Temperature-sensitive Nanogels Research Articles

Temperature-sensitive nanogels combined with polyphosphate and cisplatin for the enhancement of tumor artery embolization by coagulation activation

Transcatheter arterial chemoembolization (TACE) is the first-line therapy for hepatocellular carcinoma (HCC). However, the exacerbated hypoxia microenvironment induces tumor relapse and metastasis post-TACE. Here, temperature-sensitive block polymer complexed with polyphosphate–cisplatin (Pt–P@PND) was prepared for the enhancement of tumor artery embolization by coagulation activation. After supra-selective infusion into the tumor vessels, Pt–P@PND nanogels performed efficient embolization of tumor arteries by sol–gel transition at body temperature. Meanwhile, coagulation cascade was evoked to form blood clots in the peripheral arteries inaccessible to the nanogels by released PolyP. The blood clots-filled hydrogel networks composed of gel and clots showed a denser structure and higher modulus, thereby achieving long-term embolization of all levels of tumor arteries. Pt–P@PND nanogels efficiently inhibited tumor growth and reduced the expression of HIF-1α, VEGF, CD31, and MMP-9 on VX2 tumor-bearing rabbit model. The released Nitro-Pt stimulated the immunogenic cell death of tumor cells, thus enhancing the antitumor immune response to suppress tumor relapse and metastasis post-TACE. It is hoped that Pt–P@PND nanogels can be developed as a promising embolic agent with procoagulant activity for enhancing the antitumor immune response through a combination of embolism, coagulation, and chemotherapy. Statement of significanceClinical embolic agents, such as Lipiodol and polyvinyl alcohol (PVA) microspheres, are limited by their rapid elimination or larger size, thus lead to incomplete embolization of trans-catheter arterial chemoembolization (TACE). Herein, temperature-sensitive Pt-P@PND nanogels were developed to achieve long-term embolization of all levels of tumor arteries by gel/clot generation. The released Nitro-Pt induced immunogenic cell death in tumor cells, which improved the antitumor immune microenvironment by the maturation of DCs and lymphocytic infiltration. Pt-P@PND nanogels successfully inhibited tumor growth and activated an antitumor immune response to curb the recurrence and metastasis of residual tumor cells both in VX2 tumor-bearing rabbit model and 4T1 tumor-bearing mouse model. These findings suggested that Pt-P@PND could be developed as an ideal embolic agent for clinical TACE treatment.

The synergistic blood-vessel-embolization of coagulation fusion protein with temperature sensitive nanogels in interventional therapies on hepatocellular carcinoma

• TF-Nannogels realized the synergistic artery embolization by TVI and TACE. • TF-Nanogels improved hypoxic micro-environment, enhanced antitumor immune effects. • TF-Nanogels inhibited tumor metastasis by improving the tumor micro-environment. • TF-Nanogels protects tTF-pHLIPs from rapid degradation, sustains a thromboembolism. As one of the most extensively used clinical treatments for many solid tumors such as liver cancer, trans-arterial embolization (TAE) was greatly limited by postoperative recurrence and metastasis and poor long-term efficacy. In present work, tTF-pHLIPs was entrapped into 3D networks of poly( N -isopropylacrylamide- co -butyl methacrylate) (PIB) nanogels, named as TF-Nanogels, for improving their sustained release and in vivo PK/PD properties by temperature sensitive sol–gel transition of PIB nanogels. TF-Nanogels exhibited a synergistic effect between the extrinsic coagulation of tTF-pHLIPs and intrinsic coagulation of PIB nanogels with negative charges in in vitro clotting assays, and a distinct activation on platelets by CD62P pathways at above 0.1 mg/mL of nanogel concentration. The resultant blood fibril clots by TF-Nanogels showed thicker fibrin networks than those by free tTF-pHLIPs in SEM pictures (400 nm vs. 60 nm of fibrin diameters), suggesting the interpenetrating networks of fibril clots, platelets/ hemocytes and PIB nanogels. Compared to i.v. injection of tTF-pHLIPs, TF-Nanogels exihited an long-term vascular occlusion in VX2 tumor-bearing rabbits only at a half dose (250 μg) of i.v. injection, indicating the synergistic antitumor efficacy between PIB nanogels and tTF-pHLIPs. TF-Nanogels showed favorable supression on tumor angiogenesis and metastasis due to far lower levels of HIF-1α, VEGFs and MMP-9 than tTF-pHLIPs, and distinct antitumor immune response (higher levels of CD3 + and CD8 + T cells). TF-Nanogels were promising embolic agents to enhance TAE antitumor efficacy (angiogenesis inhibition, metastasis inhibition, antitumor immune activation, etc. ) by the synergistic effect between coagulative artery infraction of tTF-pHLIPs and temperature sensitive artery embolization of PIB nanogels in interventional therapies on hepatocellular carcinoma.

