Polymer grafted magnetic nanoparticles for delivery of anticancer drug at lower pH and elevated temperature
Graphical abstract
Introduction
Magnetic nanoparticles (MNPs) have attracted immense interest in the field of biological research owing to their large surface area, superparamagnetic nature and favorable biocompatibility. Unmodified MNPs tend to agglomerate due to their large magnetic dipole–dipole attraction and superparamagnetic behavior [1], thereby necessitates their surface modification. It also imparts good colloidal stability, improves their biological performance, and reduces immunogenicity [2], [3]. For example, polymer fabricated iron oxide nanoparticles (poly-MNPs) have shown enormous application in diverse fields, such as, hyperthermia [4], catalysis [5], [6], drug delivery [7], [8], contrast enhancement in magnetic resonance imaging [9], [10], [11] and bio-separation [12]. Among the polymers, poly(ethylene glycol) and its copolymers are being widely used for modification of iron nanoparticles due to their non-specific protein adsorption, reduced immunogenicity [13], [14], [15].
Nanoparticle-based drug delivery systems are also effective due to their improved bio-distribution and pharmacokinetics through their enhanced permeability and retention (EPR) effect [16]. Inspite of enhanced the accumulation of nanoparticles within tumor tissues as a result of enhanced EPR, insufficient and uncontrolled drug release restricts the utility of anticancer drugs, thereby undesirably affecting the effectiveness of the chemotherapy treatment [17]. Stimuli-responsive delivery systems are one of the ways to overcome this problem [18]. Among the stimuli, pH is the most frequently investigated because of its significantly different values in different tissues and cellular compartments [19], [20], [21], [22], [23]. It is now established that the extracellular medium of a tumor has a lower pH (∼6.8) than blood and normal tissues (pH 7.4) [24], [25], [26], [27], whereas pH value of lysosome are even lower (∼5.0–5.5) [28]. Thus pH-sensitive delivery systems are probably the most explored systems in the field of controlled drug-delivery [29].
Heat is another important stimulus which is capable of influencing structural changes of a thermoresponsive polymer and thereby releasing the entrapped drug molecules [30], [31], [32]. Hence, drug carriers based on thermoresponsive polymer – magnetic nanoparticle conjugates are reported [33]. We have earlier reported multifunctional dual-responsive poly(N-isopropylacrylamide)-block-poly(acrylic acid) (PNIPAM-b-PAA) tethered magnetic nanoparticles (MNPs) for targeted delivery of anti-cancer drug [34]. However, in that particular case, the thermoresponsive behavior of the block copolymer was of limited use because the thermoresponsive drug release could not be controlled at physiological temperature (37 °C). Hence, there is need for thermoresponsive polymer modified MNPs in which the drug-release can be triggered by local heating slightly above at physiological temperature (37 °C). This requires the modified polymer should not release the loaded drug at physiological temperature but release the entrapped drug when heated locally to a slightly higher temperature. It is known that the MNPs are capable of generating heat when a magnetic field is applied [35], hence, incorporation of MNPs in thermoresponsive polymer, seems to hold promise in cancer treatment as an magnetic field can increase the local temperature, thereby influence the conformation of thermoresponsive polymer which in effect may trigger the release of drugs [36].
In this present work, we have reported the synthesis of a series of pH- and temperature responsive polymer coated iron oxide nanoparticles, and studied their potential as drug delivery vehicle at different temperature and pH conditions in vitro. We have synthesized poly(N-isoproplacrylamide-ran-poly(ethylene glycol) methyl ether acrylate)-block-poly(acrylic acid) copolymers and covalently linked them on nanoparticle surfaces. Poly(ethylene glycol) (PEG), a known biocompatible and EPR enhancing polymer was incorporated as grafts in poly(N-isopropylacrylamide) backbone which is a well-known thermoresponsive polymer. It has been reported that incorporation of hydrophilic polymers like PEG lead to remarkable improvement in the solubility, stability, cell survival and biodistribution of the PEG coated nanoparticles [37], [38]. Additionally, in the present case, incorporation of PEGMEA should increase the LCST of the copolymers. All polymer coated nanoparticles were well characterized. Subsequently, the drug loading capacity and controlled release behaviors of the said nanoparticles were investigated in vitro using doxorubicin (DOX) as a model anticancer drug in different pH and temperatures. Cytotoxicity and anticancer activity of the polymer grafted nanoparticles before and after DOX loading were monitored using ME 180 cervical cancer cells.
Section snippets
Materials
Ferrous sulfate (FeSO4, 7H2O), anhydrous ferric chloride (FeCl3) and ammonia were obtained from Merck. N-isopropyl acrylamide was obtained from Sigma–Aldrich and was recrystallized from hexane. Poly(ethylene glycol) methyl ether acrylate (PEGMEA), tert-butyl acrylate (tBA), 3-aminopropyl triethoxysilane (APTES), N-hydroxysuccinimide (NHS), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC), Doxorubicin hydrochloride (DOX), azobisisobutyronitrile (AIBN), trifluoroacetic acid
Results and discussion
The process of preparation of thermo and pH responsive polymer grafted MNPs is illustrated in Scheme 1. The preparation process is similar to the method reported by us [34]. In brief, at first, the MNPs were prepared by co-precipitation method followed by grafting of APTES in order to functionalize the surface by NH2 group. Then, P(NIPA-r-PEGMEA)-b-PAA copolymers were successfully grafted with these aminated MNPs via EDC/NHS coupling.
Conclusions
We have synthesized novel pH and temperature dual responsive block copolymer-grafted biocompatible magnetic nanoparticles. The cloud points of the polymers used for conjugating with the nanoparticles could be adjusted from 32 °C to 43 °C by changing the monomer ratio in the block copolymers. HRTEM showed that particles were in nano-size range having a mean diameter of 23–27 nm with a polymer shell of thickness of 3.5–4.0 nm, which is potentially useful for drug delivery applications. The
Acknowledgements
Financial support from SRIC, Indian Institute of Technology Kharagpur (project codes ADA and NPA with institute approval numbers – IIT/SRIC/CHY/ADA/2014-15/18 and IIT/SRIC/CHY/NPA/2014-15/81 respectively) is acknowledged. S. Dutta and C. Maiti acknowledge CSIR and UGC, New Delhi, respectively for Senior Research Fellowships.
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