A versatile drug-controlled release polymer brush hybrid non-glutaraldehyde bioprosthetic heart valves with enhanced anti-inflammatory, anticoagulant and anti-calcification properties, and superior mechanical performance.

Transcatheter heart valve replacement (THVR) is a novel treatment modality for severe heart valves diseases and has become the main method for the treatment of heart valve diseases in recent years. However, the lifespan of the commercial glutaraldehyde cross-linked bioprosthetic heart valves (BHVs) used in THVR can only serve for 10-15 years, and the essential reason for the failure of the valve leaflet material is due to these problems such as calcification, coagulation, and inflammation caused by glutaraldehyde cross-linking. Herein, a kind of novel non-glutaraldehyde cross-linking agent bromo-bicyclic-oxazolidine (OX-Br) has been designed and synthesized with both crosslinking ability and in-situ atom transfer radical polymerization (ATRP) function. Then OX-Br treated porcine pericardium (OX-Br-PP) are stepwise modified with co-polymer brushes of reactive oxygen species (ROS) response anti-inflammatory drug conjugated block and anti-adhesion polyzwitterion polymer block through the in-situ ATRP reaction to obtain the functional BHV material MPQ@OX-PP. Along with the great mechanical properties and anti-enzymatic degradation ability similar to glutaraldehyde-crosslinked porcine pericardium (Glut-PP), good biocompatibility, improved anti-inflammatory effect, robust anti-coagulant ability and superior anti-calcification property have been verified for MPQ@OX-PP by a series of in vitro and in vivo investigations, indicating the excellent application potential as a multifunctional heart valve cross-linking agent for OX-Br. Meanwhile, the strategy of synergistic effect with in situ generations of reactive oxygen species-responsive anti-inflammatory drug blocks and anti-adhesion polymer brushes can effectively meet the requirement of multifaceted performance of bioprosthetic heart valves and provide a valuable reference for other blood contacting materials and functional implantable materials with great comprehensive performance.

A versatile modification strategy for functional non-glutaraldehyde cross-linked bioprosthetic heart valves with enhanced anticoagulant, anticalcification and endothelialization properties.

Valvular heart disease is a major threat to human health and transcatheter heart valve replacement (THVR) has emerged as the primary treatment option for severe heart valve disease. Bioprosthetic heart valves (BHVs) with superior hemodynamic performance and compressibility have become the first choice for THVR, and more BHVs have been requested for clinical use in recent years. However, several drawbacks remain for the commercial BHVs cross-linked by glutaraldehyde, including calcification, thrombin, poor biocompatibility and difficulty in endothelialization, which would further reduce the BHVs' lifetime. This study developed a dual-functional non-glutaraldehyde crosslinking reagent OX-VI, which can provide BHV materials with reactive double bonds (CC) for further bio-function modification in addition to the crosslinking function. BHV material PBAF@OX-PP was developed from OX-VI treated porcine pericardium (PP) after the polymerization with 4-vinylbenzene boronic acid and the subsequent modification of poly (vinyl alcohol) and fucoidan. Based on the functional anti-coagulation and endothelialization strategy and dual-functional crosslinking reagent, PBAF@OX-PP has better anti-coagulation and anti-calcification properties, higher biocompatibility, and improved endothelial cells proliferation when compared to Glut-treated PP, as well as the satisfactory mechanical properties and enhanced resistance effect to enzymatic degradation, making it a promising candidate in the clinical application of BHVs. STATEMENT OF SIGNIFICANCE: Transcatheter heart valve replacement (THVR) has become the main solution for severe valvular heart disease. However, bioprosthetic heart valves (BHVs) used in THVR exhibit fatal drawbacks such as calcification, thrombin and difficulty for endothelialization, which are due to the glutaraldehyde crosslinking, resulting in a limited lifetime to 10-15 years. A new non-glutaraldehyde cross-linker OX-VI has been designed, which can not only show great crosslinking ability but also offer the BHVs with reactive double bonds (CC) for further bio-function modification. Based on the dual-functional crosslinking reagent OX-VI, a versatile modification strategy was developed and the BHV material (PBAF@OX-PP) has been developed and shows significantly enhanced anticoagulant, anti-calcification and endothelialization properties, making it a promising candidate in the clinical application of BHVs.

