Rheological study of aqueous dispersions of in situ gelable thermosensitive polymer nanogels

Thermosensitive poly(N‐isopropylacrylamide‐co‐acrylamide) nanogels with varied monomer compositions were prepared by precipitation polymerization. The aqueous dispersions of these thermosensitive nanogels (9 wt% of nanogel particles in phosphate‐buffered saline solution) exhibited in situ gelable characteristics. A steady‐state and dynamic rheological analysis demonstrated that the nanogel dispersions were typical pseudoplastic liquids at room temperature. The viscosity of the nanogel dispersions at a constant shear rate increased with an increase of the acrylamide content. When the temperature was increased to 37°C, the pseudoplastic liquid turned into an elastic solid, as the result of a sol–gel phase transition of the nanogel aqueous dispersion during the raise of the temperature. Dynamic temperature ramp circle curves suggest that the sol–gel transition was reversible but with a clear hysteresis. POLYM. ENG. SCI., 2009. © 2008 Society of Plastics Engineers     

Nanogels of poly-N-isopropylacrylamide,poly-N,N-diethylacrylamide and acrylic acid for controlled release of thymol

Synthesis of new nanogels composed of poly N-isopropylacrylamide (PNIPAM) and poly N,N-diethylacrylamide (PNDEA) at different mole ratios of 100:0–50:50 were performed with constant acrylic acid (AA) content (NIPAM:AA mole ratio of 10:1) by free radical polymerization. The obtained nanogels were loaded with thymol and self-assembled on the surface of chitosan films to evaluate control release of the antimicrobial. The effect of temperature (8–35 °C), pH (2–8), and ions were evaluated on particle size (100–200 nm) and charge (?25--40 mv). With the increasing ratio of PNDEA in the copolymers, the lower critical solution temperature shifted gradually from 33 °C to <10 °C. When pH value decreased from 8 to 2, nanogel shrink occurred. Different ions influenced the hydrodynamic diameters of particles, causing salting out effect that followed the order of Hofmeister series. Thymol loaded within mole ratios of 50:50 of NIPAM/NDEA nanogels had longer release time (>24 h) at 4 °C than that at 25 °C (around 6 h). All thymol loaded nanogels exhibited antimicrobial activity against E. coli and B. subtilis.     

Peptide Amphiphilic Supramolecular Nanogels: Competent Host for Notably Efficient Lipase-Catalyzed Hydrolysis of Water-Insoluble Substrates

The present work depicts the development of stable nanogels in an aqueous medium that were exploited for efficient surface-active lipase-catalyzed hydrolysis of water-insoluble substrates. Surfactant-coated gel nanoparticles (neutral NG1 , anionic NG2 , and cationic NG3 ) were prepared from peptide amphiphilic hydrogelator ( G1 , G2 , and G3 , respectively) at different hydrophilic and lipophilic balance (HLB). Chromobacterium viscosum (CV) lipase activity towards hydrolysis of water-insoluble substrates (p-nitrophyenyl-n-alkanoates (C4–C10)) in the presence of nanogels got remarkably improved by ~1.7–8.0 fold in comparison to that in aqueous buffer and other self-aggregates. An increase in hydrophobicity of the substrate led to a notable improvement in lipase activity in the hydrophilic domain (HLB>8.0) of nanogels. The micro-heterogeneous interface of small-sized (10–65 nm) nanogel was found to be an appropriate scaffold for immobilizing surface-active lipase to exhibit superior catalytic efficiency. Concurrently, the flexible conformation of lipase immobilized in nanogels was reflected in its secondary structure having the highest α-helix content from the circular dichroism spectra.     

