Temperature-Induced Intracellular Uptake of Thermoresponsive Polymeric Micelles

Abstract

Well-defined diblock copolymers comprising thermoresponsive segments of poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (P(IPAAm-co-DMAAm)) and hydrophobic segments of poly(d,l-lactide) were synthesized by combination of RAFT and ring-opening polymerization methods. Terminal conversion of thermoresponsive segments was achieved through reactions of maleimide or its Oregon Green 488 (OG) derivative with thiol groups exposed by cleavage of polymer terminal dithiobenzoate groups. Thermoresponsive micelles obtained from these polymers were approximately 25 nm when below the lower critical solution temperature (LCST) of 40 degrees C, and their sizes increased to an average of approximately 600 nm above the LCST due to aggregation of the micelles. Interestingly, the OG-labeled thermoresponsive micelles showed thermally regulated internalization to cultured endothelial cells, unlike linear thermoresponsive P(IPAAm-co-DMAAm) chains. While intracellular uptake of P(IPAAm-co-DMAAm) was extremely low at temperatures both below and above the micellar LCST, the thermoresponsive micelles showed time-dependent intracellular uptake above the LCST without exhibiting cytotoxicity. These results indicate that the new thermoresponsive micelle system may be a greatly promising intracellular drug delivery tool.

Dual temperature- and pH-responsive polymeric micelle for selective and efficient two-step doxorubicin delivery

“…33 PNIPAAm exhibits a temperaturedependent phase transition at its lower critical solution temperature (LCST), 34 which can be accurately raised to a slightly higher temperature than body temperature with hydrophilic co-monomers, 35 and intracellular uptake of PNIPAAm-based polymers, and nanomaterials can be controlled with temperature-dependent hydrophilic/ hydrophobic phase transition. 17,36,37 The two diblock copolymers, obtained using PDPA and PBMA as CTA, were referred to as PDP-b-ND and PBM-b-ND, respectively (Scheme 2). The number-and weight-averaged molecular weight (M n , and M w ) and ratio of the two synthesized polymers were analyzed by 1 H NMR and gel-permeation chromatography (GPC), as shown in Table 1.…”

“…16 Besides the therapeutic effect of hyperthermia, temperature-responsive polymers, which exhibited reversible temperature-dependent hydrophilic/hydrophobic phase transition, were applied to a drug carrier for a stimuli-responsive targeting. 17,18 When this system was applied to in vivo systems, temperature-responsive polymer accumulated to local heated tissue as aggregation and precipitation. In some cases, the polymer aggregate were sheared from local heated tissue, and carried away by the blood ow.…”

Thermoresponsive Polymers for Biomedical Applications

“…Akimoto et al produced micelles of P(NIPAAm-co-DMAAm)-b-PLA, where PLA was poly(lactic acid), and showed that these micelles were able to internalize into cells above their LCST, specifically due to the increased interaction between the hydrated NIPAAm outer sphere and the cells [105]. Interestingly, they also showed that fictionalization of the PNIPAAm chain ends with thiol groups can increase this interaction and internalization, the results show promising methods for intracellular delivery of therapeutic molecules [100].…”

“…Several groups have focused on using PNIPAAm as the thermoresponsive block in the formation of thermoresponsive micelles [100][101][102][103][104]. Akimoto et al produced micelles of P(NIPAAm-co-DMAAm)-b-PLA, where PLA was poly(lactic acid), and showed that these micelles were able to internalize into cells above their LCST, specifically due to the increased interaction between the hydrated NIPAAm outer sphere and the cells [105].…”

Living Radical Polymerization by the RAFT Process – A Third Update

“…[270][271][272] the use of trithiocarbonate 140 to carry out simultaneous RAFT polymerization of St and ROP of lactide. [421] The product was used as a macromonomer in ROMP.…”