A universal strategy for the construction of polymer brush hybrid non-glutaraldehyde heart valves with robust anti-biological contamination performance and improved endothelialization potential.

With the intensification of the aging population and the development of transcatheter heart valve replacement technology (THVR), clinical demand for bioprosthetic valves is increasing rapidly. However, commercial bioprosthetic heart valves (BHVs), mainly manufactured from glutaraldehyde cross-linked porcine or bovine pericardium, generally undergo degeneration within 10-15 years due to calcification, thrombosis and poor biocompatibility, which are closely related to glutaraldehyde cross-linking. In addition, endocarditis caused by post-implantation bacterial infection also accelerates the failure of BHVs. Herein, a functional cross-linking agent bromo bicyclic-oxazolidine (OX-Br) has been designed and synthesized to crosslink BHVs and construct a bio-functionalization scaffold for subsequent in-situ atom transfer radical polymerization (ATRP). The porcine pericardium cross-linked by OX-Br (OX-PP) exhibits better biocompatibility and anti-calcification property than the glutaraldehyde-treated porcine pericardium (Glut-PP) as well as comparable physical and structural stability to Glut-PP. Furthermore, the resistance to biological contamination especially bacterial infection of OX-PP along with anti-thrombus and endothelialization need to be enhanced to reduce the risk of implantation failure due to infection. Therefore, amphiphilic polymer brush is grafted to OX-PP through in-situ ATRP polymerization to prepare polymer brush hybrid BHV material SA@OX-PP. SA@OX-PP has been demonstrated to significantly resist biological contamination including plasma proteins, bacteria, platelets, thrombus and calcium, and facilitate the proliferation of endothelial cells, resulting in reduced risk of thrombosis, calcification and endocarditis. Altogether, the proposed crosslinking and functionalization strategy synergistically achieves the improvement of stability, endothelialization potential, anti-calcification and anti-biofouling performances for BHVs, which would resist the degeneration and prolong the lifespan of BHVs. The facile and practical strategy has great potential for clinical application in fabricating functional polymer hybrid BHVs or other tissue-based cardiac biomaterials. STATEMENT OF SIGNIFICANCE: Bioprosthetic heart valves (BHVs) are widely used in valve replacements for severe heart valve disease, and clinical demand is increasing year over year. Unfortunately, the commercial BHVs, mainly cross-linked by glutaraldehyde, can serve for only 10-15 years because of calcification, thrombus, biological contamination, and difficulties in endothelialization. Many studies have been conducted to explore non-glutaraldehyde crosslinkers, but few can meet high requirements in all aspects. A new crosslinker, OX-Br, has been developed for BHVs. It can not only crosslink BHVs but also serve as a reactive site for in-situ ATRP polymerization and construct a bio-functionalization platform for subsequent modification. The proposed crosslinking and functionalization strategy synergistically achieves the high requirements for stability, biocompability, endothelialization, anti-calcification, and anti-biofouling propeties of BHVs.

A lipid droplet specific fluorescent probe for image-guided photodynamic therapy under hypoxia.

Photodynamic therapy (PDT) is a potential strategy for many superficial, esophageal, intestinal, and bronchial cancer treatments, but its therapeutic effect is limited by a lack of specificity and the hypoxic tumor environment. It is necessary to develop novel photosensitizers (Ps) with organelles targeting and the ability to generate cytotoxic species under light irradiation without the presence of oxygen. Herein, we designed and synthesized a biocompatible fluorescent Ps CPNBD for lipid droplets (LDs) fluorescence (FL) image-guided PDT. CPNBD showed FL quenching in water but FL was significantly turned on by oil with a remarkable FL enhancement compared to that in aqueous solution. Due to its strong lipophilicity (Clog P of 7.96), CPNBD could specifically stain the LDs of human clear cell renal cell carcinoma (ccRCC) tumor cells and tissues with good photostability. Meanwhile, CPNBD could efficiently generate cytotoxic reactive oxygen species under low-power white-light irradiation, which could efficiently damage DNA via a PDT process with great tumor suppression ability in vitro and in vivo. Thus, this work provides a novel strategy for designing LD-targeting Ps with efficient image-guided PDT under the tumor hypoxic environment.

pH and singlet oxygen dual-responsive GEM prodrug micelles for efficient combination therapy of chemotherapy and photodynamic therapy.