Synthesis and in vitro biological evaluation as antitumour drug carriers of folate‐targeted N‐isopropylacrylamide‐based nanohydrogels

Copolymeric nanohydrogels based on N‐isopropylacrylamide, N‐(pyridin‐4‐ylmethyl)acrylamide and tert‐butyl‐2‐acrylamidoethyl carbamate, synthesized by microemulsion polymerization, were characterized using Fourier transform infrared spectroscopy and their size (38–52 nm) determined using quasielastic light scattering. Folic acid was covalently attached to the nanohydrogels (1.40 ± 0.07 mmol g^?1). Tamoxifen (6.7 ± 0.2–7.3 ± 1.2 µg TMX mg^?1 nanohydrogel), a hydrophobic anticancer drug, and 5‐fluorouracil (7.7 ± 0.7–10.14 ± 1.75 µg 5‐FU mg^?1 nanohydrogel), a hydrophilic anticancer drug, were loaded into the nanohydrogels. Maximum in vitro TMX release (77–84% of loaded drug) depended on interactions of the drug with hydrophobic clusters of the nanogels; however, no nanogel/5‐FU interactions allowed total release of the loaded drug. The cytotoxicity of unloaded nanohydrogels in MCF7, T47D and HeLa cells was low. Cell uptake of nanogels without bound folic acid took place in the three cell types by unspecific internalization in a time‐dependent process. Cell uptake increased for folic acid‐targeted nanohydrogels in T47D and HeLa cells, which have folate receptors. The administration of 10 and 30 µmol L^?1 TMX by TMX‐loaded nanogels and 10 µmol L^?1 5‐FU by 5‐FU‐loaded nanogels was effective on the three cell types, and the best results were obtained for folic acid‐targeted nanohydrogels. Copyright © 2012 Society of Chemical Industry     

Morphology and drug release behavior of <Emphasis Type="Italic">N</Emphasis>-isopropylacrylamide/acrylic acid copolymer as stimuli-responsive nanogels

Thermo- and pH-responsive N-isopropylacrylamide (NIPAM) nanogels can be obtained by copolymerization of acrylic acid (AA) comonomer through differential microemulsion polymerization. The effects of comonomer, cross-linker, surfactant contents, and water/oil ratio were preliminarily investigated by a 2⁴ full factorial design in order to eliminate the insignificant parameters from the polymerization analysis. The smallest poly(NIPAM-co-AA) nanogel particles were 40 ± 1 nm in diameter with 6 wt% of solid content and 98% conversion without coagulation. The comonomer amounts controlled the morphologies and LCST of the poly(NIPAM-co-AA) nanogels. The hairy microgels of poly(NIPAM-co-AA) with a 10:90 mol ratio of AA/ NIPAM had a lower critical solution temperature (LCST) of 6 °C. With an increase in the AA amount to a 17 mol ratio, the LCST increased to 27 °C, resulting in core-shell morphology. The morphology of resultant nanogels was characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy, and differential scanning calorimetry. Nuclear magnetic resonance spectroscopy was used to calculate the mole ratio of NIPAM and AA in resultant nanogels after dialysis. Both nanogel mole ratio and morphology effectively retained the cationic anti-cancer drug of methylene blue for several hours, an important basic requirement for a drug delivery system. Compared to core-shell microgels, a higher methylene blue release was obtained from the hairy microgels in simulated intestinal fluid.     

Human growth hormone‐loaded nanogels composed of cinnamoyl alginate,cinnamoyl Pluronic F127, and cinnamoyl poly(ethylene glycol)

Cinnamoyl alginate (CinAlg), cinnamoyl Pluronic F127 (CinPlu), and cinnamoyl poly(ethylene glycol) (CinPEG) could be self‐assembled into nanogels, possibly due to hydrophobic interaction among cinnamic acid (CA) residues. The nanogels were nearly spherical particles on TEM photographs. The photodimerization of CA residue had little effect on the integrity and the size of nanogel. The stability of the nanogels in blood plasma for 48 h at 37°C did not depend on UV irradiation, however they were stable in deoxycholate solution (1 and 10 mM) only when they were UV‐treated. Human growth hormone (hGH) could readily be loaded in the nanogel under an acidic condition possibly due to the electrostatic interaction between hGH and CinAlg. hGH hardly released from the nanogel at body temperature (37°C) when the release medium was at acidic condition (e.g., pH 3.0, pH 5.0; <10% in 170 h). However, it readily released at the same temperature when the medium was at physiological pH (e.g., pH 7.4; around 45% in 170 h) and at an alkaline condition (e.g., pH 9.0; >50% in 170 h). However, slow release of hGH was observed for 100 h possibly due to the layer of thermally condensed Pluronic F127 chains. In addition, initial burst release was suppressed as the CinPlu content increased. For example, the release degree at pH 9 in 60 min decreased from 15.3 to 5.9% as the CinPlu content increased from 20 to 60%. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42446.     

