Multi-responsive Nanogels Research Articles

Multi-responsive nanogels with tunable orthogonal reversible covalent (TORC) core-crosslinks for AND-gate controlled release

Installation of TORC core-crosslinks in polymer nanogels is accomplished in a single pot using photo-controlled atom transfer radical polymerization-induced self-assembly (PhotoATR-PISA) resulting in nanogels with AND-gate cargo release behavior.

Recent Advances in the Biomedical Applications of Functionalized Nanogels.

Nanomaterials have been extensively used in several applications in the past few decades related to biomedicine and healthcare. Among them, nanogels (NGs) have emerged as an important nanoplatform with the properties of both hydrogels and nanoparticles for the controlled/sustained delivery of chemo drugs, nucleic acids, or other bioactive molecules for therapeutic or diagnostic purposes. In the recent past, significant research efforts have been invested in synthesizing NGs through various synthetic methodologies such as free radical polymerization, reversible addition-fragmentation chain-transfer method (RAFT) and atom transfer radical polymerization (ATRP), as well as emulsion techniques. With further polymeric functionalizations using activated esters, thiol-ene/yne processes, imines/oximes formation, cycloadditions, nucleophilic addition reactions of isocyanates, ring-opening, and multicomponent reactions were used to obtain functionalized NGs for targeted delivery of drug and other compounds. NGs are particularly intriguing for use in the areas of diagnosis, analytics, and biomedicine due to their nanodimensionality, material characteristics, physiological stability, tunable multi-functionality, and biocompatibility. Numerous NGs with a wide range of functionalities and various external/internal stimuli-responsive modalities have been possible with novel synthetic reliable methodologies. Such continuous development of innovative, intelligent materials with novel characteristics is crucial for nanomedicine for next-generation biomedical applications. This paper reviews the synthesis and various functionalization strategies of NGs with a focus on the recent advances in different biomedical applications of these surface modified/functionalized single-/dual-/multi-responsive NGs, with various active targeting moieties, in the fields of cancer theranostics, immunotherapy, antimicrobial/antiviral, antigen presentation for the vaccine, sensing, wound healing, thrombolysis, tissue engineering, and regenerative medicine.

Novel multi-responsive and sugarcane bagasse cellulose-based nanogels for controllable release of doxorubicin hydrochloride.

Nanogel based on polysaccharides has attracted the tremendous interest due to its unique performance as drug carrier for in vivo release. In this work, the multi-responsive nanogels were developed based on the tailor-modified sugarcane bagasse cellulose (SBC). In the presence of crosslinking agent cystamine bisacrylamide (CBA), the in-situ free radical copolymerization of methacrylated monocarboxylic sugarcane bagasse cellulose (MAMC-SBC) and N-isopropylacrylamide (NIPAM) in aqueous phase was conducted, thus leading to redox, pH and thermal-responsive nanogels. The results obtained from FT-IR, SEM and particle sizer showed that the nanogels were highly stable with the desired particle size ranging from 90 to 180nm and contained targeted polymeric segments and linkage for multi-responsivity. Doxorubicin hydrochloride (DOX) as a model drug was effectively loaded into the nanogels, partly driven by strong electrostatic association; and the loading efficiency reached up to 82.7%. Moreover, the drug release could be readily manipulated by the addition of reducing agent, pH and temperature, which is attributed to the multi-responsive behavior of nanogels as carrier and synergetic effects. The performance of nanogels was also governed by the ratio of reactive MAMC-SBC and NIPAM during polymerization; and the ratio at 1:1(wt) led to the optimal structure of nanogels.

Synthetic networks with tunable responsiveness, biodegradation, and molecular recognition for precision medicine applications.

Formulations and devices for precision medicine applications must be tunable and multiresponsive to treat heterogeneous patient populations in a calibrated and individual manner. We engineered modular poly(acrylamide-co-methacrylic acid) copolymers, cross-linked into multiresponsive nanogels with either a nondegradable or degradable disulfide cross-linker, that were customized via orthogonal chemistries to target biomarkers of an individual patient's disease or deliver multiple therapeutic modalities. Upon modification with functional small molecules, peptides, or proteins, these nanomaterials delivered methylene blue with environmental responsiveness, transduced visible light for photothermal therapy, acted as a functional enzyme, or promoted uptake by cells. In addition to quantifying the nanogels' composition, physicochemical characteristics, and cytotoxicity, we used a QCM-D method for characterizing nanomaterial degradation and a high-throughput assay for cellular uptake. In conclusion, we generated a tunable nanogel composition for precision medicine applications and new quantitative protocols for assessing the bioactivity of similar platforms.