Nanocarriers have been an important strategy for enhancing the combination therapy of chemotherapy and photodynamic therapy (PDT) (Chem-PDT). However, conventional nanocarriers suffer from the problems of drug leakage in blood and insufficient drug release at target sites. Herein, we have designed a chlorin e6 (Ce6)-loaded GEM prodrug polymer micelle with a singlet oxygen cleavable linker and a pH responsive switch to avoid drug leakage in blood. These Ce6-loaded prodrug micelles possessed a uniform size distribution with a particle size of 78 nm. Meanwhile, the release of Ce6 and GEM was well controlled by acidic pH and laser irradiation. In addition, these micelles showed great acid triggered particle size shrinkage and charge-conversion properties, promoting micelle penetration at tumors and cellular uptake of micelles, which were confirmed by using CLSM of in vitro cell spheres and flow cytometry. Moreover, the in vitro and in vivo1O2 generation ability and antitumor ability of these micelles were impressive. This novel nanocarrier is a potential candidate for efficient Chem-PDT therapy.

Multi-stimuli responsive polymeric prodrug micelles for combined chemotherapy and photodynamic therapy.

Nowadays, cancer therapy faces severe challenges regarding boosting therapeutic efficiency and reducing the side effects of drugs. To overcome these challenges, herein multifunctional polymeric prodrug micelles combining chemotherapy and photodynamic therapy are put forward; the multifunctional polymeric prodrug micelles are prepared through self-assembly of amphipathic copolymer and photosensitizer Chlorin e6 (Ce6). These therapeutic prodrug micelles have better intracellular uptake and deeper tumor infiltration through charge reversal and smaller size changes, respectively. The polymeric prodrug micelles have fast disassembly and release Ce6 in the case of cathepsin B existence in the lysosome. Under light irradiation at 660 nm, Ce6 can efficiently generate singlet oxygen and accelerate the release of gemcitabine (GEM) by destroying the bis-(alkylthio) alkene functional group, which is the singlet-oxygen responsive linker, to achieve the combination of chemotherapy and photodynamic therapy (PDT). Under light irradiation at 660 nm, the singlet oxygen can also efficiently destroy mitochondrial functions to activate mitochondria apoptosis pathways, including increased reactive oxygen species (ROS) levels and swollen mitochondria. Further, employing 4T1-bearing BALB/c mice as a model, the anticancer effect of the therapeutic prodrug micelles is systematically investigated in vivo. The therapeutic prodrug micelles show an efficient tumor growth inhibition in vivo after light irradiation. Meanwhile, therapeutic prodrug micelles can significantly reduce adverse effects compared with the free drug, exhibiting better biocompatibility. Therefore, this prodrug micelle with a triple sensitivity response and synergistic chemo-photodynamic therapy functions is expected to offer promising applications in efficient antitumor therapy.

Integrated prodrug micelles with two-photon bioimaging and pH-triggered drug delivery for cancer theranostics.

Nanodrug carriers with fluorescence radiation are widely used in cancer diagnosis and therapy due to their real-time imaging, less side effect, better drug utilization as well as the good bioimaging ability. However, traditional nanocarriers still suffer from unexpectable drug leakage, unsatisfactory tumor-targeted drug delivery and shallow imaging depth, which limit their further application in cancer theranostics. In this study, an integrated nanoplatform is constructed by polymeric prodrug micelles with two-photon and aggregation-induced emission bioimaging, charge reversal and drug delivery triggered by acidic pH. The prodrug micelles can be self-assembled by the TP-PEI (DA/DOX)-PEG prodrug polymer, which consists of the two-photon fluorophore (TP), dimethylmaleic anhydride (DA) grafted polyethyleneimine (PEI) and polyethylene glycol (PEG). The PEG segment, DOX and DA are bridged to polymer by acid cleavable bonds, which provides the micelles a 'stealth' property and a satisfactory stability during blood circulation, while the outside PEG segment is abandoned along with the DA protection in the tumor acidic microenvironment, thus leading to charge reversal-mediated accelerated endocytosis and tumor-targeted drug delivery. The great antitumor efficacy and reduced side effect of these pH-sensitive prodrug micelles are confirmed by antitumor assays in vitro and in vivo. Meanwhile, these micelles exhibited great deep-tissue two-photon bioimaging ability up to 150 µm in depth. The great antitumor efficacy, reduced side effect and deep two-photon tissue imaging make the TP-PEI (DA/DOX)-PEG prodrug micelles would be an efficient strategy for theranostic nanoplatform in cancer treatment.

