Complex Micelles with Glucose-Responsive Shells for Self-Regulated Release of Glibenclamide

Abstract

Complex micelles with a hydrophobic poly(e-caprolactone) (PCL) core and a mixed P(Asp-co-AspPBA)/PEG shell were prepared through co-assembly of two block copolymers PCL-b-P(Asp-co-AspPBA) and PEG-b-PCL in basic aqueous solutions. The P(Asp-co-AspPBA) chains (Asp ¼ aspartic acid; AspPBA ¼ aspartamidophenylboronic acid) collapsed and formed a shell layer around the PCL core at neutral pH while the soluble PEG chains stabilised the micelles. The collapsed P(Asp-co-AspPBA) polymer becomes soluble under higher glucose concentration and collapses onto the PCL core reversibly at lower glucose concentration. Self-regulated release of glibenclamide from the complex micelles was achieved based on the reversible change of P(Asp-co-AspPBA) chain mobility in response to the change of glucose concentration. As a result, polymeric micelles with glucose-responsive on-off switches were successfully developed.

Nanochaperones Mediated Delivery of Insulin

“…As shown in Figure h,i, upon the decrease of pH value from 10 to 7.4, the sizes of Zn-modified NCs-3 (Zn-NCs-3) decreased from ∼125 to ∼100 nm, and bright patches could also be observed in the enlarged view at pH 7.4, which also indicated the collapse of PAPBA and the formation of domains on the micelle surface. Therefore, the self-assembled mixed-shell micelles would undergo microphase separation at pH 7.4, and the collapsed PAPBA reasonably formed confined hydrophobic domains according to the above results and reports in our previous work …”

“…In alkaline aqueous solution, these two block copolymers spontaneously self-assembled into micelles composed of PCL core and mixed PEG/PAPBA shell (Figure 2a). 41 When the pH value was adjusted to 7.4, the PAPBA chains became insoluble and collapsed, forming hydrophobic domains on the surface of the PCL core. This transformation was very similar to those in our previous works, where the collapse of stimuli-responsive chains in the mixed shell resulted in microphase-separated surface for micelles.…”

“…Therefore, the self-assembled mixed-shell micelles would undergo microphase separation at pH 7.4, and the collapsed PAPBA reasonably formed confined hydrophobic domains according to the above results and reports in our previous work. 41 As illustrated in Figure 1, insulin is not stable under stirring in phosphate-buffered solution at pH 7.4 (PBS 7.4) at 37 °C and would undergo conformational transition into partially unfolded state with hydrophobic regions exposed. The partially unfolded insulin is easy to misfold, form aggregation-prone species, and subsequently aggregate into oligomers due to intermolecular hydrophobic association.…”

“…Block copolymers poly­(ε-caprolactone)- b -poly­(aspartic acid- co -aspartamidophenylboronic acid) [PCL- b -P­(Asp- co -AspPBA)] and poly­(ε-caprolactone)- b -poly­(ethylene glycol) (PCL- b -PEG) were synthesized according to literature methods, ,, and the chemical structures were confirmed by 1 H NMR spectra (Figure S1). For the convenience of the following discussion, P­(Asp- co -AspPBA) is abbreviated as PAPBA.…”

“…These two block copolymers have the same hydrophobic PCL block as well as different hydrophilic PEG and PAPBA blocks. In alkaline aqueous solution, these two block copolymers spontaneously self-assembled into micelles composed of PCL core and mixed PEG/PAPBA shell (Figure a) . When the pH value was adjusted to 7.4, the PAPBA chains became insoluble and collapsed, forming hydrophobic domains on the surface of the PCL core.…”