The Construction and Application of Various Stimuli-responsive Hybrid Nanogel Systems

In order to reduce substantially side effects and achieve enhanced therapy effects, the loaded agents had better be delivered to their targeted sites and then released at their final destination. To achieve this, stimuli-triggered hybrid nanogels have been extensively utilized as smart drug delivery systems for prolonged drug release and targeted site release by taking advantage of physiological cues such as reducing conditions, lower pH, and over-expression of various enzymes as well as some external environment changes such as heat, light and magnetic fields [55,56] (Fig. 9.4]. Similarly, diverse stimuli- responsive hybrid nanogels have also been developed according to these principles (see Table 9.1].

Schematic illustration of hybrid nanogels that can respond to a range of stimuli characteristic of tumor tissues

Figure 9.4 Schematic illustration of hybrid nanogels that can respond to a range of stimuli characteristic of tumor tissues, intracellular microenvironments and external stimuli, promoting targeted delivery and controlled release of therapeutic drugs and imaging agents. Reference from [55].











Drug delivery carrier




Polypeptide adduct(GCPVs)

Polymeric vesicle

Drug delivery carrier






Drug delivery carrier






Drug delivery carrier

Ibuprofen (IB)





Gene delivery carrier






Drug delivery carrier and imaging contrast agent





Au NPs

Drug delivery carrier and PTT



Light and temperature

PS and PEG

Ag-Au NPs

Drug delivery carrier and PTT



Light and temperature


Graphene oxide (CRGO)

Drug delivery carrier and PTT



pH and magnetic




Drug delivery carrier, PTT and MRI contrast agent






Drug delivery carrier and MRI contrast agent



pH, GSH and light

Hyaluronic acid


Drug delivery carrier and PTT



Ph-Responsive Hybrid Nanogel Systems

Different from weakly alkaline normal tissues, tumor tissues and intracellular organelles, including endosomes and lysosomes, are slightly acidic. Thus, pH-sensitive hybrid nanogels have been considered as promising drug carriers for the target administration. Maria-Teodora Popescu and co-workers developed a novel liposome/ hydrogel nanocomposite [57]. In this case, a pH-responsive triblock terpolymer poly (2-vinyl pyridine)-b-poly (acrylic acid)-b-poly (n-butylmethacrylate) (PVP2s-PAA576-PnBMA36) was selected as the injectable gel and calcein-loadedPC/Chol liposomes were physically encapsulated into gel matrix. The resulting data demonstrated that liposome/hydrogel nanocomposite could not only overcome the major limitation of liposomes to preserve the original vesicle structure but also further realize the pH-responsive controlled release based on the characteristic of the nanogel coating.

Wen-Hsuan Chiang designed a dual layered hybrid nanogel consisting of pH-sensitive nanogels and doxorubicin (DOX)-loaded polymeric vesicle [58]. The first layer was constructed by chitosan on the outer surfaces of the drug-loaded vesicles. The second layer was formed via the cooperative electrostatic interaction between chitosan and poly(c-GA-co-c-GAOSu)-g-mPEG. The particle size of drug-loaded nanocomposites was significantly amplified compared to that of polymeric vesicles. In vitro release results manifested that the dual layered nanogel composites exhibited a smart pH-sensitive coupled with a relative prolonged release performance comparing to the polymeric vesicles.

Apart from these mentioned polymer-nanogel composites, inorganic nanoparticle-nanogel hybrid systems with the pH- responsive characteristics have been developed. The combined system composed of hydroxyapatite (HAP) nanoparticles and chitosan/polyacrylic acid (CSPAA) nanogel was built by the study group of Jinli Qin [59]. For this system, the charged groups including numerous carboxyl and amino groups on the surface of nanogel acted as nucleation sites and regulated the formation of HAP crystals. Bovine serum albumin (BSA) was selected as the model drug to investigate the release behavior. The release profile of BSA showed a clearly pH-dependent feature which could be attributed to the electrostatic interaction between BSA and HAP. Pengkun Zhao and co-workers reported a complex system based on drug-loaded mesoporous silica nanoparticles embedded into a chitosan hydrogel which could regulate the release rate according to the pH-sensitive nature [60]. Interestingly, through depositing the composites on a titanium plate, they simultaneously adjusted the controlled drug release by electrical potentials with the advantages of simplicity, accurate dosage control. Furthermore, the hybrid nano-system formed by nanostructured inorganic silica core and an organic pH-triggered nanogel shell has also been explored further by Sm Z. Khaled and co-workers [61] to deliver small interfering RNA (siRNA).

