Nitrilotriacetic Acid-Functionalized Glucose-Responsive
Complex Micelles for the Efficient Encapsulation and Self-Regulated Release of
Insulin
Li, C (Li, Chang)[ 1 ] ; Huang, F (Huang, Fan)[ 3,4 ] ; Liu, Y (Liu, Yong)[ 1 ] ; Lv, J (Lv, Juan)[ 1 ] ; Wu, G (Wu, Gang)[ 1 ] ; Liu, Y (Liu, Ying)[ 1 ] ; Ma, RJ (Ma, Rujiang)[ 1 ] ; An, YL (An, Yingli)[ 1 ] ; Shi, LQ (Shi, Linqi)[ 1,2 ]
LANGMUIR,
2018, 34(40): 12116-12125
DOI: 10.1021/acs.langmuir.8b02574
WOS:000447239100022
Abstact
Insulin
plays a significant role in diabetes treatment. Although a huge number of
insulin-loaded, glucose responsive nanocarriers have been developed in past
decades, most of them showed a lower loading capacity and efficiency due to the
weak interaction between insulin and nanocarriers. In this work, a novel
insulin -encapsulated glucose-responsive polymeric complex micelle (CM) is
devised, showing (i) enhanced insulin-loading efficiency owing to the zinc
ions' chelation by nitrilotriacetic acid (NTA) groups of NTA-functioned
glycopolymer and the histidine imidazole of insulin, (ii) the glucose triggered
pulse release of insulin, and (iii) long stability under physiological
conditions. This CM was fabricated by the self assembly of block copolymer
PEG-b-P(Asp-co-AspPBA) and glycopolymer P(Asp-co-AspGA-co-AspNTA), resulting in
complex micelles with a PEG shell and a cross-linked core composed of
phenylboronic acid (PBA)/glucose complexations. Notably, the modified
nitrilotriacetic acid (NTA) groups of CM could specifically bind insulin via
chelated zinc ions, thus enhancing the loading efficacy of insulin compared to
that of nonmodified CM. The dynamic PBA/glucose complexation core of CM
dissociates under the trigger of high glucose concentration (>2 g/L) while
being quite stable in low glucose concentrations (<2 g/l), as demonstrated by the pulse release of insulin in vitro. finally, in a murine model of type 1 diabetes, nta-modified complex micelles loading an insulin (nta-cm-ins) group exhibited a long hypoglycemic effect which is superior to that of free insulin in the pbs (pbs-ins) group and insulin -loaded complex micelles without an nta modification (cm-ins) group. this long-term effect benefited from zn(ii) chelation by nta-modified complex micelles and could avoid hypoglycemia caused by the burst release of insulin. taken together, this constitutes a highly effective way to encapsulate insulin and release insulin via an on-demand manner for blood glucose control in diabetes.