Temperature/pH/magnetic triple‐sensitive nanogel–hydrogel nanocomposite for release of anticancer drug

Hydrogels, nanogels and nanocomposites show increasing potential for application in drug delivery systems due to their good chemical and physical properties. Therefore, we were encouraged to combine them to produce a new compound with unique properties for a long‐term drug release system. In this regard, the design and application of a nanocomposite hydrogel containing entrapped nanogel for drug delivery are demonstrated. To this aim, we first prepared an iron oxide nanocomposite nanogel based on poly(N‐isopropylacrylamide)‐co‐((2‐dimethylaminoethyl) methacrylate) (PNIPAM‐co‐PDMA) grafted onto sodium alginate (NaAlg) as a biocompatible polymer and iron oxide nanoparticles (ION) as nanometric base (PND/ION‐NG). This was then added into a solution of PDMA grafted onto NaAlg. Through dropwise addition of mixed aqueous solution of iron salts into the prepared polymeric solution, a novel hydrogel nanocomposite with excellent pH, thermal and magnetic responsivity was fabricated. The synthesized samples were fully characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy with energy‐dispersive X‐ray analysis, vibrating sample magnetometry and atomic force microscopy. A mechanism for the formation of PNIPAM‐co‐PDMA/NaAlg‐ION nanogel–PDMA/NaAlg‐ION hydrogel and PND/ION nanogel is suggested. Swelling capacity was measured at various temperatures (25 to 45 °C), pH values (from 2 to 11) and magnetic field and under load (0.3 psi) and the dependence of swelling properties of the nanogel–hydrogel nanocomposite on these factors was well demonstrated. The release rate of doxorubicin hydrochloride (DOX) as an anticancer drug was studied at different pH values and temperatures in the presence and absence of a magnetic field. The results showed that these factors have a high impact on drug release from this nanocomposite. The result showed that DOX release could be sustained for up to 12.5 days from these nanocomposite hydrogels, significantly longer than that achievable using the constituent hydrogel or nanogel alone (<1 day). The results indicated that the nanogel–hydrogel nanocomposite can serve as a novel nanocarrier for anticancer drug delivery. © 2019 Society of Chemical Industry     

A thermo/pH/magnetic-responsive nanogel based on sodium alginate by modifying magnetic graphene oxide: Preparation,characterization, and drug delivery

A novel thermo/pH/magnetic-triple-responsive nanogel was synthesized by grafting N-isopropylacrylamide and acrylic acid onto sodium alginate to modify magnetic graphene oxide as a drug delivery system. The synthesized nanogel was characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), vibrating sample magnetometer (VSM), atomic force micrographs (AFM), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). The obtained nanogel displayed excellent reversible transmittance changes in response to pH, temperature, and magnetic field. The performance of the nanogels to load doxorubicin (DOX) drug and to sustain doxorubicin release was tested upon exposure to pH, temperature, and magnetic field variations. The mechanism of drug release was proposed in this paper by different kinetic models. In addition, the effects of nanogels and DOX-loaded nanogels on MCF-7 cells were examined and results were compared with free DOX drug. The in vitro results demonstrated that this triple-responsive nanogel can be an appropriate candidate for applications in cancer therapy.     

Surface‐active amphiphilic poly[(2‐acrylamido‐2‐methylpropanesulfonic acid)‐co‐(N‐isopropylacrylamide)] nanoparticles as stabilizer in aqueous emulsion polymerization

This work reports the effect of nanogel solid particles on the surface and interfacial tension of water/air and water/styrene interfaces. Moreover, the work aimed to use nanogels as a stabilizer for miniemulsion aqueous polymerization. A series of amphiphilic crosslinked N‐isopropylacrylamide (NIPAm) and 2‐acrylamido‐2‐methylpropanesulfonic acid (AMPS) copolymer nanogels were synthesized based on an aqueous copolymerization batch method. Divinylbenzene and N,N‐methylene bisacrylamide were used as crosslinkers. The morphologies of the prepared nanogels were investigated using transmission and scanning electron microscopies. The lower critical transition temperatures were determined using differential scanning calorimetry. The surface tension of colloidal NIPAm/AMPS dispersions was measured as functions of surface age, temperature and the morphology of the NIPAm/AMPS nanogels. The NIPAm/AMPS nanogels reduced the surface tension of water to about 30.1 mN m^?1 at 298 K with a small increase at 313 K. Surface activities of these nanogels in water were determined by surface tension measurements. The NIPAm/AMPS dispersions had high surface activity and were used as a stabilizer to prepare a crosslinked poly(styrene‐co‐AMPS) microgel based on emulsion crosslinking polymerization. © 2013 Society of Chemical Industry     

