Dual pH Responsiveness Research Articles

Customizable Supraparticles Constructed from Catechol-Terminated Molecular Building Blocks with Controllable Intermolecular Interactions.

Colloidal supraparticles integrated with multicomponent primary particles come with emerging or synergetic functionalities. However, achieving the functional customization of supraparticles remains a great challenge because of the limited options of building blocks with tailorability and functional extensibility. Herein, we developed a universal approach to construct customizable supraparticles with desired properties from molecular building blocks obtained by the covalent conjugation of catechol groups with a series of orthogonal functional groups. These catechol-terminated molecular building blocks can assemble into primary particles driven by various intermolecular interactions (i.e. metal-organic coordination, host-guest, and hydrophobic interactions), and then further assemble into supraparticles governed by catechol-mediated interfacial interactions. Our strategy enables the formation of supraparticles with diverse functionalities, such as dual-pH responsiveness, light-controllable permeability, and non-invasive fluorescence labeling of living cells. The ease with which these supraparticles can be fabricated, and the ability to tailor their chemical and physical properties through the choice of metals and orthogonal functional groups used, should enable a variety of applications.

PH-Responsive Hyperbranched Polymer Nanoparticles to Combat Intracellular Infection by Disrupting Bacterial Wall and Regulating Macrophage Polarization.

Intracellular bacterial infections pose a serious threat to public health. Macrophages are a heterogeneous population of immune cells that play a vital role in intracellular bacterial infection. However, bacteria that survive inside macrophages could subvert the cell signaling and eventually reduce the antimicrobial activity of macrophages. Herein, dual pH-responsive polymer (poly[(3-phenylprop-2-ene-1,1-diyl)bis(oxy)bis(enthane-2,1-diyl)diacrylate-co-N-aminoethylpiperazine] (PCA)) nanoparticles were developed to clear intracellular bacteria by activating macrophages and destructing bacterial walls. The presence of acid-labile acetal linkages and tertiary amine groups in the polymer's backbone endow hyperbranched PCA dual pH-response activity that shows acid-induced positive charge increase and cinnamaldehyde release properties. The biodegraded PCA nanoparticles could significantly inhibit the growth of bacteria by damaging the bacterial walls. Meanwhile, PCA nanoparticles could uptake by macrophages, generate reactive oxygen species (ROS), and remodel the immune response by upregulating M1 polarization, leading to the reinforced antimicrobial capacity. Furthermore, PCA nanoparticles could promote bacteria-infected wound healing in vivo. Therefore, these dual pH-responsive PCA nanoparticles enabling bacteria-killing and macrophage activation provide a novel outlook for treating intracellular infection.

Halloysite nanotubes-based composite material with acid/alkali dual pH response and foliar adhesion for smart delivery of hydrophobic pesticide

Smart pesticide delivery systems with pH response are arousing huge interests recently, but single pH sensitivity may bring about constraint in different agricultural situations. We have developed a novel type of responsive material with acid/alkali dual pH sensitivity to deliver hydrophobic pesticide by the combination of acid-sensitive calcium ion (Ca2+)-ethylenediamine tetraacetate (EDTA2-) complex and base-sensitive calcium alginate. During the loading of chlorpyrifos, assembly occurs spontaneously by mixing Ca2+-modified acid-treated halloysite nanotubes (a-HNTs) with EDTA2-, followed by the functionalization of alginate gel to obtain the foliar-adhesive pesticide, namely HCECA (each letter representing halloysite, Ca2+, EDTA2-, chlorpyrifos and alginate, respectively). With loading capacity and loading efficiency of chlorpyrifos at 130 mg/g and 65 %, this engineered pesticide exhibits characteristic sustained release behavior of chlorpyrifos with dual pH response, displaying the release ratio of 58 % and 83 % in 24 h at pH = 4.0 and pH = 8.5, respectively, which is further demonstrated by prolonged control efficiency of corn borers. Owing to the strong interaction of alginate with plant leaves, the foliar adhesion property of HCECA against rain rinsing was strengthened by 86 % and 45 %, in comparison to pristine chlorpyrifos and HCEC (the control pesticide without alginate). The stability of HCECA was investigated, showing its resistance to high temperature (50 °C) and ultraviolet irradiation. Notably, the carrier material shows excellent biocompatibility by testing toxicity on zebrafish. Featured by green preparation, acid/alkali dual pH response and multifaceted stability, the halloysite nanotubes-based gel material serves as a promising carrier for hydrophobic pesticide to be applied in controlled management of agricultural hazards.

