pH-sensitive Nanogels Research Articles

Synthesis, characterization and stability of crosslinked chitosan-maltodextrin pH-sensitive nanogels

Polysaccharide-based nanogels offer a wide range of chemical compositions and are of great interest due to their biodegradability, biocompatibility, non-toxicity, and their ability to display pH, temperature, or enzymatic response. In this work, we synthesized monodisperse and tunable pH-sensitive nanogels by crosslinking, through reductive amination, chitosan and partially oxidized maltodextrins, by keeping the concentration of chitosan close to its overlap concentration, i.e. in the dilute and semi-dilute regime. The chitosan/maltodextrin nanogels presented sizes ranging from 63 ± 9 to 279 ± 16 nm, showed quasi-spherical and cauliflower-like morphology, reached a ζ-potential of +36 ± 2 mV and maintained a colloidal stability for up to 7 weeks. It was found that the size and surface charge of nanogels depended both on the oxidation degree of maltodextrins and chitosan concentration, as well as on its degree of acetylation and protonation, the latter tuned by pH. The pH-responsiveness of the nanogels was evidenced by an increased size, owed to swelling, and ζ-potential when pH was lowered. Finally, maltodextrin-chitosan biocompatible nanogels were assessed by cell viability assay performed using the HEK293T cell line.

Agar Graft Modification with Acrylic and Methacrylic Acid for the Preparation of pH-Sensitive Nanogels for 5-Fluorouracil Delivery.

Agar, a naturally occurring polysaccharide, has been modified by grafting it with acrylic (AcA) and methacrylic (McA) acid monomers, resulting in acrylic or methacrylic acid grafted polymer (AA-g-AcA or AA-g-McA) with pH-sensitive swelling behavior. Different ratios between agar, monomers, and initiator were applied. The synthesized grades of both new polymer series were characterized using FTIR spectroscopy, NMR, TGA, DSC, and XRD to ascertain the intended grafting. The percentage of grafting (% G), grafting efficiency (% GE), and % conversion (% C) were calculated, and models with optimal characteristics were further characterized. The swelling behavior of the newly synthesized polymers was studied over time and in solutions with different pH. These polymers were subsequently crosslinked with varying amounts of glutaraldehyde to obtain 5-fluorouracil-loaded nanogels. The optimal ratios of polymer, drug, and crosslinker resulted in nearly 80% loading efficiency. The performed physicochemical characterization (TEM and DLS) showed spherical nanogels with nanometer sizes (105.7-250 nm), negative zeta potentials, and narrow size distributions. According to FTIR analysis, 5-fluorouracil was physically incorporated. The swelling and release behavior of the prepared nanogels was pH-sensitive, favoring the delivery of the chemotherapeutic to tumor cells. The biocompatibility of the proposed nanocarrier was proven using an in vitro hemolysis assay.

Preparation of pH-sensitive nanogels bioconjugated with shark antibodies (VNAR) for targeted drug delivery with potential applications in colon cancer therapies.

Cancer is the second leading cause of death worldwide. To combat this disease, novel and specialized therapeutic systems are urgently needed. This is the first study to explore a system that combines shark variable domain (Fv) of new antigen receptor (VNAR) antibodies (hereinafter VNARs), PEGylated nanogels (pH-sensitive poly(N,N-diethylaminoethyl methacrylate, PDEAEM), and the anticancer drug 5-fluorouracil (5-FU) to explore its potential applications in colon cancer therapies. Nanogels were functionalized in a scalable reaction with an N-hydroxysuccinimide (NHS)-terminated polyethylene glycol derivative and bioconjugated with shark antibodies. Dynamic light scattering measurements indicated the presence of monodispersed nanogels (74 to 236 nm). All systems maintained the pH-sensitive capacity to increase in size as pH decreased. This has direct implications for the release kinetics of 5-FU, which was released faster at pH 5 than at pH 7.4. After bioconjugation, the ELISA results indicated VNAR presence and carcinoembryonic antigen (CEA) recognition. In vitro evaluations of HCT-116 colon cancer cells indicated that functionalized empty nanogels are not cytotoxic and when loaded with 5-FU, the cytotoxic effect of the drug is preserved. A 15% reduction in cell viability was observed after two hours of contact with bioconjugated nanogels when compared to what was observed with non-bioconjugated nanogels. The prepared nanogel system shows potential as an effective and site-specific nanocarrier with promising applications in in vivo studies of colon cancer therapies.