Temperature-Responsive Hybrid Nanogel Systems

In addition, in situ thermosensitive nanogels have attracted increasing interest as sustained-release drug carriers for localized cancer treatment.However,itislimitedforthesinglenanogelsystemtoachieve high drug-loading and sustained and stable drug release simultaneously. As a result, the combined applications of various other nanocarriers and nanogels have been exerted to address the challenges. Hongbo Zhu and co-workers prepared thermosensitive Bi203 quantum dot (QD)-PVA nanogel hybrid nanocomposite (Bi203@PVA hybrid nanogels]. The Bi203 quantum dots were incorporated into PVA nanogels and then the PVA chains were cross-linked under y-ray irradiation. The reversible temperature- induced volume phase transition of Bi203@PVA hybrid nanogels was functioned by the cooperation of the immobilized QDs with PVA nanogel networks chain which was different from the conventional thermosensitive hybrid nanogels based on the temperature response polymers. The research testified that Bi203@PVA hybrid nanogels could exhibit a high-resolution fluorescent signal in response to the change in environmental temperature over the physiological range of 37-40°C. Bi203@PVA hybrid nanogels were further developed as drug carriers for the temperature regulated controlled release of anticancer drug temozolomide (TMZ) for chemotherapy, which provided the potential in theranostic action of simultaneous cancer diagnostics, therapy, and monitoring [62]. Similarly, a doxorubicin- loaded hybrid system (Au-DOX-Gel) consisting of Pluronic® F127- based thermosensitive nanogels and Au NPs was designed to realize the chemoradiotherapy through the chemotherapeutics of DOX and radiation of Au NPs, which effectively inhibited the tumor growth compared to the controls [63].

Light-Responsive Hybrid Nanogel Systems

In the past few years, various near-infrared (NIR) light-sensitive nanoparticles have been explored to control the precise release of drugs in the specific site systemically. As water and blood cells hardly absorb NIR, NIR can penetrate the tissues to reach the deep position where optically sensitive nanoparticles are located to release drugs avoiding damage atnontargeted regions. Meanwhile, the penetrating NIR radiation can be transduced into local heat by the nanoparticles, which can be envisaged for photothermal therapy (PTT). Hence, these heat-transducing nanoparticles might be used to construct the drug delivery systems through combination these nanoparticles with other thermoresponsive carriers, especially nanogels. These hybrid nanogels can control drug release through the transducing of heat to thermoresponsive drug-loaded nanogel by heat-transducing nanoparticles. In addition, thermosensitive hybrid nanogels are the most popular candidates to construct the hybrid drug delivery systems for PTT. A core-shell hybrid nanogel composite formed by coating the Ag/Au nanoparticle core with a thermosensitive hydrophobic-hydrophilic double-layer gel shell has been designed for thermo-photothermal-regulated drug delivery [63]. The inner hydrophobic polystyrene (PS) gel layer can provide high loading capability for hydrophobic curcumin, while the thermosensitive outer PEG-based gel layer formed by 2-(2-methoxyethoxy)ethyl meth-acrylate and oligo (ethylene glycol)methyl ether methacrylate with a cross-linker polyethylene glycol) dimethacrylate can trigger the drug release either by the change of temperature of the local microenvironments(endogenous activation) or the heat generated by NIR irradiation (exogenous activation). Furthermore, the NIR-accelerated release property of the curcumin-loaded hybrid nanogels resulted in the enhancement in the therapeutic efficacies.