Performance design of a highly anti-fouling porous membrane with dual pH-responsiveness

With the increasingly extensive application of membrane technology, facing the wastewater system with complex components, it is urgent to develop a porous membrane with excellent pollution-resistant and easily cleaned after pollution. Herein, a membrane with dual pH-responsiveness effects was successfully fabricated via a facile and eco-friendly method. The isoelectric point of zeta potential of the modified membrane (M-D-IA) appeared at pH = 4.31. It exhibited positive-charged and the water intake rate reached 427% under strongly acidic conditions, while it showed negative-charged with the water intake rate reaching 492% under strongly alkaline conditions, showing an excellent dual pH-responsiveness. Meanwhile, the membrane M-D-IA possessed good super-hydrophilic and underwater super-oleophobic surface characteristics. Furthermore, the membrane M-D-IA displayed an excellent oil-fouling resistance in the treatment of hexadecane/water mixed emulsion, with the water flux decay rate (FDR) only 17.5% after 7 cycles of operation and the water flux recovery rate (FRR) remained above 99.7% after alkali cleaning. Notably, the membrane M-D-IA also had excellent dual pH-responsiveness when treating typical polluted wastewater HA/CaCO3 feed solution. The FRR was as high as 98.3% after washing with alkali and acid solution in turn, indicating that the membrane not only possessed a significant resistance to organic/inorganic pollution but also had an outstanding recovery of membrane flux after cleaning. Moreover, the water flux of the membrane M-D-IA was maintained at 850 L m−2 h−1 during 30 days of storage, displaying an excellent resistance to biological pollution.

Dual pH responsive via double - layered microencapsulation for controlled release of active ingredients in simulated gastrointestinal tract: A model case of chitosan-alginate microcapsules containing basil oil (Ocimum basilicum Linn.)

Phytogenic feed additives (PFAs) have gained more attention to replace antibiotic growth promoters (AGPs) in poultry industry. However, the efficiency of PEAs might be lost during feed pelleting, storage and gastrointestinal (GI) tract resulting in an insufficient level at the small intestine. The present work demonstrates the use of double-layered polymers with opposite charges leading to a dual pH responsiveness where the encapsulated ingredients are remained active through the acidic gastric stage and ready to be released at the intestine. Anionic sodium alginate (SA) and cationic chitosan (CS) are a good combination to represent double-layered polymer of which an effective incorporation of active ingredient, i.e. basil oil (BO), a model PEA, can be achieved. By simply fabricating SA porous microcapsules followed by the absorption of BO before the surface coating with CS, the double-layered microcapsules, CS-SA, are obtained. The release performances confirm that CS-SA retains the antioxidant and antimicrobial activities of BO under storage in addition to a great tolerance of acids, bile, trypsin, including the thermal conditions. The present work, for the first time, proposes the concept of porous double-layered polymer in microcapsule form which shows the dual pH responsive for controlled release application. The use of ionic polysaccharides is simple, biocompatible and environmentally friendly, whereas the plausible upscaling for wide range of controlled release applications has to be further investigated.

Synthesis of Amphiphilic and Double Hydrophilic Star-like Block Copolymers and the Dual pH-Responsiveness of Unimolecular Micelle

A series of amphiphilic star-like triblock copolymers with well-defined molecular architectures, molecular weight, and narrow polydispersity were successfully synthesized by sequential atom transfe...

