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    Weakly acidic carboxy group-grafted beta-cyclodextrin-threaded acid-degradable polyrotaxanes for modulating protein interaction and cellular internalization

    Year: 2021

    Journal: Sci. Technol. Adv. Mater., Volume 22, DEC 31, page 494–510

    Authors: Zhang, Shunyao; Tamura, Atsushi; Yui, Nobuhiko

    Organizations: Japan Society for the Promotion of Science (JSPS) KAKENHI [JP18K19904, JP20H04527]; Ministry of Education, Culture, Sports, Science, and Technology (MEXT)

    Keywords: Polyrotaxane; beta-cyclodextrin; carboxy group; protein interaction; intracellular uptake

    To improve the therapeutic potential of beta-cyclodextrin (beta-CD)-threaded acid-degradable polyrotaxanes (beta-CD PRXs) in cholesterol-related metabolic disorders, we investigated the effect of carboxylation of beta-CD PRXs on intracellular uptake. In this study, we established a synthetic method for the modification of carboxylalkyl carbamates on beta-CD PRXs without degradation and synthesized three series of carboxyalkyl carbamate group-modified beta-CD PRXs with different alkyl spacer lengths. The modification of carboxymethyl carbamate (CMC), carboxyethyl carbamate (CEC), and carboxypropyl carbamate (CPC) on the beta-CD PRXs slightly reduced the interaction of the PRXs with the lipid layer model compared with the modification of 2-(2-hydroxyethoxy)ethyl carbamate (HEE-PRX), which was used in our previous studies. However, all the carboxylated beta-CD PRXs showed a significantly stronger interaction with a protein model compared with HEE-PRX. The carboxylated beta-CD PRXs showed significantly high intracellular uptake, through macrophage scavenger receptor A (MSR-A)-mediated endocytosis, in MSR-A-positive RAW 264.7 cells compared with HEE-PRX. Interestingly, the carboxylated beta-CD PRXs also showed significantly higher intracellular uptake even in MSR-A-negative cells compared with HEE-PRX. Carboxylated beta-CD PRXs are considered to strongly interact with other membrane proteins, resulting in high intracellular uptake. The length of the alkyl spacer affected the intracellular uptake levels of carboxylated PRXs, however, this relationship was varied for different cell types. Furthermore, none of the carboxylated beta-CD PRXs exhibited cytotoxicity in the RAW 264.7 and NIH/3T3 cells. Altogether, carboxylation of beta-CD PRXs is a promising chemical modification approach for their therapeutic application because carboxylated beta-CD PRXs exhibit high cellular internalization efficiency in MSR-A-negative cells and negligible toxicity.
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