Hierarchical Responsive Nanoplatform with Two-Photon Aggregation-Induced Emission Imaging for Efficient Cancer Theranostics.

Theranostic nanoplatforms haev been proven to be a feasible strategy against cancer for convenient diagnosis, efficient drug release, and reduced side effects. However, the drug leakage during blood circulation, poor cellular uptake of drug-loaded nanoparticles, and insufficient drug release still remain to be overcome. Herein, a hierarchical pH and reactive oxygen species (ROS)-responsive nanoplatform is constructed labeling with a two-photon fluorophore developed by us, aiming for a programmed drug delivery and an intensive two-photon bioimaging. With the capecitabine (Cap) conjugated, the prodrug polymer PMPC-b-P[MPA(Cap)-co-TPMA]-PAEMA (PMMTAb-Cap) can be self-assembled into the core-shell structured micelles, which can stay stable in the blood stream. Once the micelles accumulate at the tumor tissue, the outside PMPC shell can be desquamated while the inner PAEMA become hydrophilic and electropositive under the acidic extracellular tumor microenvironment, leading to a shrunken micellar size for the better penetration along with enhanced endocytosis. After cellular internalization, the overexpressed intracellular ROS can eventually trigger the drug delivery for an accurate tumor therapy, which is confirmed by the in vivo antitumor experiments. Furthermore, the in vivo micellar biodistribution can be traced by a deep tissue imaging up to 150 µm because of the aggregation-induced emission active two-photon fluorophore. As a theranostic nanoplatform with two-photon bioimaging and hierarchical responsiveness, these PMMTAb-Cap micelles can be a potential candidate for tumor theranostical applications.

Two-photon AIE luminogen labeled multifunctional polymeric micelles for theranostics.

Intelligent polymeric micelles with fluorescence imaging feature have been emerged as promising tools for theranostics. However, conventional fluorescent dyes are limited by short wavelength excitation, interference of tissue autofluorescence, limited imaging depth and quenched emission in aggregation state. Methods: We synthesized a novel mPEG-SS-Poly (AEMA-co-TBIS) (mPEATss) copolymer to develop multifunctional polymeric micelles with great AIE feature for cancer therapy and AIE active two-photon bioimaging. The stimuli-responsive behavior and AIE active two-photon cell and tissue imaging as well as in vitro and in vivo antitumor ability of DOX-loaded mPEATss were studied. Results: mPEATss micelles showed excellent AIE active two-photon cell imaging ability and deep tissue imaging ability. Antitumor drug DOX could be encapsulated to form a drug-loaded micellar system with a small diameter of 65 nm. The disassembly and charge-conversion of mPEATss micelles could be triggered by acidic environment, resulting in accelerated drug release and great antitumor efficacy. In vivo, ex vivo imaging and in vivo pharmacokinetic study demonstrated that mPEATss micelles could efficiently accumulate in tumor sites, which ensured ideal anticancer effect. Conclusions: This pH and redox dual responsive and AIE active two-photon imaging polymeric micelles would be a promising candidate for theranostics.

Dual-Responsive Micelles with Aggregation-Induced Emission Feature and Two-Photon Aborsption for Accurate Drug Delivery and Bioimaging.