Dual charged folate labelled chitosan nanogels with enhanced mucoadhesion capacity for targeted drug delivery

Nanometric gel particles (CsSH/PEGBCOOH) were successfully synthesized through water in oil (W/O) emulsion by the covalent cross–linking between the primary amines of thiolated chitosan (CsSH) and the dicarboxylic poly(ethylene glycol) (PEG) derivative as cross–linker (PEGBCOOH). Thus, the amidation reaction led to the formation of stable nanosized networks positively or negatively charged by the ionization of either amines or thiol moieties depending on the surrounding pH. This double response, which has not been studied before, was markedly observed and quantified during the characterization of the nanogels, concluding the high impact that could suppose these promising nanoparticles in the biomedical field. Besides, the presence of thiol groups in the nanogels was demonstrated to greatly improve the nanoparticle–mucus interactions, highlighting the potential of this novel strategy in the field of nanotechnology. Finally, nanogels were further labelled with folate ligand as an example of a simple and easy functionalization route via thiol–Michael addition (MA) reaction for future studies of tumour targeting therapies of these nanocarriers. Therefore, the synthesized chitosan–based labelled nanogels presented an adaptable character to the environmental conditions due to their dual pH response and mucoadhesion capacity, making them great candidates as nanocarriers for biomedical applications.

Efficacy-shaping nanomedicine by loading Calcium Peroxide into Tumor Microenvironment-responsive Nanoparticles for the Antitumor Therapy of Prostate Cancer.

Rationale: Prostate cancer has become one of the most threatening malignant tumors in men, leading to an imperative need to develop effective and safe therapies. Because of the unique metabolism of tumor cells, the tumor microenvironment (TME) exhibits distinctive properties compared with normal tissues, among which the pH difference has been utilized as an ideal antitumor strategy. Herein, we introduce a reactive oxygen species (ROS)-controlled-release nanosystem with TME-responsiveness by applying hollow mesoporous silica nanoparticles (HMSNs) as carriers loaded with calcium peroxide (CaO2) and coated with polyacrylic acid (PAA) to construct the functional material CaO2@HMSNs-PAA. The differences in pH values and exogenous ROS scavenging abilities between the tumor tissue and normal tissues and the dual pH-responsiveness from CaO2 and PAA lay a scientific foundation for the application of CaO2@HMSNs-PAA in the tumor-selective therapy for prostate cancer.Methods: The morphology and the structure of the nanosystem were characterized by the transmission electron microscope, scanning electron microscope, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, zeta potential, dynamic light scattering measurement, low-angle X-ray diffraction patterns and nitrogen adsorption/desorption isotherm. The CaO2 loading capacity and release profiles in different buffer solutions were determined by inductively coupled plasma-mass spectrometry. The in vitro intracellular uptake of CaO2@HMSNs-PAA was explored on the PC-3 prostate cancer cell line via confocal laser scanning microscopy. The CCK-8 cell proliferation assay was conducted to evaluate the cytotoxicity of CaO2@HMSNs-PAA against PC-3 cells. ROS produced by CaO2@HMSNs-PAA was observed by a fluorescence microscope. The flow cytometry was utilized to analyze the apoptosis of PC-3 cells induced by CaO2@HMSNs-PAA. The Western blot analysis was performed to detect expressions of critical mitochondria-mediated apoptosis markers in PC-3 cells after incubation with CaO2@HMSNs-PAA. The in vivo biosafety and antitumor efficacy were evaluated out on BALB/c mice and BALB/c nude mice subcutaneously transplanted with PC-3 cells, respectively.Results: Comprehensive characterizations indicated the successful synthesis of CaO2@HMSNs-PAA with significant TME-responsiveness. The experimental results demonstrated that the well-developed nanocarrier could efficiently deliver CaO2 to the tumor site and release ROS in response to the decreased pH value of TME, exerting ideal antitumor effects both in vitro and in vivo by activating the mitochondria-mediated apoptosis pathway. Simultaneously, this nanoplatform caused no detectable damage to normal tissues.Conclusions: After loading into the above nanocomposite, the free CaO2 without a significant antitumor effect can exert excellent antitumor efficacy by responsively releasing ROS under the acidic TME to induce the mitochondria-mediated apoptosis via remarkable oxidative stress and simultaneously minimize damages to normal tissues. The current study presents a new concept of “efficacy-shaping nanomedicine” for the tumor-selective treatment of prostate cancer.