Preparation of multiresponsive nanogels and their controlled release properties

Multiresponsive nanogels, which are sensitive to pH/temperature/glucose concentration have been synthesized by using N,N-diethylacrylamide (DEA) and 4-vinylphenylboronic acid (VPBA) as reaction monomer. The influence of the VPBA/DEA feeding ratio and emulsifier concentration on the as-prepared nanogel’s size and size distribution was investigated. Under the optimized condition, the diameter of the as-prepared P(DEA-co-VPBA) nanogel was 186.9 nm with excellent monodispersity (PDI 0.005); its entrapment efficiency reached 88.67% and loading efficiency of insulin reached 17.73%. The release rate of insulin loaded in the P(DEA-co-VPBA) nanogels could be adjusted by glucose concentration, which could adjust and control the blood glucose concentration in a stable concentration range intelligently. The multiresponsive nanogels could potentially be used in the fields of self-regulated drug delivery systems, real-time optical diagnosis, and monitoring of the response to treatment.

Switchable conformational changes of DNA nanogel shells containing disulfide-DNA hybrids for controlled drug release and efficient anticancer action.

Oligonucleotide strands containing dithiol (–SS–) groups were used as the co-crosslinkers in PNIPA–AAc based nanogels (NGs). They hybridized with PEG–oligonucleotides introduced into the gels. The specific DNA hybrid formed in the nanogel/nanocarrier was involved in highly efficient accumulation of intercalators. The presence of –SS– groups/bridges improved the storing efficiency of doxorubicin (Dox) in DNA hybrids by 53, 40 and 20% compared to regular, single stranded and regular double stranded DNA crosslinkers, respectively. The explicit arrangement of the hybrids in the carrier enabled their reduction by glutathione and an effective cancer treatment while the side toxicity could be reduced. Compared to the NGs with traditional crosslinkers and those containing typical dsDNA-based hybrids, an improved, switchable and controlled drug release occurred in the novel NGs. Since the novel NGs can release the oligonucleotide strands during their degradation, this gives an opportunity for a combined drug-gene therapy.

Photothermally Enhanced Chemotherapy Delivered by Graphene Oxide-Based Multiresponsive Nanogels.

To develop multifunctional anticancer nanomedicines, photothermal nanogels with multistimulative properties are fabricated by hybridizing graphene oxide (GO) with poly(N-isopropylacrylamide, PNIPAM) matrix. This technique allows for easy monomer-intercalation between GO sheets, followed by in situ polymerization to promote GO exfoliation as nanoplatelets inside emulsified PNIPAM nanodrops, followed by fixation using a disulfide-containing cross-linker. The resulting nanogels own significantly improved colloidal stability and biocompatibility as compared to native GO. They can effectively encapsulate an anticancer drug and accelerate its release under conditions mimicking acidic/reducible solid tumor and intracellular microenvironments. Drug delivery can be further enhanced via remote photothermal treatment. The local photothermal effect and drug release smartness make the nanogels as an ideal nanoplatform for synergistic anticancer therapy upon their arrival at tumor tissue or inside cancer cells.

Multiresponsive Nanogels for Targeted Anticancer Drug Delivery.

Nanogels with a biomolecular coating (biocoating) were shown to be capable of triggered delivery of anticancer drug Doxorubicin. The biocoating was formed utilizing binding between glycogen and the tetra-functional lectin Concanavalin A, which can be triggered to disassemble (and release) upon exposure to glucose and changes in solution pH. We also show the nanogel's thermoresponsivity can be used to accelerate Doxorubicin release. Moreover, we showed that transferrin immobilized on the nanogel surface could accelerate nanogel uptake by cancer cells. In these experiments, we showed that Doxorubicin was able to be released to the nucleus of human liver cancer cell line (HepG2) within 3 h. Doxorubicin-loaded nanogels exhibit a strong growth inhibition ability toward HepG2. This investigation showcases how nanogel design and chemistry can be tuned to achieve useful biomedical applications.

Photo, pH and redox multi-responsive nanogels for drug delivery and fluorescence cell imaging

A light, pH and redox triple-responsive spiropyran-based nanogel is prepared and applied for the efficient delivery of anticancer drugs and fluorescence cell imaging for the strong emission of merocyanine photoisomers.