Dual pH and Temperature-Sensitive Nanogels Loaded with Eugenol for Regulating Central Nervous System.

Fragrances have many biological activities such as anti-anxiety, anti-depression, and improving cognitive memory. However, most fragrances are so volatile that the useful lifespan of the fragrances is very short and excessive fragrance concentration makes us uncomfortable. In this study, dual pH and temperature-sensitive nanogels named EG@CPMONGs were prepared to encapsulate eugenol. This nano-fragrance was then applied to silk. In the following, the effects of EG@CPMO-NGs on the regulation of central nervous systems were evaluated. Open-field tests showed that EG@CPMONGs had an obvious effect on stress relief. Elevated plus-maze tests proved the significant effect of EG@CPMO-NGs on anti-anxiety. Morris water maze tests demonstrated the positive impact of nano-fragrance on spatial learning and memory. Therefore, these dual pH and temperature-sensitive nanogels loaded with eugenol had significant and positive effects on the central nervous system.

Temperature and pH Dual Responsive Nanogels of Modified Sodium Alginate and NIPAM for Berberine Loading and Release.

pH- and temperature-sensitive nanogels (NGs) were prepared from sodium alginate (SA) and N-isopropylacrylamide (NIPAM), as the sensitivity at pH 5.5 and 31 °C. SA was pH-modified with glutamic acid (Glu) and ethylenediamine (EDA). The products Glu-SA (Glu-modified SA) and EGSA (EDA- and Glu-modified SA) were characterized by ninhydrin color reaction, infrared spectroscopy, and zeta potential, and the best reactant ratio was selected. Moreover, temperature-sensitive, pH-sensitive EGSA-NGs possessing a semi-interpenetrating network structure were prepared by radical polymerization using N-isopropylacrylamide. The morphology of EGSA-NGs was characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM). The cytotoxicity test shows the low cytotoxicity and high biocompatibility of the NGs. The newly prepared NGs were also subjected to pH-sensitive temperature-sensitive in vitro drug-loading and drug-release experiments. The pH-sensitive and temperature-sensitive experiments showed that the particle size of EGSA-NGs was reduced at pH 5.5 and above 31 °C. The drug-loading and drug-release experiments also confirmed this finding, indicating that the newly synthesized NGs could release the drug according to the environmental changes. Therefore, the material has potential application value in solid tumor targeted therapy.

Stiffness Tomography of Ultra-Soft Nanogels by Atomic Force Microscopy.

The softness of nanohydrogels results in unique properties and recently attracted tremendous interest due to the multi‐functionalization of interfaces. Herein, we study extremely soft temperature‐sensitive ultra‐low cross‐linked (ULC) nanogels adsorbed to the solid/water interface by atomic force microscopy (AFM). The ultra‐soft nanogels seem to disappear in classical imaging modes since a sharp tip fully penetrates these porous networks with very low forces in the range of steric interactions (ca. 100 pN). However, the detailed evaluation of Force Volume mode measurements allows us to resolve their overall shape and at the same time their internal structure in all three dimensions. The nanogels exhibit an extraordinary disk‐like and entirely homogeneous but extremely soft structure—even softer than polymer brushes. Moreover, the temperature‐sensitive nanogels can be switched on demand between the ultra‐soft and a very stiff state.

Tuneable peptide cross-linked nanogels for enzyme-triggered protein delivery.

Many diseases are associated with the dysregulated activity of enzymes, such as matrix metalloproteinases (MMPs). This dysregulation can be leveraged in drug delivery to achieve disease- or site-specific cargo release. Self-assembled polymeric nanoparticles are versatile drug carrier materials due to the accessible diversity of polymer chemistry. However, efficient loading of sensitive cargo, such as proteins, and introducing functional enzyme-responsive behaviour remain challenging. Herein, peptide-crosslinked, temperature-sensitive nanogels for protein delivery were designed to respond to MMP-7, which is overexpressed in many pathologies including cancer and inflammatory diseases. The incorporation of N-cyclopropylacrylamide (NCPAM) into N-isopropylacrylamide (NIPAM)-based copolymers enabled us to tune the polymer lower critical solution temperature from 33 to 44 °C, allowing the encapsulation of protein cargo and nanogel-crosslinking at slightly elevated temperatures. This approach resulted in nanogels that were held together by MMP-sensitive peptides for enzyme-specific protein delivery. We employed a combination of cryogenic transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS), small angle neutron scattering (SANS), and fluorescence correlation spectroscopy (FCS) to precisely decipher the morphology, self-assembly mechanism, enzyme-responsiveness, and model protein loading/release properties of our nanogel platform. Simple variation of the peptide linker sequence and combining multiple different crosslinkers will enable us to adjust our platform to target specific diseases in the future.