Chitosan oligosaccharide-based dual pH responsive nano-micelles for targeted delivery of hydrophobic drugs

In this study, chitosan oligosaccharide (COS)-vanillin imine (COS-Vani Imine)-based dual pH responsive nano-micelles (DPRNs) were synthesized. The resultant DPRNs were used for encapsulating genistein and its ultimate release upon pH change. The overall concept of DPRNs for the targeted delivery of hydrophobic anticancer drugs was successfully demonstrated. The DPRNs were spherical in shape, nanoscale in dimension (71.2–163.4 nm), with dual pH response. The encapsulation/loading of genistein into DPRNs was achieved and the resultant genistein-loaded DPRNs were stable under the physiological pH (˜7.4); under the cancer cell extracellular pH (˜6.8), the amino groups in COS is protonated, thus becoming positively charged, facilitating their adsorption onto negatively charged cancer cells. Under the cancer cell intracellular pH (˜5.0), the genistein-loaded DPRNs were destroyed as a result of the cleavage of pH sensitive benzoic imine, thereby releasing the loaded genistein.

Combination antitumor immunotherapy with VEGF and PIGF siRNA via systemic delivery of multi-functionalized nanoparticles to tumor-associated macrophages and breast cancer cells

Given that vascular endothelial growth factor (VEGF) and placental growth factor (PIGF), over-expressed in breast cancer cells and M2-like tumor-associated macrophages (M2-TAMs) within tumor microenvironment (TME), work synergistically and independently in mediating tumor progression and immunosuppression, combinatorial immune-based approaches targeting them are expected to be a potent therapeutic modality for patients. Here, polyethylene glycol (PEG) and mannose doubly modified trimethyl chitosan (PEG = MT) along with citraconic anhydride grafted poly (allylamine hydrochloride) (PC)-based nanoparticles (NPs) (PEG = MT/PC NPs) with dual pH-responsiveness were developed to deliver VEGF siRNA (siVEGF)/PIGF siRNA (siPIGF) to both M2-TAMs and breast cancer cells for antitumor immunotherapy. With prolonged blood circulation and intelligent pH-sensitivity, PEG = MT/PC NPs were highly accumulated in tumor tissues and then internalized in M2-TAMs and breast cancer cells via mannose-mediated active targeting and passive targeting, respectively. With the charge-reversal of PC, PEG = MT/PC NPs presented effective endosomal/lysosomal escape and intracellular siRNA release, resulting in efficient gene silencing. Due to the synergism between siVEGF and siPIGF in anti-proliferation of tumor cells and reversal of the TME from pro-oncogenic to anti-tumoral, PEG = MT/PC/siVEGF/siPIGF NPs (PEG = MT/PC/siV-P NPs) exerted robust suppression of breast tumor growth and lung metastasis. This combination strategy may provide a promising alternative for breast cancer therapy.

Hydrogen bond reinforced poly(1-vinylimidazole-co-acrylic acid) hydrogels with high toughness, fast self-recovery, and dual pH-responsiveness

As a promising structural material, various tough hydrogels have been developed in recent years by incorporating different kinds of noncovalent bonds as the energy-dissipating segments. Among these systems, it is challenging to use hydrogen bonds due to their instability in aqueous environment. Here we report a tough hydrogel of poly(1-vinylimidazole-co-acrylic acid) (P(VI-co-AAc)) reinforced by the robust hydrogen bonds between imidazole and carboxylic acid groups. The hydrogels with different composition possess excellent mechanical performances, with tensile breaking stress, breaking strain, Young's modulus, and tearing fracture energy being 0.3–1.8 MPa, 920–1400%, 0.1–0.7 MPa, and 0.7–5.6 kJ/m2, respectively, which are well maintained over a wide pH range (3 ≤ pH ≤ 10). The high stability of hydrogen bonds should be rooted in the strong proton donor-acceptor pair. However, when pH ≤ 2 or pH ≥ 11, the gels become highly swelled due to the dissociation of imidazole and carboxylic acid groups, respectively, accompanying with dramatic decrease in mechanical properties. The tough hydrogels also show temperature- and deformation rate-dependent mechanical properties, as well as shape memory and self-recovery abilities, due to the dynamic nature of noncovalent bonds. Such hydrogels with remarkable mechanical properties and dual pH-responsiveness should find applications in load-bearing soft actuators, flexible electronics, etc.

Two-component self-assembly of a tetra-guanidiniocarbonyl pyrrole cation and Na4EDTA: formation of pH switchable supramolecular networks.