Dual-responsive semi-IPN copolymer nanogels based on poly (itaconic acid) and hydroxypropyl cellulose as a carrier for controlled drug release

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 semi-interpenetrating (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.     

Low charge polyvinylamine nanogels offer sustained,low‐level gene expression

Cationic polymer charge and polymer degradability each play a crucial role for packaging and delivering plasmid DNA. High density cationic charge has been shown to enhance transfection efficiency but may give rise to undesirable toxicity. Polyvinylamine (PVAm) nanogels bearing discrete amounts of surface charge were used to systematically examine the balance between transfection efficiency and cytotoxicity. Poly(N‐vinylformamide) (PNVF) nanogels were prepared via an inverse emulsion polymerization reaction and crosslinked with a nondegradable or acid‐labile crosslinker. The nanogels were then hydrolyzed to yield varying degrees of primary amines. The degree of conversion from PNVF to PVAm was controlled using different concentrations of NaOH and hydrolysis times. PVAm nanogel size and charge ranged from 150 to 310 nm, and +3.5 to +18 mV, respectively. These cationic particles were then complexed with pDNA encoding for luciferase. The cytotoxicity of PVAm nanogels and the transfection efficiency of PVAm/DNA complexes were evaluated in carcinomic human alveolar basal epithelial cells (A549). The cytotoxicity of PVAm nanogels increased with increasing accessible charge as expected. Transfection efficiency increased with increasing amounts of amine groups for nondegradable nanogels. Interestingly, acid‐labile nanogels bearing low charge demonstrated more sustained gene transfection when compared with the more highly charged nanogels. These observations suggested that the use of degradable particles with less charge may reduce cytotoxicity without compromising overall transfection efficiency. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

pH-responsive PEGylated nanogel containing platinum nanoparticles: Application to on–off regulation of catalytic activity for reactive oxygen species

Synthesis of pH-responsive PEGylated nanogels platinum nanoparticles (PtNPs: <2 nm) was successfully carried out through the reduction of K₂PtCl₆ within the PEGylated nanogels constructed from cross-linked poly[2-(N,N-diethylamino)ethyl methacrylate] (PDEAMA) core and tethered PEG chains. The resulting PEGylated nanogels containing PtNPs showed significant catalytic activity for reactive oxygen species (ROS) in response to skin-environmental pH (acid), whereas the almost no catalytic activity for ROS was observed at physiological pH due to the volume phase transition of the PDEAMA gel core. Thus, pH-responsive and PEGylated nanogel containing PtNPs can be utilized to the skin-specific ROS-scavengers for the skin aging.     

Synthesis of poly(N,N-dimethylaminoethyl methacrylate) nanogels in reverse micelles for delivery of plasmid DNA and small interfering RNAs into living cells

Hydrogel nanoparticles of poly(N,N-dimethylaminoethyl methacrylate) with hydrodynamic radii of 40?C50 nm are synthesized via the copolymerization of a water-soluble monomer and N,N??-methylenebis(acrylamide) in a solution of Brij-97 reverse micelles in cyclohexane. All amino groups of nanoparticles are protonated in a weakly acidic solution; however, almost one-third of them remain inaccessible to a flexible polystyrenesulfonate polyanion, while almost two-thirds of them remain inaccessible to rigid double-helical DNA. Complexes of nanogels with plasmid DNA carrying the firefly luciferase gene transfect eukaryotic cells in a cultural medium, and the products of interaction of nanogels with small interfering RNAs suppress expression of the marker enzyme. In both systems, the replacement of linear polyamine with nanogel significantly increases the efficiency of delivery. The activity of nanogels in transfection experiments depends in an extremum pattern on the crosslink degree and achieves a maximum value at a crosslinking-agent concentration of 5 mol %. The results of this study suggest that the developed procedure offers promise for the synthesis of cationic nanogels as vectors for delivery of genetic material into living cells.     