Nanogel: Types, Methods of Preparation, Limitation, Evaluation and Application – A Systematic Review

Nanogels combine the characteristics of nanomaterials with hydrogels. To meet the expanding demands from various areas, a sizable number of nanogels have been designed and manufactured using the emulsion solvent diffusion nano precipitated method, emulsion evaporation of the solvent method, reverse micellar method and modified diffusion emulsification method. Thermosensitive nanogel, pH-sensitive nanogel, ultrasound-sensitive magnetic response, response to multiple stimuli, chain transfer polymerization, photo-induced crosslinking polymerization and modifications for active targeting are the types of nanogels based on response towards stimuli and polysaccharide, chitosan, pullulan, hyaluronic acid, alginate, cyclodextrin, gum acacia, protein are used to prepare nanogel. Nanogels have considerable potential and novelty within the biomedical sector due to their uniformity, adjustable dimensions, little toxicity, resilience in the presence of serum, and capacity for responsive behavior with a comparatively high drug encapsulation capacity. Nanogels have considerable potential in bioactive substance delivery, organ targeting, and chemotherapy. The article highlighted the preparation, types, evaluation and applicability of nanogel as a targeted delivery system.

Nanogel-mediated drug delivery system for anticancer agent: pH stimuli responsive poly(ethylene glycol/acrylic acid) nanogel prepared by gamma irradiation

The popularity of nanogel as nano drug carrier lies in its adjustable physical properties, and the ability to encapsulate drug particles with improved properties is being developed to meet the diverse pH-sensitive nanogel for anticancer agent. Monitoring pH has been identified as an important diagnostic element during the treatment process. A pH-sensitive nanogel consisting of (PEG/PMAc) in the ratio of (50:50%) hasbeen cross-linkedby γ-irradiation techniques at an irradiation dose of 5 kGy. Compound 4 and its nanogel 5 were synthesized and assessed for their anticancer effects against HepG2, A549, MCF-7 and HCT-116 as dual VEGFR-2 and EGFR tyrosine kinases inhibitors. The molecular design was performed to investigate the binding mode of compound 4 with VEGFR-2 and EGFR receptors. Our compound 5 in nanogel showed enhanced anticancer activities against the four tested cancer cell lines and also showed higher inhibition activities against VEGFR-2 and EGFRT790M kinases than the derivative 4. Finally, our derivative 4 showed good in silico calculated ADMET profile. It was expected to show good GIT absorption in human, lower CNS side effects, no hepatotoxic actions and higher acute and oral chronic toxic doses in comparing to sorafenib and erlotinib. The obtained results showed that, our compound could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective dual VEGFR-2/EGFRT790M inhibitors with higher anticancer activity.

Correction to: Sulfonate-functionalized polyacrylonitrile-based nanoparticles; synthesis, and conversion to pH-sensitive nanogels

Correction to: Sulfonate-functionalized polyacrylonitrile-based nanoparticles; synthesis, and conversion to pH-sensitive nanogels

PH-Sensitive nanogels for drug delivery in cancer therapy.

As a commonly used treatment method for cancer, chemotherapy is greatly limited by the side effects of chemotherapy drugs and the multiple drug resistance that develops. Nanogels are considered ideal drug carriers due to their high stability, high water content and excellent drug loading capacities. To achieve more precise and intelligent drug delivery in tumor tissues, various environmentally responsive nanogels have been widely developed. Compared to normal tissue, tumor tissue exhibits a lower pH value. Therefore, the pH gradients between the tumor microenvironment and the normal physiological environment can be used to design pH-sensitive nanogels to regulate the delivery and release of antitumor drugs. This article mainly introduces the application of pH-sensitive nanogels in cancer treatment, hoping to provide a reference for the development of cancer treatment.

Preparation of nanogels based on kappa-carrageenan/chitosan and N-doped carbon dots: study of drug delivery behavior

In this study, new pH-sensitive nanogels containing rivastigmine as a model drug were synthesized by graft polymerization of Acrylamid/Sodium Acrylate monomers onto chitosan (CS) and kappa-carrageenan (CG or κ-carrageenan) backbone in the presence of N, N'-Methylenebisacrylamide (MBA) as cross-linker, nitrogen-doped carbon dots (N-CDs) and ammonium persulfate as an initiator. The prepared nanogels were characterized by FE-SEM, XRD, FTIR, EDX and TGA techniques. The swelling behavior of the nanogels was affected by MBA content, monomer content, amount of CG or CS, and pH in the synthesis. The nanogels exhibited well pH-sensitivity during drug release investigation under simulated gastric (< 61% at pH 1.2) and intestinal (~ 95% at pH 7.4) media. The cytotoxicity test was investigated on human fibroblast cells using MTT assay. The results indicated that cell survival rate was more than 88% in < 62.5 μg/mL concentration of nanogels. Incorporating of N-CDs in the nanogel network increased the swelling capacity, entrapment efficiency, and ensuring the controlled release of the entrapped drug. In this work, we were able to enhance the properties of drug-loaded chitosan nanogels in pH 7.4.