Multifunctional nanogels with dual temperature and pH responsiveness

Over the last 10 years, the development of intelligent biomaterials for medical and pharmaceutical applications has attracted growing interest by combining interdisciplinary efforts. Between them nanogels represent one of the most attractive carriers for innovative drug delivery systems. In the present investigation new variants of multi-responsive nanogels have been synthesized by crosslinking poly(itaconic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5] undecane) copolymer (having different molar ratios between comonomers) with 1,12-dodecandiol. The new structures were obtained by using modification of itaconic anhydride moieties in the copolymer. This is a convenient method for the preparation of a network with increased functionality, which further may ensure new strategies for coupling various bioactive compounds, especially owing to the behavior of the used copolymers, which present dual pH and temperature sensitive characteristics. The chemical structure of the new compounds was confirmed by FTIR and 1H RMN spectra. Also, the evaluation of thermal stability by thermogravimetric analysis sustains the covalent bonds occurring between the copolymer and diol. The dual responsiveness of the nanogel structures to temperature and pH was put into evidence by DLS studies. This feature can be used for the development of drug delivery systems, which can mimic biological response behavior to a certain extent. The new synthesized nanogels were tested as drug delivery systems by using diclofenac as a model drug. The results obtained from in vitro and in vivo investigation confirm the bioactivity of the nanogel networks.

Galactose-functionalized multi-responsive nanogels for hepatoma-targeted drug delivery.

We report here a hepatoma-targeting multi-responsive biodegradable crosslinked nanogel, poly(6-O-vinyladipoyl-D-galactose-ss-N-vinylcaprolactam-ss-methacrylic acid) P(ODGal-VCL-MAA), using a combination of enzymatic transesterification and emulsion copolymerization for intracellular drug delivery. The nanogel exhibited redox, pH and temperature-responsive properties, which can be adjusted by varying the monomer feeding ratio. Furthermore, the volume phase transition temperature (VPTT) of the nanogels was close to body temperature and can result in rapid thermal gelation at 37 °C. Scanning electron microscopy also revealed that the P(ODGal-VCL-MAA) nanogel showed uniform spherical monodispersion. With pyrene as a probe, the fluorescence excitation spectra demonstrated nanogel degradation in response to glutathione (GSH). X-ray diffraction (XRD) showed an amorphous property of DOX within the nanogel, which was used in this study as a model anti-cancer drug. Drug-releasing characteristics of the nanogel were examined in vitro. The results showed multi-responsiveness of DOX release by the variation of environmental pH values, temperature or the availability of GSH, a biological reductase. An in vitro cytotoxicity assay showed a higher anti-tumor activity of the galactose-functionalized DOX-loaded nanogels against human hepatoma HepG2 cells, which was, at least in part, due to specific binding between the galactose segments and the asialoglycoprotein receptors (ASGP-Rs) in hepatic cells. Confocal laser scanning microscopy (CLSM) and flow cytometric profiles further confirmed elevated cellular uptake of DOX by the galactose-functionalised nanogels. Thus, we report here a multi-responsive P(ODGal-VCL-MAA) nanogel with a hepatoma-specific targeting ability for anti-cancer drug delivery.

One-pot synthesis of doxorubicin-loaded multiresponsive nanogels based on hyperbranched polyglycerol.

Doxorubicin-loaded nanogels with multiresponsive properties are prepared using hyperbranched polyglycerol as a biocompatible scaffold. The nanogels are synthesized in a single step combining free-radical polymerization and a mild nanoprecipitation technique. The nanogels respond to different biological stimuli such as low pH and reductive environments, resulting in a more efficient cell proliferation inhibition in A549 cells.

A New Multiresponsive Drug Delivery System using Smart Nanogels

This paper addresses the synthesis and characterization of a novel temperature- and pH-responsive nanogel system based on poly(vinylcaprolactam-co-2-dimethylaminoethyl methacrylate) [P(VCL-co-DMAEMA)] by using a surfactant-free emulsion polymerization procedure for the multiresponsive drug delivery of hydrophobic drugs. The effects of solvent, monomer, pH, and temperature were studied to tailor the average particle hydrodynamic diameters and the polydispersity index of the final particles. According to dynamic light-scattering measurements, the obtained nanogels show a narrow particle-size distribution and their hydrodynamic diameters can be varied from 81 to 368 nm. The nanogels display a re-entrant phase-transition state, and the equilibrium volume swelling ratio of the nanogels decreases drastically down to 47 °C and then increases up to 65 °C. In addition, the nanogels show pH-dependent behavior. They exhibit a maximum size at pH 5.0. Rhodamine B (RhB) was chosen as a model compound for drug loading and release studies from P(VCL-co-DMAEMA) on the basis of particles in different phosphate buffer solutions at different temperatures. The temperature/pH-dependent cumulative release and ultrasound-enhanced pulsatile release properties were investigated for RhB-loaded nanogels for long-term and one-shot delivery. The nanogels display efficient delivery for both long-term and one-shot delivery systems. We provide here a proof of concept for the novel use of multiresponsive nanogels having an overall size below 200 nm as a cargo system for hydrophobic drugs and for controlled release mediated by temperature/pH and ultrasound.

