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

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