Characterization of stimuli-responsive and cross-linked nanohydrogels for applications in ophthalmiatrics therapy

Despite high drug-loading capacity, the ocular surface retention and corneal permeability of conventional nano eye drops are still unsatisfactory, thereby limiting therapeutic efficacy. Therefore, the objective of this study was to formulate dexamethasone loaded temperature-sensitive, pH-sensitive and ion-sensitive nanogels by incorporating stimuli-responsive elements, in order to enhance the ocular surface retention and corneal permeability of the encapsulated drug. The nanogels showed excellent rheological properties, along with good strength and viscosity under physiological conditions. Both in vitro and in vivo studies showed that the nanogels enhanced the ocular surface retention and corneal permeability of drugs. The temperature-sensitive gel showed the optimum behavior. The stimuli-responsive nanogels are stable delivery systems that can release drugs into the posterior ocular segment in a targeted and sustained manner.

Straightforward Access to Glycosylated, Acid Sensitive Nanogels by Host-Guest Interactions with Sugar-Modified Pillar[5]arenes.

The introduction of specific targeting units to polymer nanogels usually requires tedious chemical modifications, which limits flexibility in the design of combinatorial approaches. Here, we present a straightforward and versatile method to reversibly introduce various carbohydrate-based targeting units to a pH-sensitive nanogel via host-guest interactions. Glucose-, mannose-, or fructose-modified pillar[5]arenes can adaptably and conveniently be introduced to the surface of the nanogel. Binding studies between these nanogels and the lectin Concanavalin A revealed a high selectivity and strong interaction with only the mannose-modified nanogels. With the addition of other pillar[5]arenes, the interaction can be influenced proving a dynamic exchange of the targeting units. In comparison with common covalent modifications of polymer nanostructures, the presented combination of straightforward precipitation polymerization and supramolecular interactions promises convenient access to adaptable nanostructures for high-throughput screening of targeted delivery systems.

Tunable nanogels by host-guest interaction with carboxylate pillar[5]arene for controlled encapsulation and release of doxorubicin.

Nanogels have become one of the most attractive systems for application as delivery vectors or for theragnostic approaches in nanomedicine, which is mainly related to the ease of their synthesis by precipitation polymerization. However, only a few suitable monomers have been reported so far and stabilization of the nanogels requires the incorporation of rather defined amounts of in most cases charged co-monomers, such as acrylic acid, which limits the flexibility in their design. Here, we present an alternative approach using a pyridinium based monomer, which not only provides stability due to the positive charge, but also allows the attachment of functional carboxylate-pillar[5]arene by the formation of a host-guest complex. This approach is tested on pH-sensitive nanogels based on the monomer N-[(2,2-dimethyl-1,3-dioxolane)methyl]acrylamide (DMDOMA) featuring an acetal group, which is hydrolysed under acidic conditions. As carboxylates are known to catalyze this hydrolysis, we tested different amounts of carboxylate-pillar[5]arenes to tune the hydrolysis rate of the acetal group and found a direct correlation. Additional encapsulation studies with doxorubicin (DOX) revealed that surface potential and charge density represent additional key factors not only for the loading capacity, but also for the release profile of the nanogels. The option to tune such properties simply by the addition of a co-factor, in this case, the carboxylate-pillar[5]arenes provides a powerful tool to optimize characteristics of functional nanogels for drug delivery or other applications.

PH-sensitive and pluronic-modified pullulan nanogels for greatly improved antitumor in vivo

It remains a crucial challenge to achieve efficient cellular uptake in tumor cells for nanoscale drug delivery systems. This work described that two multi-functional pullulan nanogels were prepared by co-polymerization between methacrylated pullulan (Pullulan-M) and different crosslink agents, an acid-labile ortho ester-modified pluronic (L61-MOE) or non-acid-sensitive methacrylated pluronic (L61-M). The prepared nanogels showed a regular spherical structure with the size about 200 nm measured by dynamic light scattering and transmission electron microscopy (TEM). Doxorubicin as a model drug was successfully encapsulated into nanogels. As expected, Pul-L61-MOE showed pH-dependent DOX release, and 25% of DOX was released at pH 7.4 while 84.48% of DOX was released at pH 5.0. In vitro cellular uptake and MTT results indicated that pH-sensitive nanogels (Pul-L61-MOE) displayed higher cellular internalization and cytotoxicity than acid-insensitive nanogels (Pul-L61-M) and free DOX. Flow cytometry assay suggested these nanogels remarkably increased intracellular reactive oxygen species (ROS) level and induced more cell apoptosis by the function of pluronic. Finally, in vivo antitumor results indicated that the multi-functional nanogels exhibit supreme antitumor efficiency, and the tumor growth inhibition (TGI) was 83.37%. Therefore, the pH-sensitive pullulan nanogels can be potential nano-carriers for drug delivery in tumor treatment.