Facile aqueous-phase synthesis of multi-responsive nanogels based on polyetheramines and bisepoxide.

A new strategy for the preparation of nanogels from commercially available monomers of bisepoxide and aliphatic polyetheramine has been developed. The nanogels are generated in a one-pot process through aggregation polymerization of an in situ formed thermal sensitive intermediate polymer in an additive-free and catalyst-free aqueous environment. Such a facile process allows easy size tuning of the gel particles from the nanometer to the micron scale, simply by adjusting the reactant concentration. The obtained nanogels demonstrated responsiveness to multiple biologically relevant stimuli, including temperature, pH, and oxidation. Nile red was encapsulated in the nanogels as a model hydrophobic drug. In vitro drug release studies showed stimuli-triggered release from the nanogels, suggesting the potential for controlled drug delivery.

Multi-responsive nanogels containing motifs of ortho ester, oligo(ethylene glycol) and disulfide linkage as carriers of hydrophobic anti-cancer drugs

A family of multi-responsive nanogels with different compositions and crosslinking degrees have been prepared by the miniemulsion copolymerization of monomethyl oligo(ethylene glycol) acrylate (OEGA) and an ortho ester-containing acrylic monomer, 2-(5,5-dimethyl-1,3-dioxan-2-yloxy) ethyl acrylate (DMDEA), with bis(2-acryloyloxyethyl) disulfide (BADS) as a crosslinker. These nanogels are thermoresponsive and labile in the weakly acidic or reductive environments. The thermoresponsive behaviors, acid-triggered hydrolysis, and reduction-induced degradation of these nanogels were studied by means of dynamic light scattering (DLS), transmission electron microscopy (TEM) and atomic force microscopy (AFM). The results indicate that the volume phase transition temperature (VPTT), thermally induced deswelling ratio, and acid-triggered swelling ratio of the nanogels are closely relevant to their compositions and crosslinking degrees. Although these nanogels could be reductively disrupted by dithiothreitol (DTT), single polymer chains with sizes smaller than 20 nm were not detected by DLS. This is probably due to the existence of some unbreakable linkages formed by chain transfer to the disulfide bond during the radical polymerization. These nanogels are capable of encapsulating hydrophobic compounds. The loading capability of the nanogels for Nile Red (NR), paclitaxel (PTX), and doxorubicin (DOX), and the release behaviors of the drug-loaded nanogels were investigated by UV–vis spectrometry and HPLC. As expected, drug release can be greatly accelerated by a cooperative effect of both acid-triggered hydrolysis and DTT-induced degradation. Finally, the PTX-loaded nanogels exhibit a concentration-dependent toxicity to MCF-7 cells while the intact unloaded nanogels are non-toxic, thereby they may be used as potential carriers for hydrophobic anticancer drugs.

Stimulus responsive nanogels for drug delivery

Stimulus responsive nanogels are polymeric nanoparticles which are capable of responding to external stimuli by changing their physico-chemical properties, such as volume, water content, refractive index, permeability, and hydrophilicity–hydrophobicity. Compared with other polymer nanoparticles used for drug delivery, stimulus responsive nanogels are noted for their ability to encapsulate bioactive drugs, their high stability for prolonged circulation in the blood stream, and their controlled release and site-specific targeting of loaded drugs modulated by environment stimuli. Particularly, the application of stimulus responsive nanogels provides an interesting opportunity for drug delivery in which the delivery system becomes an active participant, rather than a passive carrier, in the optimization of disease therapy. In this article, the authors review the recent developments in the preparation and application in drug delivery of stimulus responsive nanogels which can respond to small temperature and pH changes, light, magnetic field, biomolecule recognition (specifically glucose responsive nanogels for insulin delivery), and multi-responsive nanogels. The limitations and future improvements of stimulus responsive nanogels are also discussed.