Reversibly crosslinked thermo- and redox-responsive nanogels for controlled drug release (original) (raw)
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International Journal of Pharmaceutics, 2009
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Journal of Colloid and Interface Science, 2019
Hypothesis: Facile approaches for the development of new tailored drug carriers are of high importance for the controlled administration of drugs. Herein we report a method for the synthesis of water-soluble reactive copolymers with well-defined architectures for fabrication of redox-sensitive degradable prodrug nanogels for intracellular drug release. Experiments: Primary amine-functionalized statistical copolymers were obtained by hydrolysis of poly(N-vinylpyrrolidone-coN -vinylformamide) copolymers which were 2 synthesized via Reversible Addition−Fragmentation chain-Transfer (RAFT) polymerization. Redox-sensitive degradable nanogels with varying crosslinking densities were synthesized with a redox-sensitive cross-linker. Doxorubicin (DOX) was loaded to form prodrug nanogels (DNG) with hydrodynamic radius from 142 nm to 240 nm. Findings: The nanogels demonstrated slower degradation and retarded drug release rate with increased crosslinking density in the presence of 10 mM reduced glutathione (GSH) at 37℃. The in vitro release studies revealed that maximum 85% DOX was released in 24 h under a reductive environment. Intracellular drug release profiles in HeLa cells indicated that the DOX delivery rate was tunable via varying crosslinking density of the nanogels. Cell viability assay demonstrated that the blank nanogels were biocompatible in wide concentrations up to 0.5 mg/mL while the DOX-loaded nanogels displayed medium antitumor activity with IC50 (half-maximal inhibitory concentration) of 1.80 μg/mL, 2.57 μg/mL, 3.01 μg/mL for DNG5, DNG10 and DNG15 respectively.
Journal of Polymer Research, 2017
Dual-responsive nanogels were prepared by polymerization of itaconic acid (IA) and copolymerization with methacrylic acid (MA) in aqueous solution of hydroxypropyl cellulose (HPC) and cross-linking with N, N′-methylenebisacrylamide (MBAm) through an easy and green process. FTIR spectroscopy, TEM, AFM, DLS and zeta potential studies confirmed the semiinterpenetrating (semi-IPN) polymer network structure of nanogels. The LCST of HPC was increased to a higher temperature than HPC's intrinsic LCST, while the presence of the MA comonomer improved the hydrophobicity of the copolymer and reduced LCST to about body temperature and suppressed the excessive nanogel aggregation. It was found that the concentration of reactants impacted the process of nanogel formation. Additionally, an increasing of cross-linker concentration led to a reduced size of HPC nanogels. Besides, the diameter of nanogels was changed with the temperature and pH. TEM and AFM photographs of copolymer nanogels illustrated that the nanoparticles with small diameters (<100 nm) were prepared. With loading the doxorubicin into the copolymer nanogels, the particle size became larger (about 150 nm) and due to the electrostatic interaction of the cationic drug with anionic particles, the zeta potential was increased. Drug release processes were followed at pH = 5.0 and 7.4 and with 37-and 41-°C temperatures, respectively. The maximum in-vitro release studies of drug-loaded nanogels, which is 91% for the pH 5.0 buffer solution at 41°C, demonstrated the temperature-and pH-sensitivity of prepared copolymer nanogels.
Turkish Journal of Chemistry
Introduction Nanogels are chemically or physically intramolecularly crosslinked polymer coils with sizes typically ranging from 10 to a few hundreds of nanometers. The crosslinked structures provide size and shape stability high water content desirable mechanical properties and high-loading capacity with additional advantages in physicochemical and rheological properties [1-3]. These unique properties make nanogels suitable for various applications, such as chemical and biological sensors [1, 2], controlled release and drug delivery systems [3, 4], contrast agents [5], biomedical implants [6], and in tissue engineering [7], and cancer treatment [8]. Starting from the first work of Staudinger when they prepared divinylbenzene microgels [9], there have been many reports on nanogels prepared from natural polymers such as chitosan [10], alginate [11], and synthetic polymers such as poly(vinyl alcohol) (PVA) [12], poly(acrylic acid) (PAA) [13], poly(vinyl pyrrolidone) (PVP) [14], poly(ethylene oxide) (PEO) [15], and poly(N-isopropylacrylamide) (PNiPAAm) [16]. In this work PVP and PNiPAAm were selected for the preparation of nanogels. PVP was preferred due to its low cytotoxicity, excellent biocompatibility with living tissue, and noncarcinogenic and nonallergic properties [17, 18]. PVP has been widely used in many biomedical applications such as drug delivery [19-21] and tissue engineering [22]. PNiPAAm was selected for its temperature responsive properties where it possesses lower critical solution temperature (LCST) in water around 32 °C [23], which is close to human body temperature. Hence, PNiPAAm nanogels show high potential for a variety of applications especially in biotechnology [24], drug delivery [25], and bioseparation [26]. Nanogels are generally prepared by one of the four methods as described by Kabanov and Vinogradov [27]; i) Physical assembly of interactive polymers, ii) Polymerization of monomers in a homogeneous or nanoscale heterogeneous environment, iii) Crosslinking of preformed polymers, iv) Template-assisted nanofabrication. Among these methods, the easiest and the most straightforward is formation of nanogels by intramolecular crosslinking of hydrophilic or amphiphilic polymers in aqueous solutions. Intramolecular covalent bonds can be formed by using some Abstract: An easy method is proposed to prepare poly(vinyl pyrrolidone) (PVP) and poly(N-isopropylacrylamide) (PNiPAAm) nanogels with sizes less than 100 nm. The underlying principle is to prepare dilute polymer solutions in acetone/water mixtures where acetone acts to break tridimensional structure of water hence disrupting the H-bonds bridging polymer coils causing separation and shrinkage in their sizes. Irradiation of these solutions by gamma-rays directly leads to the formation of intramolecular crosslinks within the coils resulting with nanogels with sizes smaller than precursor coils. While the average size of nanogels of PVP irradiated in water only is 236 nm, they were reduced to about 44 nm when irradiation was carried out in acetone/water solutions at near theta compositions. PNiPAAm nanogels were also synthesized by irradiating their dilute acetone/water solutions. Multimodal coil size distribution of PNiPAAm was converted into monomodal distribution with 70 nm average size and low dispersity by the addition of acetone. Irradiation of such solutions yielded PNiPAAm nanogels with 50 nm average size. Stability of nanogels was followed for 1 year not showing any changes in their sizes or size distributions. Nanogels were characterized by dynamic light scattering, scanning electron microscopy, and atomic force microscopy techniques.