precursor protein cleaving enzyme 1 (BACE1) mRNA [117]. Variations in the design of 13-mer LNA/DNA gapmer modified with α-tocopherol have also been carried out to test the influence of this lipidic moiety in the delivery of ASOs [120]. In this report, it was shown that the direct conjugation of α-tocopherol to 13-mer LNA/DNA gapmer reduces drastically the silencing effect in the mouse liver, mainly due to sterical impediments hampering ASO activity. However, when using the same LNA/DNA gapmer (HDO) and its complementary strand (sRNA), and conjugating this latter with α-tocopherol at the 5’-end, there exists an increment in the binding of α-tocopherol-HDO with serum lipoproteins, thus increasing their transport into the cells and enhancing the silencing activity of the gapmer by 20-fold (compared with parent unmodified HDO) when targeted to the liver [121]. In a proof-of-concept study, α-tocopherol-HDO conjugates were administrated intravenously in mice to reduce the expression of the organic anion transporter 3 (OAT3) gene in brain microvascular endothelial cells, the major component of the BBB [122]. Results indicate the ability of α-tocopherol-HDO conjugates to silence OAT3 at the gene and protein levels, thus modulating the protein function at the BBB.
A critical review on the bioaccumulation, transportation, and elimination of per- and polyfluoroalkyl substances in human beings
Published in Critical Reviews in Environmental Science and Technology, 2023
Yao Lu, Ruining Guan, Nali Zhu, Jinghua Hao, Hanyong Peng, Anen He, Chunyan Zhao, Yawei Wang, Guibin Jiang
The existing half-life values from the literature were mainly focused on PFCAs and PFSAs, and the values varied greatly owing to the number and type of the samples, as well as the calculation method. As for the docking scores for PFCAs and PFSAs, except for a few congeners, the successfully docked congeners generally showed a pattern of decreased binding capacity with increased chain length for all these four proteins. Based on the binding cavity area of proteins, it can be found that OAT1 protein (362.894 Å3) and OAT4 protein (325.164 Å3) with larger cavity area presented a more obvious trend, compared with OAT3 (244.216 Å3) and URAT1 (207.172 Å3) with smaller cavity area (Fig. S2). The possible reason for this phenomenon is that with the gradual increase of the chain length, the volume of the congeners gradually increases, which eventually makes the protein–PFAS docking more difficult.