Adsorption studies of Cu2+ onto poly (vinyl alcohol)/poly (acrylamide-co-N-isopropylacrylamide) core–shell nanogels synthesized through surfactant-free emulsion polymerization

Poly (vinyl alcohol) (PVA) nanoparticle core and poly (acrylamide-co-N-isopropylacrylamide) P(AAm-co-NIPAm) hydrogel shell were fabricated to produce well-defined PVA/P(AAm-co-NIPAm) core–shell nanogels using Surfactant Free Emulsion Polymerization (SFEP). The nanogel was characterized by the FTIR, TEM TGA thermogram and SEM techniques. The adsorbent was utilized for Cu²⁺ removal from aqueous solution. Batch adsorption process indicated that 0.9 mol% PAAm nanogel exhibited higher adsorption affinity toward Cu²⁺. The kinetics parameters were investigated according to the pseudo-first-order, pseudo-second-order and intraparticle diffusion rate models. The adsorption equilibrium match with Langmuir adsorption isotherm rather than Freundlich isotherm. The Cu²⁺ loaded nanogels were effectively desorbed using 0.1 mol/l from HCl as stripping agent.     

One-step synthesis of pegylated cationic nanogels of poly(N,N′-dimethylaminoethyl methacrylate) in aqueous solution via self-stabilizing micelles using an amphiphilic macroRAFT agent

Cationic nanogels of Pegylated poly(N,N′-Dimethylaminoethyl methacrylate) (PEG-PDAEMA) have been synthesized in aqueous solution by a one-step surfactant-free reversible addition-fragmentation transfer (RAFT) process. A Pegylated amphiphilic macroRAFT agent (mPEG₅₅₀-TTC) with a hydrophobic dodecyl chain was utilized to stabilize the micelles and control the polymerization and crosslinking of DMAEMA in aqueous solution. ¹H NMR, GPC, Elemental analysis, Dynamic light scattering (DLS), Zeta potential and Atomic force microscopy (AFM) measurements confirmed the formation of the cationic nanogels in size of about 20 nm with a narrow distribution. It also revealed that the concentration of monomer and the kinds of crosslinker are the key factors to control the formation of nanogel. This cationic nanogel has potential application in gene delivery.     

Preparation of stimuli‐responsive nanogels of poly [2‐(dimethylamino) ethyl methacrylate] by heterophase and microemulsion polymerization using gamma radiation

Poly [2‐(dimethylamino) ethyl methacrylate], PDMAEMA, was synthesized by heterophase polymerization at 70°C using sodium dodecylsulfate (SDS) as stabilizer and potassium persulfate (KPS) as the initiator. Conversions were 60%, polymer content 18%, and intensity average particle diameter, D_p, 32 nm. γ‐rays irradiation of PDMAEMA nanolatexes and DMAEMA/H₂O/SDS microemulsions using ethyleneglycol dimethacrylate produced nanogels responding to temperature and pH. Nanogels shrinked as temperature increased, swelled excessively in acidic solutions (maximum D_p: 498 nm) and deswelled (minimum D_p: 257 nm) in basic solutions for the case of the nanogels obtained from PDMAEMA nanolatexes. pH response to swelling is due to protonation of amine groups in the backbone of PDMAEMA in acidic conditions leading to electrostatic interactions in the nanogel. POLYM. ENG. SCI., 54:1625–1631, 2014. © 2013 Society of Plastics Engineers     

pH/redox/thermo-stimulative nanogels with enhanced thermosensitivity via incorporation of cationic and anionic components for anticancer drug delivery

To explore the potential biomedical applications of nanogels, it is a key factor to improve their thermosensitivity. In this paper, triple-responsive nanogels poly(N-isopropylacrylamide–N,N′-dimethylaminoethyl methacrylate–acrylic acid) (PNDA) were synthesized via in situ incorporating both cationic components and anionic components into a normal thermosensitive polymer matrix. The triple-monomer constructed PNDA nanogels displayed an enhanced thermosensitivity as compared with dual-monomer constructed PND nanogels. The PNDA nanogels presented higher encapsulation efficiency (～89%) and exhibited better pH/redox/thermo-responsivenesses in an anticancer drug delivery. In vitro biological study indicated that the PNDA nanogels have excellent biocompatibility and improved anticancer cytotoxicity to A549 cells after loading drug DOX.     

