Synthesis and Drug Delivery Application of Thermo- and pH-Sensitive Hydrogels: Poly(β-CD-co-N-Isopropylacrylamide-co-IAM)

Abstract

Copolymerization of N-isopropylacrylamide (NIPAM), itaconamic acid (IAM; 4-amino-2-methylene-4-oxobutanoic acid) and β-cyclodextrin was investigated in this study. β-cyclodextrin was at first modified by reacting with allyl glycidyl ether to substitute its OH end groups with moieties containing double bonds to facilitate the subsequent radical copolymerization with NIPAM and IAM. It was reported that poly(NIPAM-IAM) can respond to the change of temperature as well as pH value. In this study, the structure of β-cyclodextrin was introduced to poly(NIPAM-IAM) copolymers because of its cavity structure capable of encapsulating a variety of drug molecules. The tri-component copolymers, poly(CD-NIPAM-IAM), were synthesized with different monomeric ratios of NIPAM/IAM/β-CD and the hydrogels of the tri-component copolymers were also synthesized by additionally adding N,N′-methylenebisacrylamide as a cross-linking agent. The results show that the lower critical solution temperature (LCST) of the copolymer (or hydrogel) increases as the molar fraction of IAM increases. The transmission electron microscopic (TEM) images of linear copolymers (no cross-linking) show that molecules undergo self-assembly to have a distinct core–shell structure, compared to poly(CD-NIPAM) which contains no IAM. On the other hand, the scanning electron microscopic (SEM) images of hydrogels show that the pores gradually become sheet-like structures as the molar fraction of IAM increases to enhance the water absorption capacity. In order to exhibit the thermal and pH sensitivities of poly(CD-NIPAM-IAM) as the drug carrier, the drug release of the newly synthesized hydrogels at 37 °C and different pH values, pH = 2 and pH = 7.4, was investigated using atorvastatin which was used primarily as a lipid-lowering drug. The drug release experimental result shows that poly(CD-NIPAM-IAM) as a drug carrier was pH-sensitive and has the largest release rate at pH = 7.4 at 37 °C, indicating it is useful to release drugs in a neutral or alkaline (intestinal) environment.

Synthesis and characterization of poly(N-isopropylmethacrylamide-co-N-isopropylacrylamide) copolymers

“…A medium intensity absorption band with the maximum at 2934 cm -1 originates from asymmetric valence vibrations of the C-H bond in the NIPAM isopropyl group, νas(C-H). The amide bands I, II and III with the maxima at 1659, 1549 cm -1 [43,44], and 1310 cm -1 , respectively, confirm the presence of the amide group in the NIPAM molecule. The result of C=C bond vibrations is a strong intensity absorption band with the maximum at 1619 cm -1 [45].…”

Hybrid Injectable Sol-Gel Systems Based on Thermo-Sensitive Polyurethane Hydrogels Carrying pH-Sensitive Mesoporous Silica Nanoparticles for the Controlled and Triggered Release of Therapeutic Agents

“…For instance, Guar gum was block copolymerized with PNIPAM by Lang et al (2006) to provide thermo-sensitive PNIPAM-based hydrogels with additional pH-sensitivity (slower release of sinomenine hydrochloride at pH 6.8 compared to pH 1.0). More recently, N-isopropylacrylamide (NIPAM), itaconamic acid (AIM) and β-cyclodextrin (β-CD) were copolymerized to get a polymer which aqueous solutions showed responsiveness to temperature and pH provided by NIPAM and AIM, respectively, and additional capability to encapsulate drug molecules due to β-CD moieties (Rwei et al, 2016). Similar results were also published by Roy et al (2019) that developed pH-and thermo-responsive gels by grafting and crosslinking PNIPAM and poly(methacrylic acid) on β-cyclodextrins for preferential release of metronidazole and ofloxacin at colonic pH (i.e., 7.4) instead of stomach pH (acid pH).…”

Synthesis and Characterization of pH and Thermo Dual-Responsive Hydrogels with a Semi-IPN Structure Based on N-Isopropylacrylamide and Itaconamic Acid

“…In our previous studies, itaconamic acid (IAM) was used as a pH-sensitive segment to prepare thermo- and pH-responsive copolymers [ 30 , 31 , 32 ]. In addition, we reported the synthesis of conventional hydrogel between NIPAM, IAM, and β-cyclodextrin with high swelling ratio, because IAM has two hydrophilic functional groups simultaneously (–NH 2 and –COOH) [ 33 ]. In the present work, unlike the conventional structure, the semi-IPN hydrogels are investigated.…”