Nitrilotriacetic Acid (NTA) and Phenylboronic Acid (PBA) Functionalized Nanogels for Efficient Encapsulation and Controlled Release of Insulin

Abstract

Protein drugs play a significant role in the treatment of many diseases such as diabetes, cancers, and immune system diseases. Though polymeric nanocarriers have been designed to deliver protein drugs for prolonging circulation lifetime and providing stimuli-triggered release, problems are still often encountered including lower loading efficiency and capacity as well as poor circulation stability because of the weak interaction between protein drugs and nanocarriers. Herein, we described a new kind of bifunctional polymeric nanogels for efficient loading and glucose-triggered release of insulin. Biodegradable poly­(N-isopropylacrylamide) (PNIPAM)-based nanogels was synthesized with nitrilotriacetic acid (NTA) and phenylboronic acid (PBA) as functional groups and ethylene glycol dimethacrylate (EGDMA) as cross-linker. The NTA groups could specifically bind imidazole-containing protein drugs such as insulin via chelated zinc ions, leading an efficient loading of insulin. The structure, morphology, and drug-loading properties of the nanogels were well-characterized, and glucose-triggered insulin release was achieved based on the glucose-responsiveness of PBA groups. MTT assay and enzymatic degradation revealed good biocompatibility and biodegradability for the nanogels. This kind of bifunctional nanogels would be promising candidates for glucose-responsive delivery of insulin in the future.

Polymeric Nanostructures Containing Proteins and Peptides for Pharmaceutical Applications

“…Hydrophobic connections and electrostatic interactions are involved in physical embedding, whereas chemical linking of PEG (PEGylation) is involved in the chemical bonding process. Apropos of hydrophobic association, therapeutic proteins are encapsulated in the micellar core of amphiphilic block copolymers when micellization occurs [63]. On the other hand, when a block copolymer with a neutral and a charged block is mixed with an oppositely charged protein, polyion complex micelles (PIC) are formed in aqueous media with a narrow size distribution.…”

“…Li and coworkers [63] published an equally significant study on novel bifunctional, bio-decomposable nanogels able to load and release insulin according to predetermined glycose levels. Poly(N-isopropylacrylamide) (PNIPAM) nanogels were prepared with nitrilotriacetic acid (NTA) and phenylboronic acid (PBA) as active groups, while ethylene glycol dimethacrylate (EGDMA) acted as the crosslinker.…”

Nanoparticles capable of managing hypoglycemia and preventing myocardial ischemia‐reperfusion injury

“…Most of the PBA in the polymer is not in the ionized state, and this unionized PBA group does not easily react with glucose to produce a response. 12,13 However, using PBA and another unit to form a new type of high molecular weight polymer can significantly reduce its pKa value. Considerable research has been done in this area.…”

A Glucose‐Responsive Polymer Nanocarrier Based on Sulfonated Resorcinarene for Controlled Insulin Delivery

“…[3][4][5][6][7] One of the most promising approaches is the creation of nanocarriers that release insulin at high glucose concentrations. [8][9][10][11][12][13][14][15][16][17][18] The structure of many carriers obtained consists of phenylboronic acid, [19][20][21][22][23][24][25][26][27] and their action is based on the interaction of boronates with glucose. [28][29][30][31][32][33] Boronic acid and their esters are sensitive to many carbohydrates containing cis-1,2-and cis-1,3-diol fragments.…”

“…Nanotechnology and nanomedicine provide an alternative way for diabetes therapy . One of the most promising approaches is the creation of nanocarriers that release insulin at high glucose concentrations . The structure of many carriers obtained consists of phenylboronic acid, and their action is based on the interaction of boronates with glucose .…”