Sulfonate-functionalized polyacrylonitrile-based nanoparticles; synthesis, and conversion to pH-sensitive nanogels

The present paper reports the synthesis of polyacrylonitrile (PAN)-based nanoparticles through soap-free emulsion polymerization (SFEP). Employing different types of co-solvent, as well as ionic commoners, synthesis of pure PAN nanoparticles was unsuccessful. However, when vinyl acetate,or methyl (meth) acrylate was introduced (conc. > 10 mol%), crystallization of PAN was decreased and consequently stable nanoparticles in the size range of 80–250 nm were achieved. Such a co-polymerization not only produced clean and functionalized nanoparticles but also allowed addition of a cross-linker without sacrificing colloidal stability. As a model, the cross-linked poly(acrylonitrile-co-vinyl acetate) nanoparticles were hydrolyzed in alkaline media, which yielded poly(acrylic acid-co-vinyl alcohol) nanogels. The swelling measurement exhibited that the prepared nanogels have a pH-sensitive behavior.

PH-responsive carbon nanotube-based hybrid nanogels as the smart anticancer drug carrier

Tumour drug delivery using nanocarriers is attracting ample attentions due to their high drug-loading capacity. Regarding specific tumour microenvironment properties as acidic pH, smart nanocarriers with the ability of responding to the microenvironment, can have a profound effect on the level of drug release and subsequent tumour treatment. In this study, by combining the advantages of multiwall carbon nanotube and pH-sensitive nanogels, multifunctional magneto/pH-responsive nano-hybrid system is developed to deliver the doxorubicin as a general cancer chemotherapeutic drug. The chemical and physical properties of the nanocarrier, as well as drug-loading efficiency and drug releasing characteristics were analysed. It was showed functionalized CNT has low pH-responsiveness in acidic environment, whereas chitosan-coated magnetic nanocomposite can result in greater pH-responsiveness and subsequently higher drug release over a week compared to nanocomposite system without chitosan. This behaviour was proved in Live/Dead assay of the U-87 glioblastoma cell lines exposed to DOX release supernatant at different time intervals so that significant effect of DOX supernatant on cancer cell proliferation suppression was showed.

Smart pH-Sensitive Nanogels for Controlled Release in an Acidic Environment.

The encapsulation of therapeutic compounds into nanosized delivery vectors has become an important strategy to improve efficiency and reduce side effects in drug delivery applications. Here, we report the synthesis of pH-sensitive nanogels, which are based on the monomer N-[(2,2-dimethyl-1,3-dioxolane)methyl]acrylamide (DMDOMA) bearing an acid cleavable acetal group. Degradation studies revealed that these nanogels hydrolyze under acidic conditions and degrade completely, depending on the cross-linker, but are stable in physiological environment. The best performing system was further studied regarding its release kinetics using the anticancer drug doxorubicin. In vitro studies revealed a good compatibility of the unloaded nanogel and the capability of the doxorubicin loaded nanogel to mediate cytotoxic effects in a concentration and time-dependent manner with an even higher efficiency than the free drug. Based on the investigated features, the presented nanogels represent a promising and conveniently prepared alternative to existing carrier systems for drug delivery.

PH-controlled doxorubicin delivery from PDEAEMA-based nanogels

In this work, the feasibility of some poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA)-based pH-sensitive nanogels as drug nanocarriers is evaluated. The anticancer drug doxorubicin (DOXO) is successfully encapsulated into the nanogels, achieving high drug loading and encapsulation efficiency. It has been found that the in vitro delivery of DOXO from the nanogels was pH-dependent: DOXO release rate is accelerated by decreasing pH from 7.4 (healthy cells) to 5.2 (pH condition for endo/lysosomial compartments and unhealthy cells) due to the swelling of the nanogel particles. The uptake of DOXO-loaded nanogels into MDA-MB-231 tumoral cells and the progressive release of the drug from the nanogels to the cell nuclei are demonstrated by fluorescence microscopy measurements. These results suggest a great potential of these DOXO-loaded nanogels for antitumor drug delivery.