Interaction of nanogel with cyclodextrin or protein: Study by dynamic light scattering and small-angle neutron scattering

The structure of hydrogel nanoparticles (CHP nanogels), formed by self-aggregation of cholesterol-bearing pullulan (CHP) was studied by dynamic light scattering (DLS) and small-angle neutron scattering (SANS). The interactions between the CHP nanogel and methyl-β-cyclodextrin (CD) or protein (hen egg white) were also investigated. It was revealed by SANS that the nanogels were spherical in shape with a radius of 6.7 nm. The following two functions were disclosed. (1) CHP nanogels were dissociated by the addition of CD and formed inclusion complexes with cholesteryl groups, leading to suppression of hydrophobic interaction between the cholesteryl groups. (2) The nanogel behaved as a molecular chaperone (heat shock protein-like activity) when CHP nanogel was mixed with hen egg white and heated up to 75 °C. The egg white aqueous solutions with CHP nanogel remained transparent while the egg white without CHP nanogel became opaque.     

Characterization and phase‐transition behavior of thermoresponsive PVME nanogels in the presence of cellulose nanowhiskers: Rheology,morphology, and FTIR studies

The effects of cellulose nanowhiskers (CNWs) and irradiation dose on phase separation behavior as well as rheological and physical properties of Poly vinyl methyl ether (PVME) nanogels are investigated. Interactions between CNWs and polymer chains lead to the dehydration of PVME chains. Increasing the irradiation dose or CNW weight fraction enhances the VPTT, due to the decreased chain mobility. The phase separation behaviors of hybrid and nonhybrid nanogels are investigated at two different quench depths. At the shallow quench depth, the samples phase separate through nucleation and growth (NG) mechanism. However in the case of hybrid nanogels with a higher temperature, as a result of the enhanced dynamic asymmetry induced by the increased quench depth and the interaction of PVME chains with CNWs, the phase separation mechanism changes from NG to viscoelastic phase separation (VPS). The linear rheological behavior of nanogels was well correlated with the evolution of corresponding phase‐separating morphologies. At 40°C, a shoulder appeared in the storage modulus curve in the intermediate frequency range, due to shape relaxation of the droplets formed by NG mechanism. However, a solid‐like behavior was observed due to the existence of a percolated network structure induced by VPS at 60°C. POLYM. ENG. SCI., 59:899–912, 2019. © 2018 Society of Plastics Engineers     

Poly[N-(2-hydroxypropyl)methacrylamide]-Modified Magnetic γ-F2O3 Nanoparticles Conjugated with Doxorubicin for Glioblastoma Treatment

With the aim to develop a new anticancer agent, we prepared poly[N-(2-hydroxypropyl)methacrylamide-co-methyl 2-methacrylamidoacetate] [P(HP-MMAA)], which was reacted with hydrazine to poly[N-(2-hydroxypropyl)methacrylamide-co-N-(2-hydrazinyl-2-oxoethyl)methacrylamide] [P(HP-MAH)] to conjugate doxorubicin (Dox) via hydrazone bond. The resulting P(HP-MAH)-Dox conjugate was used as a coating of magnetic γ-Fe₂O₃ nanoparticles obtained by the coprecipitation method. In vitro toxicity of various concentrations of Dox, P(HP-MAH)-Dox, and γ-Fe₂O₃@P(HP-MAH)-Dox nanoparticles was determined on somatic healthy cells (human bone marrow stromal cells hMSC), human glioblastoma line (GaMG), and primary human glioblastoma (GBM) cells isolated from GBM patients both at a short and prolonged exposition time (up to 7 days). Due to hydrolysis of the hydrazone bond in acid milieu of tumor cells and Dox release, the γ-Fe₂O₃@P(HP-MAH)-Dox nanoparticles significantly decreased the GaMG and GBM cell growth compared to free Dox and P(HP-MAH)-Dox in low concentration (10 nM), whereas in hMSCs it remained without effect. γ-F₂O₃@PHP nanoparticles alone did not affect the viability of any of the tested cells.