Hill-type pH probes.

Sensitive detection of the minute and yet pathologically significant pH variation is important and in fact challenging for the conventional pH probes following the Henderson-Hasselbalch equation, i.e., HH-type probes. A paradigm shift to Hill-type pH probes is ongoing. Bestowed by their positive cooperative acid-base chemistry, their pH-responsive profile follows the Hill equation, which exhibits a narrower acid/base transition width than HH-type probes and warrants a higher detection sensitivity. A polymer-based Hill-type pH-responsive material was first developed. More recently, there emerged several distinct small-molecular approaches to achieve Hill-type pH-responsive profiles. They complement the polymer-based sensing materials in applications where membrane permeability is a concern. In this trends article, we rationalize the molecular origins of their positive cooperativity in pH sensing and highlight some interesting proof-of-concept applications. We also discussed future directions of this dynamic research area.

Glycopolymer Nanoparticles with On-Demand Glucose-Responsive Insulin Delivery and Low-Hypoglycemia Risks for Type 1 Diabetic Treatment.

Diabetic patients with type 1 or advanced type 2 stages need timely and precise insulin injection to regulate the daily blood glucose levels (BGLs). Otherwise, risks of serious or even deadly diabetes-associated complications occur. To achieve prolonged glucose regulation and low hypoglycemia risks, a novel on-demand glucose-responsive glycopolymer system was constructed for insulin delivery, which was self-assembled into nanoparticles by dynamic covalent bonds between two polymers: fluorophenylboronic acid-grafted polymer (poly-F) and polyol polymer (poly-G). Insulin was loaded during the assembly process. The nanoparticles showed excellent glucose responsiveness in vitro, with controlled insulin release at different glucose concentrations. In vivo treatment on type 1 diabetic mice showed prolonged BGL regulation and lower hypoglycemia risks. The mild preparation of the nanoparticles and outstanding glucose control shed light on the optional diabetic treatment for further clinical use.

NIR Activated Upper Critical Solution Temperature Polymeric Micelles for Trimodal Combinational Cancer Therapy.

The balance between drug efficiency and its side effects on normal tissues is still a challenging problem to be solved in current cancer therapies. Among different strategies, cancer therapeutic methods based on nanomedicine delivery systems have received extensive attention due to their unique advantages such as improved circulation and reduced toxicity of drugs in the body. Herein, we constructed dual-responsive polymeric micelles DOX&ALS@MFM based on an upper critical solution temperature (UCST) polymer to simultaneously combine chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT). Amphiphilic block copolymer P(AAm-co-AN)-b-PEI-ss-PEG-FA with a critical point of 42 °C was able to self-assemble into polymeric micelles under physiological conditions, which further encapsulated anticancer drug doxorubicin (DOX) and photosensitizer ALS to obtain drug-loaded micelles DOX&ALS@MFM. Micelles aggregated at tumor sites due to folate targeting and an enhanced permeability retention (EPR) effect. After that, the high intracellular concentration of glutathione (GSH) and near-infrared (NIR) light prompted disassembly of the polymer to release DOX and ALS. ALS not only plays a role in PTT but also produces singlet oxygen, therefore killing tumor cells by PDT. Both in vitro and in vivo studies demonstrated the photothermal conversion and reactive oxygen species generation ability of DOX&ALS@MFM micelles, at the same time as the excellent inhibitory effect on tumor growth with NIR light irradiation. Thus, our research substantiated a new strategy for the biomedical application of UCST polymers in the cited triple modal tumor therapy.

Visualizing Drug Release from a Stimuli-Responsive Soft Material Based on Amine-Thiol Displacement.

In this research, we developed a photoluminescent platform using amine-coupled fluorophores, generated from a single conjugate acceptor containing bis-vinylogous thioesters. Based on the experimental and computational results, the fluorescence turn-on mechanism was proposed to be charge separated induced energy radiative transition for the amine-coupled fluorophore, while the sulfur-containing precursor was not fluorescent since the energy internal conversion occurred through vibrational 2RS- (R represents alkyl groups) as energy acceptor(s). Further utilizing the conjugate acceptor, we establish a new fluorogenic approach via a highly cross-linked soft material to selectively detect cysteine under neutral aqueous conditions. Turn-on fluorescence emission and macroscopic degradation occurred in the presence of cysteine as the stimuli, which can be visually tracked due to the generation of an optical indicator and the cleavage of linkers within the matrix. Furthermore, a novel drug delivery system was constructed, achieving controlled release of sulfhydryl drug (6-mercaptopurine) which was tracked by photoluminescence and high-performance liquid chromatography. The photoluminescent molecules developed herein are suitable for visualizing polymeric degradation, making them suitable for additional "smart" material applications.