TPGS-functionalized and ortho ester-crosslinked dextran nanogels for enhanced cytotoxicity on multidrug resistant tumor cells

Herein pH-sensitive nanogels (NG1) and P-glycoprotein-repressive nanogels (NG2) were prepared by copolymerization between an ortho ester crosslinker (OEAM) and tocopheryl polyethylene glycol succinate (TPGS)-free or conjugated dextran. Nanogels with or without TPGS possessed a uniform diameter (∼180 nm) and excellent stability in various physiological environments. Doxorubicin (DOX) was successfully loaded into NG1 and NG2 to give NG1/DOX and NG2/DOX, both of them showed appropriate drug release profiles under mildly acidic conditions (pH 5.0). NG2/DOX possessed higher drug enrichment and lethality than NG1/DOX did on MCF-7/ADR cells. Analysis of corresponding index of efflux activity showed that NG2 could induce depolarization of mitochondrial membrane and interfere with ATP metabolism. NG2/DOX also displayed increased penetration and growth inhibition on MCF-7/ADR multicellular spheroids. These results demonstrated that pH-sensitive TPGS-functionalized nanogels (NG2) as drug carriers had great potential to suppress drug efflux in MCF-7/ADR cells and even overcome MDR on cancer cells.

Hybrid pH-sensitive nanogels surface-functionalized with collagenase for enhanced tumor penetration

Densely extracellular matrix (ECM) is one of the main barriers that hinder the penetration of drug into tumor parenchyma, compromising the therapeutic activity. In this work, alginic acid was copolymerized with an acid-labile monomer to give the acid-degradable nanogels (ALG NG), which was then immobilized with collagenase to obtain the surface-functionalized nanogels (Co@ALG NG). The introduction of collagenase would enhance the diffusion ability of nanogels in tumor parenchyma based on the hydrolytic activity to tumor ECM. The stability of these nanogels in various physiological environment and the pH-triggered degradation and drug release at different pH were then investigated. Monolayer cell and tumor-like spheroids were used to illustrate the penetration and drug delivery. In vivo drug distribution and antitumor efficiency of these nanogels were investigated using H22 tumor-bearing mice. The immobilization of collagenase significantly enhance the nanogels' penetration and diffusion ability in tumor area upon the digestion of tumor ECM, leading to higher drug concentration and superior antitumor effect.

PH-triggered poly(ethylene glycol) nanogels prepared through orthoester linkages as potential drug carriers

ABSTRACTThe new acid-labile poly(ethylene glycol) (PEG) nanogels were prepared by copolymerization of a new crosslinking agent containing orthoester groups (OEAM) and methoxypolyethylene glycol acrylate (MPEGAC). DOX was loaded into PEG nanogels with a loading content of 18.2%, which was highly desirable for targeted cancer therapy without premature drug release in neutral environment. The cellular uptake and cytotoxicity of DOX-loaded PEG nanogels were measured using SH-SY5Y and HepG2 cells. Tumor penetration and antitumor activity were investigated using SH-SY5Y tumor-like spheroids. All results demonstrate that the pH-sensitive PEG nanogels may be used as potential drug carriers for chemotherapy.

PH-Sensitive nanogels based on the electrostatic self-assembly of radionuclide 131I labeled albumin and carboxymethyl cellulose for synergistic combined chemo-radioisotope therapy of cancer.

Development of biocompatible and biodegradable nanocarriers with multiple functionalities has attracted great interest in recent years. In this study, a hybrid hydrogel nanoparticle (nanogel) platform based on the self-assembly of carboxymethyl cellulose (CMC) and bovine serum albumin (BSA) is presented for the first time. It was facile to realize the efficient co-delivery of radionuclide 131I and chemotherapeutic drugs such as camptothecin (CPT) to achieve the combined chemo-radioisotope therapy of cancer. Notably, a nanogel was prepared by a simple and green electrostatic interaction approach, instead of chemical reaction, showing typical spherical shape with average size about 120 nm, high drug loading capacity, robust stability and low hemolysis. Interestingly, such nanogels exhibited pH-dependent drug release profile, leading to significant reduction of damage to normal tissues. Furthermore, the as-prepared nanogels could effectively promote intracellular uptake, prolong blood circulation time and enhance accumulation in the tumor tissues. As a result, an excellent therapeutic effect was achieved both in vitro and in vivo through combined chemo-radioisotope therapy. Collectively, this study presents the preparation of a novel green nanocarrier by a reliable and simple approach, and offers an effective strategy for the combination of chemotherapy and radiotherapy.