A guanidiniocarbonyl pyrrole (GCP) cation forms stable H-bond assisted ion pairs with carboxylates even in aqueous solutions. A tetra GCP cation 1 undergoes efficient two-component self-assembly with Na4EDTA, a tetra-carboxylate, leading to 3D supramolecular networks. These networks show dual pH responsiveness and reversibly dissociate back into monomers upon addition of either acid or base.

Site-Specific Drug-Releasing Polypeptide Nanocarriers Based on Dual-pH Response for Enhanced Therapeutic Efficacy against Drug-Resistant Tumors.

To enhance effective drug accumulation in drug-resistant tumors, a site-specific drug-releasing polypeptide system (PEG-Phis/Pasp-DOX/CA4) was exploited in response to tumor extracellular and intracellular pH. This system could firstly release the embedded tumor vascular inhibitor (CA4) to transiently 'normalize' vasculature and facilitate drug internalization to tumors efficiently, and then initiate the secondary pH-response to set the conjugated active anticancer drug (DOX) free in tumor cells. The encapsulated system (PEG-Phis/DOX/CA4), both CA4 and DOX embedding in the nanoparticles, was used as a control. Comparing with PEG-Phis/DOX/CA4, PEG-Phis/Pasp-DOX/CA4 exhibited enhanced cytotoxicity against DOX-sensitive and DOX-resistant cells (MCF-7 and MCF-7/ADR). Moreover, PEG-Phis/Pasp-DOX/CA4 resulted in enhanced therapeutic efficacy in drug-resistant tumors with reduced toxicity. These results suggested that this site-specific drug-releasing system could be exploited as a promising treatment for cancers with repeated administration.

Smart pH‐Responsive Nanocarriers Based on Nano‐Graphene Oxide for Combined Chemo‐ and Photothermal Therapy Overcoming Drug Resistance

A pH-responsive nanocarrier is developed by coating nanoscale graphene oxide (NGO) with dual types of polymers, polyethylene glycol (PEG) and poly(allylamine hydrochloride) (PAH), the latter of which is then modified with 2,3-dimethylmaleic anhydride (DA) to acquire pH-dependent charge reversibility. After loading with doxorubicin (DOX), a chemotherapy drug, the obtained NGO-PEG-DA/DOX complex exhibits a dual pH-responsiveness, showing markedly enhanced cellular uptake under the tumor microenvironmental pH, and accelerated DOX release under a further lowered pH inside cell lysosomes. Combining such a unique behavior with subsequently slow efflux of DOX, NGO-PEG-DA/DOX offers remarkably improved cell killing for drug-resistant cancer cells under the tumor microenvironmental pH in comparison with free DOX. Exploiting its excellent photothermal conversion ability, combined chemo- and photothermal therapy is further demonstrated using NGO-PEG-DA/DOX, realizing a synergistic therapeutic effect. This work presents a novel design of surface chemistry on NGO for the development of smart drug delivery systems responding to the tumor microenvironment and external physical stimulus, with the potential to overcome drug resistance.

Triggered Rapid Degradation of Nanoparticles for Gene Delivery

Effective gene delivery tools offer the possibility of addressing multiple diseases; current strategies rely on viruses or polyplexes. Encapsulation of DNA within nanoparticles is an attractive alternative method for gene delivery. We investigated the use of our recently developed Logic Gate Nanoparticle for gene delivery. The nanoparticles, composed of a dual pH response random copolymer (poly-β-aminoester ketal-2), can undergo a two-step “in series” response to endosomal pH. The first sep is a hydrophobic-hydrophilic switch, which is followed immediately by rapid degradation. Rapid fragmentation is known to increase cytoplasmic delivery from nanoparticles. Therefore, we hypothesized that our Logic Gate Nanoparticles would enable increased gene delivery and expression relative to nanoparticles that degrade more slowly such as PLGA-based nanoparticles. Passive nanoparticle entry into cells was demonstrated by delivering Cy5-labeled pDNA encoding EGFP into HCT116, a colon carcinoma cell line. Flow cytometry analysis showed that cells are positive for Cy5-DNA-nanoparticles and produced EGFP expression superior to PLGA nanoparticles. Inhibition of V-ATPases using bafilomycin A1 demonstrates that expression of EGFP is dependent on low endosomal pH. The advanced Logic Gate Nanoparticles offer new therapeutic possibilities in gene delivery and other applications where rapid release is important.