Engineering near-infrared laser-activated gold nanorod vesicles with upper critical solution temperature for photothermal therapy and chemotherapy.

Multimodal synergistic therapy based on nanomedicine drug delivery systems can achieve accurate cancer treatment. The anisotropy of gold nanorods (AuNRs) allows the adjustment of the longitudinal localized surface plasmon resonance absorption to the near-infrared band, which shows potential application in the field of photothermal therapy of cancer. Here, we report a new type of thermal-sensitive gold nanorod drug-loaded vesicles (UGRV-DOX) via the self-assembly of AuNRs modified with the amphiphilic polymer (PEG45-b-PS150) and upper critical solution temperature (UCST) polymer (P(AAm-co-AN)). The hollow structure of the vesicle can increase the drug loading capacity, and the polymers on its surface are intertwined to reduce drug leakage. As-prepared UGRV-DOX vesicles exhibits excellent photothermal conversion efficiency and can achieve light-controlled drug release. In vivo anti-tumor experiments showed that UGRV-DOX could ablate HepG2 transplanted tumors significantly under 808 nm laser irradiation, and the inhibition rate was as high as 99.3 %. These tumor-specific nanovesicles prefigure great potentials for high-precision cancer treatment.

DNA-Based Daisy Chain Rotaxane Nanocomposite Hydrogels as Dual-Programmable Dynamic Scaffolds for Stem Cell Adhesion.

Interlocked DNA nanostructures perform programmable movements in nanoscales such as sliding, contraction, and expansion. However, utilizing nanoscaled interlocked movements to regulate the functions of larger length scaled matrix and developing their applications has not yet been reported. Herein we describe the assembly of DNA-based daisy chain rotaxane nanostructure (DNA-DCR) composed of two hollow DNA nanostructures as macrocycles, two interlocked axles and two triangular prism-shaped DNA structures as stoppers, in which three mechanical states─fixed extended state (FES), sliding state (SS), and fixed contracted state (FCS)─are characterized by using toehold-mediated strand displacement reaction (SDR). The DNA-DCRs are further used as nanocomposites and introduced into hydrogel matrix to produce interlocked hydrogels, which shows modulable stiffness by elongating the interlocked axles to regulate the hydrogel swelling with hybridization chain reaction (HCR) treatment. Then the DCR-hydrogels are employed as dynamic biointerfaces for human mesenchymal stem cells (hMSCs) adhesion studies. First, hMSCs showed lower cell density on bare DCR-hydrogel treated with HCR-initiated swelling for stiffness decreasing. Second, the cell adhesion ligand (RGD) modified DNA-DCRs are constructed for hydrogel functionalization. DCR(RGD) hydrogel endows the mobility of RGDs by switching the mechanical states of DNA-DCR. HMSCs showed increased cell density on DCRSS(RGD) hydrogel than on DCRFCS(RGD) hydrogel. Therefore, our DNA-DCR nanocomposite hydrogel exhibit dual-programmable performances including swelling adjustment and offering sliding for incorporated ligands, which can be both utilized as dynamic scaffolds for regulating the stem cell adhesion. The dual-programmable cross-scale regulation from interlocked DNA nanostructures to hydrogel matrix was achieved, demonstrating a new pathway of DNA-based materials.

Modulating the pKa Values of Hill-Type pH Probes for Biorelevant Acidic pH Range.