Multiresponsive and Self-Healing Hydrogel via Formation of Polymer-Nanogel Interfacial Dynamic Benzoxaborole Esters at Physiological pH.

Nanocomposite hydrogels with multiresponsiveness and self-healing property are attracting extensive interest due to their enhanced performance for a wide range of applications. In this work, we have successfully developed novel hydrogels based on interfacial polymer-nanogel benzoxaborolate cross-linking at physiological pH. Temperature-sensitive nanogels (NG-Gal) containing galactose residues on the nanosurface were prepared and subsequently used as macro-cross-linkers to form a hydrogel network through formation of dynamic adducts with benzoxaborole groups of a hydrophilic copolymer poly(DMA-st-MAABO). Benefiting from the low pKa value of benzoxaborole (∼7.2), hydrogels can be constructed rapidly at physiological pH, which is of great significance for biomedical applications. Changing the molar ratio between benzoxaborole and galactose was found to alter the mechanical properties of hydrogels as confirmed by rheological measurements. The dynamic nature of benzoxaborole esters endowed the hydrogel with moldability and self-healing ability after disruption. Moreover, the hydrogel showed multiresponsiveness toward pH, sugar, adenosine triphosphate (ATP), hydrogen peroxide (H2O2), and temperature. Therefore, the novel nanocomposite hydrogel we demonstrated here exhibits great potential for biomedical applications such as tissue engineering and controlled drug delivery.

Design and Fabrication of Temperature-Sensitive Nanogels with Controlled Drug Release Properties for Enhanced Photothermal Sterilization.

For better removal of excessive free radicals and harmful bacteria from the human body, the development of synergistic antioxidant and antibacterial agents is urgently required. Herein, we designed novel temperature-sensitive, curcumin (Cur)-loaded nanogels for the application of scavenging reactive oxygen species and killing pathogenic bacteria. Photothermal sterilization, different from traditional antibiotics, is a promising and effective treatment for pathogenic bacterial infection. The nanogels were fabricated by using poly(N-isopropylacrylamide) (a temperature-sensitive hydrogel) to encapsulate poly(3,4-ethylenedioxythiophene) nanoparticles (photothermal agents) and Cur through a reformative precipitation polymerization. When triggered by near-IR light, the Cur-loaded nanogels exhibited high (56.8 %), and excellent temperature-sensitive effects. Moreover, the light-induced temperature increase can also weaken the interaction between the networks of PNIPAAm and Cur, to show excellent antioxidant and antibacterial performance (90 % cell death) of the nanogels.

Temperature-sensitive nanogels in the presence of salt: explicit coarse-grained simulations.

In this work, coarse-grained simulations of two charged thermo-shrinking nanogels (with degrees of ionization of 0.125 and 0.250) in the presence of 1:1 and 3:1 electrolytes have been explicitly performed through the bead-spring model of polyelectrolyte. In a first set of simulations, salt concentrations for 1:1 and 3:1 electrolytes ranged from 1 to 100 mM and from 0.167 to 16.7 mM, respectively, whereas temperature remained fixed at a value for which hydrophobic forces were negligible in our case (288 K). The sizes of swollen nanogels are smaller when trivalent cations are present, but they do not change significantly in the range of concentrations of 3:1 electrolyte studied here. It should be also stressed that trivalent cations neutralize the nanogel charge more efficiently. According to these results the electrostatic repulsion plays an important role. In a second set of simulations, the temperature varied from 288 to 333 K to study the effect of salt on the thermal response when hydrophobic forces are not negligible. For the nanogels with the lowest degree of ionization, the behavior of the radius with increasing the temperature can be described by a sigmoid function, which shifts towards lower temperatures in the presence of salt. This shift is more clearly observed for trivalent cations, even at low concentrations. For the nanogels with the highest degree of ionization, the effect of additional electrolyte is also noticeable. In this case, hydrophobic forces are not the only responsible for their shrinkage in the presence of trivalent cations. The surface electrostatic potential and the concentration of salt cations inside the nanogel have been computed from simulations and a modified Poisson-Boltzmann (PB) cell model. The thermosensitivity in size have certain influence on the sensitivity of these properties to temperature changes. The rich behavior of the surface electrostatic potential and the uptake of salt cations are successfully predicted by the modified PB cell model proposed (at least qualitatively). Particularly, the model is able to predict how the retention of salt cations depends on their charge and the ionic valence when nanogels shrink.

The studies on highly concentrated complex dispersions of gold nanoparticles and temperature-sensitive nanogels and their application as new blood-vessel-embolic materials with high-resolution angiography.

