Poly(N-isopropylacrylamide-co-acrylamide) cross-linked thermoresponsive microspheres obtained from preformed polymers: Influence of the physico-chemical characteristics of drugs on their release profiles
Introduction
Thermally responsive drug delivery systems have attracted ever-increasing attention because they can control the release of drug in response to changes in body temperature and therefore act as self-regulating systems [1], [2], [3], [4]. Poly(N-isopropylacrylamide) (PNIPAAm) is the most popular polymer among the thermoresponsive polymers since it exhibits a sharp phase transition close to 32 °C [5], [6]. The temperature at which this transition occurs is called the lower critical solution temperature (LCST). Below the LCST the polymer chain is hydrated and adopts an extended coil conformation, while above it the polymer is dehydrated and adopts a globular conformation. Correspondingly, the cross-linked hydrogels obtained from these polymers swell under the LCST and shrink above it. The biomedical and biological applications of such gels usually involve the chemical modification of poly(NIPAAm). These modifications are usually performed to introduce functional groups that can increase the LCST towards body temperature [7], [8], to improve the mechanical properties [9] or to interact with certain drugs [10]. However, copolymerization of NIPAAm with acrylate-type comonomers usually leads to gels possessing relatively weak thermosensitivity [11]. Therefore, the comonomer needs to be chosen carefully to preserve the thermosensitivity of the gel structure. Most of the studies concerning the applications of thermoresponsive hydrogels have focused on the use of devices in the form of discs or slabs [12], [13], [14]; few papers have dealt with the preparation and characterization of thermoresponsive microspheres. The majority of microspheres are prepared from monomers by suspension polymerization [15], [16]. Thermoresponsive microspheres from preformed polymers are prepared by dropping a polymer solution into a liquid at a temperature above the LCST [17], [18], [19]. These microspheres are not stable or easy to handle, and have a reduced number of biomedical applications. The most studied drug used as a model for pulsatile on–off drug release from thermoresponsive hydrogels is the hydrophobic indomethacin [20], [21].
The main objectives of this paper were the preparation of stable thermoresponsive microspheres from performed polymers and the study of the influence of physico-chemical characteristics of drugs on their release profile.
Here, the poly(NIPAAm-co-AAm) copolymer was prepared as a thermoresponsive polymer with it’s LCST tailored towards body temperature. This copolymer was transformed into thermoresponsive stable microspheres by an original approach that assumes the cross-linking of the amide group of acrylamide with glutaraldehyde under particular conditions (long reaction time, temperature slightly below the LCST, concentrated polymer solution). The microspheres were characterized by optical and scanning electron microscopy in the dried, swollen and shrunken state, and the degree of swelling and rate of swelling/deswelling were determined. Finally, the influences of drug hydrophilicity/hydrophobicity and molecular weight on the release profiles were examined.
Section snippets
Materials
N-isopropylacrylamide (NIPAAm) (from Aldrich Chemical Corp., Milwaukee, WI, USA) was recrystallized with hexane. Acrylamide (AAm), glutaraldehyde (GA) aqueous solution (25% W/V) and N,N′-azobisisobutyronitrile (AIBN) were supplied from Fluka AG (Buchs, Switzerland). AIBN was purified in methanol before use. Blue dextran (BD) was provided from Pharmacia (Uppsala, Sweden). 1,4-Dioxane, from Fluka AG, was purified by refluxing. Light mineral oil (d = 0.84 g ml−1) was supplied by Sigma Chemical Co.
Preparation and characterization of poly(NIPAAm-co-AAm) copolymer
Acrylamide was one of the monomers chosen in this study to increase the LCST. As reported in Table 1 and proven by 13C NMR spectra (see Fig. 1), the copolymer formation and the percentage of comonomers in the copolymer follow those in the feed. It should be noted that increasing the AAm content of the poly(NIPAAm-co-AAm) results in a shift of the LCST value to a higher temperature while maintaining a sharp phase transition (Fig. 2). Of the thermoresponsive copolymers synthesized by this
Conclusions
Thermoresponsive poly(N-isopropylacrylamide-co-acrylamide) microspheres were prepared from preformed polymers by chemical cross-linking of amide groups with glutaraldehyde using a concentrated copolymer solution at a temperature lower than LCST. The most important characteristics of these microspheres are the rapidity of the volume change as a response to temperature modifications.
The release rate of the drugs from thermoresponsive microspheres depends mainly on the hydrophilic/hydrophobic
Acknowledgements
The authors thank Dr. Loris Leboffe (Department of Biology, University “Roma Tre”, Rome, Italy) for helpful discussions. This study was partly supported by Grants from Ministry of Education and Research, Romania.
References (29)
- et al.
A novel thermo-responsive drug delivery system with positive controlled release
Int J Pharm
(2002) - et al.
Effect of thermal cycling on the properties of thermoresponsive poly (N-isopropylacrylamide) hydrogels
Int J Pharm
(2003) Poly (N-isopropylacrylamide): experiment, theory, and application
Prog Polym Sci
(1992)- et al.
Synthesis and application of thermally reversible heterogels for drug delivery
J Contr Release
(1990) Temperature modulated protein release from pH/temperature-sensitive hydrogels
Biomaterials
(1999)- et al.
Heparin release from thermosensitive hydrogels
J Contr Release
(1992) - et al.
Synthesis, characterization and controlled drug release of thermosensitive IPN–PNIPAAm hydrogels
Biomaterials
(2004) - et al.
Preparation, characterization, and drug release from thermoresponsive microspheres
Int J Pharm
(1995) - et al.
Chemical modulations of thermosensitive poly (N-isopropylacrylamide) microsphere swelling: a new strategy for chemical sensing
Sens Actuat B Chem
(2005) - et al.
Modulating insulin release profile from pH/thermoresponsive polymeric beads through polymer molecular weight
J Contr Release
(1999)
Polymeric microspheres composed of pH/temperature-sensitive polymer complex
Biomaterials
Squeezing hydrogels for controlled oral drug delivery
J Contr Release
Hybrid nanogels for sustainable positive thermosensitive drug release
J Contr Release
Poly[(N-isopropylacrylamide-co-acrylamide-co-(hydroxyethyl methacrylate)] thermoresponsive microspheres. An accurate method for the determination of the volume phase transition temperature based on solute exclusion technique
Eur Polym J
Cited by (93)
Sodium hypochlorite activated dual-layer hollow fiber nanofiltration membranes for mono/divalent ions separation
2023, Chemical Engineering Research and DesignPaliperidone palmitate depot microspheres based on biocompatible poly(alkylene succinate) polyesters as long-acting injectable formulations
2022, Journal of Drug Delivery Science and TechnologyCharacterization of the phase transition mechanism of P(NiPAAm-co-AAc) copolymer hydrogel using 2D correlation IR spectroscopy
2021, Spectrochimica Acta - Part A: Molecular and Biomolecular SpectroscopyCitation Excerpt :This is a very important property to apply to a tumor-targeted drug because the cloud point temperature of a cancer cell is higher than the physiological body temperature. Therefore, its biological applications, especially as a candidate for treatment of tumors and characterizations, have been extensively studied [4–6,12,15,18,22–25]. Spectroscopy is popularly used for polymer studies.
Stimuli-sensitive cross-linked hydrogels as drug delivery systems: Impact of the drug on the responsiveness
2020, International Journal of PharmaceuticsSmart drug delivery system activated by specific biomolecules
2020, Materials Science and Engineering C