The resulting data revealed that the combined chemo-photothermal therapy exhibited higher therapeutic efficacy compared to the chemo- and photothermal treatment alone [64].

Apart from Au or Ag nanomaterials, more convenient particles like graphene and fluorescent carbon nanoparticles (FCNPs) with excellent photothermal conversion ability under NIR radiation have been also studied in photothermal therapy for cancer. A hybrid nanogel involving graphene was fabricated by Chunyan Wang [65]. Chitosan-modified reduced graphene oxide (CRGO) served as the photothermal stimulus in the inner core and the thermoresponsive poly (N-isopropylacrylamide) (PNIPAM) served as coating. PNIPAM as coating can not only modify the physicochemical properties of the embedded particles in response to the variation of the environmental temperature but also regulate the releasing rate of the loaded drugs. In this case, the drug carrier could not only realize the stimulus- responsive release at the site but also achieve a high drug loading of model drugDOX [65].

Magnetic-Responsive Hybrid Nanogels Systems

For the past years, magnetic nanoparticles (MNPs] have attracted great attention for the use in several biomedical applications, such as drug delivery, magnetic separation and MRI contrast agents for diagnostics. However, the agglomeration behavior of MNPs, which is caused by the large surface area to volume ratio, limits their application greatly. Therefore, the surface modification is extremely crucial to guarantee the stability of MNPs. The most commonly used method is to coat various biocompatible polymers onto the surface. Among them, nanogels have become the most popular candidates because of biocompatibility, nontoxicity, and strong stability. The resultant MNP hybrid nanogels are endowed with the ability of controlled releasing carried therapeutic agents at the targeted sites under an external magnetic field. The functionalized hybrid nanogel based on MNPs was reported that this system greatly accelerated the doxorubicin (DOX) release in vitro by the combined regulating pH and high frequency magnetic fields (HFMF), thereby exhibiting enhanced cell cytotoxicity than the treatment by free DOX alone [22]. Interestingly, the application of the super paramagnetic SPION/DOX- loaded NPs as a MRI contrast agent for cancer diagnosis was also evaluated in this study. The result demonstrated that the SPION/ DOX-loaded NPs maintained the enhanced MRI sensitivity whether in aqueous solution or in intracellular environment. Hence, nanogelcoating MNPs hybrid systems provided potential for high effective therapy and diagnosis in medicine application.

Other Stimuli-Responsive Hybrid Nanogel Systems

In addition to the aforementioned responsive hybrid nanogel systems, a number of attempts have been made to develop other stimuli- responsive hybrid nanogel systems like metalloproteinase (MMP)- sensitive and glutathione (GSH)-triggered redox-sensitive hybrid nanogels. Caner Nazli provided potential for simultaneous imaging of tumor-targeted drug delivery and triggered drug release into the tumor site [67]. In this fabricated hybrid nanogel, magnetic iron oxide nanoparticles (MIONP) with entrapping chemotherapeutic drug served as a contrast agent in MRI, and located in the inner core, while metalloproteinase (MMP)-sensitive PEG hydrogel conjugated to the surface of MIONPs. Results revealed that the amount of doxorubicin (DOX) release from the nanogels was higher in the presence of collagenase type 1 enzyme than that in absence of enzyme [67]. A novel hybrid nanogel combination of pH, glutathione, and light stimuli was designed to achieve synergetic effect of targeting to the tumor site [66]. DOX was conjugated to the light-responsive graphene through pH-sensitive ester linkages. Then the graphene-DOX conjugates were coated with disulfide-cross- linked hyaluronic acid that might create a glutathione-responsive release. Results verified that multiple factors such as the presence of glutathione, an acidic extracellular pH and light irradiation could accelerate the accumulation of DOX at the tumor sites. Furthermore, photothermal-chemotherapy of the hybrid nanogel was investigated both in vitro and in vivo and confirmed the generation of adequate heat to obtain a photo-ablation effect sufficient to kill cancer cells [66].

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