Recently temperature sensitive polymers have been developed as novel embolization materials. However, their flowability and embolization have been seriously impacted by iodine-based X-ray contrast agents. In order to resolve the drawbacks of these contrast agents, highly concentrated complex (HCC) dispersions of gold nanoparticles (GNPs) with p(N-isopropylacrylamide-co-butyl methylacrylate) (PIB) nanogels were developed as new blood-vessel-embolic materials with high-resolution angiography. Although GNPs have better X-ray attenuation than iodinated compounds, their poor dispersion stability limits their application in digital subtraction angiography (DSA). HCC dispersions show excellent X-ray attenuation ability which is 2.6 times higher than Omnipaque at 0.31 mol L-1. This can be attributed to the fact that the sol-gel transition of nanogel dispersions improves the colloid stability of GNPs. In the two sol-gel transition temperatures (Tg-s and T's-g) of nanogel dispersions, GNPs have no influence on T's-g, and a great influence on Tg-s. The in vivo experimental data indicate that HCC dispersions show high angiographic ability and good blood-vessel embolization, and can be used for postoperative examination for long periods owing to the entrapment of GNPs into the embolic sites. The HCC dispersions have potential to be developed as new blood-vessel-embolic materials with high-resolution angiography.

Soft nanoparticles (thermo-responsive nanogels and bicelles) with biotechnological applications: from synthesis to simulation through colloidal characterization

The use of nanotechnology in biotechnological applications has attracted tremendous attention from researchers. Currently many nanomaterials, such as soft nanoparticles, are under investigation and development for their use in biomedicine. Among soft nanoparticles, polymeric gels in the nanometre range, known as nanogel particles, have received considerable attention. Nanogel particles, which are formed by polymeric chains loosely cross-linked to form a three-dimensional network, swell by a thermodynamically good solvent but do not dissolve in it. Nanogels are composed of hydrophilic polymers capable of undergoing reversible volume-phase transitions in response to environmental stimuli. Among them, temperature-sensitive nanogels showing a volume phase transition temperature (VPTT) near physiological temperature have been investigated in detail. Nanogels based on biocompatible and temperature-sensitive polymers having a lower critical solution temperature (LCST) around 32 °C in aqueous solutions swell at low temperatures and collapse at high ones. This unique behavior makes these nanogels attractive for pharmaceutical, therapeutical, and biomedical applications. In this review, different synthesis strategies to produce this type of nanogels in dispersed media are revised. Special attention is paid to poly(N-vinylcaprolactam) (PVCL)-based nanogels due to their proven biocompatibility. On the other hand, an extensive review on the characteristics, preparation, and physicochemical properties of another type of soft nanoparticles, which are the bicelles, is presented. The different morphologies obtained depending on experimental conditions such as temperature, lipid concentration, and long- and short-chain phospholipids molar ratio are revised, emphasizing on an important property of bicelles: their alignment in the presence of a magnetic field, and presenting the most important applications of bicelles as membrane models in diverse conformational studies of proteins and membrane peptides, together with the possibilities of administration of such vesicles by systemic routes. A key challenge for the characterization of both soft nanoparticles (nanogels and bicelles) involves the elucidation of their colloidal properties. In this work, some colloidal features of these nanoparticles such as their size, electric double layer or the internal structure and motions of their chains are analyzed. In addition, an overview on the previous and current understanding of the methods and techniques employed in this colloidal characterization is presented, mainly from an experimental point of view. Finally, the most recent results on polyelectrolyte gels and bicelles obtained from computer simulations are also briefly commented. Concerning polyelectrolyte gels, this review is mainly focused on the most important feature of these systems, their large capacity of swelling, which has been explored by simulation in the last decade.

A novel route to prepare pH- and temperature-sensitive nanogels via a semibatch process

A novel method via a semibatch process in the absence of surfactant has been adopted to prepare pH- and temperature-sensitive nanogels. The shape, charge distribution, temperature, and pH-induced volume phase transition behavior of the latexes were investigated by scanning electronic microscopy, zeta potentials, dynamic laser light scattering, and UV/vis spectroscopy. It was found that, in the absence of surfactant, with increasing the amount of AAc from 5 to 20 mol% of N-isopropylacrylamide (NIPAM), the hydrodynamic diameters ( D H ) decrease from 230 to 60 nm. With increasing pH value from 3 to 11, the D H values increase slightly, which is different than the dramatic increase seen when using a conventional batch method with a range from 680 to 1700 nm. However, at pH 3, the turbidity curves of these kinds of particles increase dramatically at temperatures between 33 and 37 °C, while remaining constant at first and then increasing directly at pH 11. Furthermore, the distribution of carboxylic groups located not only on the interior but also on the exterior of colloidal particles as a result of adoption of the semibatch method, other than simple surface distribution of poly(NIPAM- co-AAc) latexes via the batch method.