Superparamagnetic Hollow Hybrid Nanogels as a Potential Guidable Vehicle System of Stimuli-Mediated MR Imaging and Multiple Cancer Therapeutics

Abstract

Hollow hybrid nanogels were prepared first by the coassembly of the citric acid-coated superparamagnetic iron oxide nanoparticles (SPIONs, 44 wt %) with the graft copolymer (56 wt %) comprising acrylic acid and 2-methacryloylethyl acrylate units as the backbone and poly(ethylene glycol) and poly(N-isopropylacrylamide) as the grafts in the aqueous phase of pH 3.0 in the hybrid vesicle structure, followed by in situ covalent stabilization via the photoinitiated polymerization of MEA residues within vesicles. The resultant hollow nanogels, though slightly swollen, satisfactorily retain their structural integrity while the medium pH is adjusted to 7.4. Confining SPION clusters to such a high level (44 wt %) within the pH-responsive thin gel layer remarkably enhances the transverse relaxivity (r2) and renders the MR imaging highly pH-tunable. For example, with the pH being adjusted from 4.0 to 7.4, the r2 value can be dramatically increased from 138.5 to 265.5 mM(-1) s(-1). The DOX-loaded hybrid nanogels also exhibit accelerated drug release in response to both pH reduction and temperature increase as a result of the substantial disruption of the interactions between drug molecules and copolymer components. With magnetic transport guidance toward the target and subsequent exposure to an alternating magnetic field, this DOX-loaded nanogel system possessing combined capabilities of hyperthermia and stimuli-triggered drug release showed superior in vitro cytotoxicity against HeLa cells as compared to the case with only free drug or hyperthermia alone. This work demonstrates that the hollow inorganic/organic hybrid nanogels hold great potential to serve as a multimodal theranostic vehicle functionalized with such desirable features as the guidable delivery of stimuli-mediated diagnostic imaging and hyperthermia/chemotherapies.

Redox/pH stimuli-responsive biodegradable PEGylated P(MAA/BACy) nanohydrogels for controlled releasing of anticancer drugs

“…1a-d) A c c e p t e d M a n u s c r i p t 12 spherical morphology with uniform in size was also confirmed as shown by TEM images in Fig. 1.…”

“…For instance, cancer cells usually thrive in acid environments, and have reducing propensity as a result of their elevated intracellular glutathione (GSH) level [9]. Moreover, exploiting lower pH values of tumor cells, pH-sensitive carriers containing reversibly ionizable groups, such as carboxylic or amino groups, have been reported [10][11][12][13]. As for the higher GSH levels, many investigations have been published which utilize disulfide-functionalized linkages in the drug delivery systems that can be broken by GSH, thus endowing the drug carriers with biodegradability [14][15][16][17].…”

Biodegradation and Toxicity of Protease/Redox/pH Stimuli-Responsive PEGlated PMAA Nanohydrogels for Targeting Drug delivery

“…[24][25][26][27][28] Nanohydrogels with carboxyl groups can change their ionic states according to intracorporal pH, thus can control the releasing of the electrostatic binding drugs. [29][30][31] Generally, the kidney can excrete compounds smaller than 50 kDa, so a biocompatible polymer that can biodegrade to small oligomers is very important for the metabolism in human body. [32][33][34] The disulfide-cross-linked nanohydrogels can be rapidly dissociated by the glutathione (GSH) in tumor cells and promote the release of non-covalent encapsulated drugs.…”

Classification of stimuli–responsive polymers as anticancer drug delivery systems

“…By magnetic transport guidance toward the target and subsequent exposure to an alternating magnetic field, their Dox-loaded nanogel system demonstrated capabilities of hyperthermia and Figure 3. Formation of ultrasound and pH dually responsive PEO43-b-P(DEA33-stat-TMA47) vesicle and controlled drug release triggered by ultrasound radiation or decreasing pH value (Chen & Du, 2013). magnetic-triggered drug release in a cancer cell model in vitro (Chiang et al, 2013).…”