The pH-responsive profile of the traditional pH probes (the HH-type pH probes) is governed by the Henderson-Hasselbalch equation. Despite their widespread use, pH probes with further enhanced pH sensitivity, i.e., Hill-type pH probes, are sought after. As a result of positive cooperativity toward protonation, they exhibit a smaller acid-base transition width than that of a HH-type pH probe, which is 2 pH unit. As a result, the Hill-type pH probes have an improved capability to differentiate minor biorelevant pH changes. We previously devised a class of small-molecule Hill-type pH probes (PHX) with pKa in the range of 6.2-6.8. Subcellular organelles with a physiological pH lower than 6.2 are abundant and consequently Hill-type probes for use in these organelles are expected to exhibit a pKa lower than 6.2 as well. Through a rational and systematic structure-property relationship study, we showcased that the pKa values of the PHN type probes could be lowered by increasing the steric bulkiness or the electron-withdrawing capability of the dialkylamino groups on the bottom phenol moiety. The pKa values of the PHN-type probes now cover the wide biorelevant acidic range from 3.5 to 6.8. The potentials of these probes for biological imaging are exemplified and they are expected to be adopted in biological studies and medical diagnosis.

Supramolecular ensembles modified by near-infrared dyes and their biological applications.

Near-infrared dyes possess the qualities of lower interference with biological autofluorescence, low photon scattering, and deep tissue penetration, and are being increasingly involved in the development of biomaterials for sensing and precision medicine. However, dyes usually suffer from the disadvantages of poor water solubility and photobleaching, factors that limit their application in vivo. The introduction of supramolecular ensembles can provide an ideal solution. This review presents recently developed supramolecular ensembles modified by near-infrared dyes. Compared with small-molecule fluorophores, the specific size of a supramolecular-based fluorophore endows it with longer circulation time in the bloodstream, increasing its chances of reaching a specific target. In addition, the construction of supramolecule-based fluorophores with versatile functions can be achieved by simple encapsulation or doping, instead of by complicated chemical synthesis. Thus, supramolecular-complex-based fluorophores offer high potential in diagnosis and therapy. This review outlines four different species of near-infrared dye based ensembles in terms of their method of formation, including simple encapsulation or doping and copolymerisation. Recently, a new technology has employed modified fluorophores for in situ self-assembly that form supramolecular ensembles at a specific position, thus solving the problem of poor uptake of nanoparticles by cells, and is included in this review. Finally, the future of this field is considered.

2,3,6,7-Tetraamino-9,9-bis(2-ethylhexyl)fluorene: new multifunctional monomer for soluble ladder-conjugated molecules and polymers.

2,3,6,7-Tetraamino-9,9-bis(2-ethylhexyl)fluorene (TABEF), as a new multifunctional monomer for ladder-type conjugated molecules and polymers, was efficiently synthesized via a six-step procedure with an overall yield of 30%. Two isomeric ladder compounds based on TABEF building blocks were also synthesized and preliminarily studied.

Temperature-sensitive copolymer-coated fluorescent mesoporous silica nanoparticles as a reactive oxygen species activated drug delivery system.

In this study, a temperature and ROS-responsive drug delivery system ROSP@MSN based on mesoporous silica nanoparticles has been designed and synthesized by taking advantage of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate modified polymers (ROSP) as "nano-valve", which can respond selectively to cancer exclusive microenvironment and implement targeted drug release. Due to the superior temperature-sensitive properties of ROSP, ROSP@MSN could achieve cargo loading in cold water, and subsequently close the pore by raising temperature to obtain ROSP@MSN@DOX. Upon the stimulus of ROS, ROSP@MSN@DOX shows good release performance at physiological conditions. The cytotoxicity study demonstrates that the cell viability is about 80% after Hela cells are treated with ROSP@MSN at a concentration of 100 µg/mL for 24 h, exhibiting the good biocompatibility of ROSP@MSN. Furthermore, after treated with ROSP@MSN@DOX at a concentration of 100 µg/mL for 24 h, the viability of Hela cells is reduced to 40.5%; Control experiments demonstrate that, when Hela cells are pretreated with active oxygen scavenger, cell viability is about 65.3% due to the significant decrease of intracellular reactive oxygen species. Therefore, the therapeutic nanocarrier with effective encapsulation and release capacity in particular situation is a great candidate for the new drug delivery platform for targeted cancer therapy.

A dual pH and temperature responsive polymeric fluorescent sensor and its imaging application in living cells.

A polymeric fluorescent sensor PNME, consisting of A4 and N-isopropylacrylamide (NIPAM) units, was synthesized. PNME exhibited dual responses to pH and temperature, and could be used as an intracellular pH sensor for lysosomes imaging. Moreover, it also could sense different temperature change in living cells at 25 and 37 °C, respectively.