Intelligent polymeric micelles provide great potential for accurate cancer theranostics. Herein, gemcitabine (GEM)-conjugated redox-responsive prodrug micelles based on a pH-responsive charge-conventional PMPC-b-P (DEMA-co-SS-GEM-co-TPMA) copolymer and a two-photon absorbing aggregation-induced emission (AIE) fluorescence probe have been developed for lysosome-targeted drug release and bioimaging. The multifunctional copolymer has been synthesized via RAFT polymerization, and GEM is conjugated to the copolymer via GSH-cleavable disulfide bonds. These GEM-conjugated micelles exhibit great pH responsiveness at pH 5.0, while being stable at pH 6.0. GSH-triggered drug release can be observed with the GSH concentration increased from 0 to 10 mM. Moreover, the high-quality AIE-active two-photon imaging is confirmed by cell and deep-tissue imaging. More importantly, the distribution of these nanocarriers can be traced because of the AIE feature of the micelles. Along with good in vitro and in vivo tumor-suppression ability and significantly reduced side effects, this smart two-photon AIE micelle would be a potential candidate for cancer diagnosis and therapy.

Multifunctional Two-Photon AIE Luminogens for Highly Mitochondria-Specific Bioimaging and Efficient Photodynamic Therapy.

In recent years, photodynamic therapy (PDT) has drawn much attention as a noninvasive and safe cancer therapy method due to its fine controllability, good selectivity, low systemic toxicity, and minimal drug resistance in contrast to the conventional methods (for example, chemotherapy, radiotherapy, and surgery). However, some drawbacks still remain for the current organic photosensitizers such as low singlet oxygen (1O2) quantum yield, poor photostability, inability of absorption in the near-infrared (NIR) region, short excitation wavelength, and limited action radius of singlet oxygen, which will strongly limit the PDT treatment efficiency. As a consequence, the development of efficient photosensitizers with high singlet oxygen quantum yield, strong fluorescent emission in the aggregated state, excellent photostability, NIR excitation wavelength ranging in the biological transparency window, and highly specific targeting to mitochondria is still in great demand for the enhancement of PDT treatment efficiency. In this study, two new two-photon AIEgens TPPM and TTPM based on a rigid D-π-A skeleton have been designed and synthesized. Both AIEgens TPPM and TTPM show strong aggregation-induced emission (AIE) with the emission enhancement up to 290-folds, large two-photon absorption with the two-photon absorption cross section up to 477 MG, and highly specific targeting to mitochondria in living cells with good biocompatibility. They can serve as two-photon bioprobes for the cell and deep tissue bioimaging with a penetration depth up to 150 µm. Furthermore, high 1O2 generation efficiency with high 1O2 quantum yield under white light irradiation has been found for both TPPM and TTPM and high PDT efficiency to HeLa cells under white light irradiation has also been proven. To the best of our knowledge, AIEgens in this work constitute one of the strongest emission enhancements and one of the highest 1O2 generation efficiencies in the reported organic AIEgens so far. The great AIE feature, large two-photon absorption, high specificity to mitochondria in living cells, and high PDT efficiency to living cells as well as excellent photostability and biocompatibility of these novel AIEgens TPPM and TTPM reveal great potential in clinical applications of two-photon cell and tissue bioimaging and image-guided and mitochondria-targeted photodynamic cancer therapy.

Oxidation-Responsive and Aggregation-Induced Emission Polymeric Micelles with Two-Photon Excitation for Cancer Therapy and Bioimaging.

Polymeric micelles with stimuli-triggered drug release and AIE active bioimaging have emerged as potential candidates for theranostics. Herein, a curcumin (Cur) loaded oxidation-responsive mPEG-b-PLG (Se)-TP polymeric micelle system with great aggregation-induced emission (AIE) active and two-photon imaging property has been developed for simultaneous antitumor treatment and bioimaging. Cur-loaded polymeric micelles with a core-shell structure and a homogeneous size of 136 nm show great physiological stability while rapidly disassemble under oxidation environment with accelerated drug release. The excellent biocompatibility and great AIE property and two-photon excitation endow these functional mPEG-b-PLG (Se)-TP micelles as bioprobes for the two-photon imaging of cells and deeper tissues. Furthermore, the biodistribution of nanocarriers and intracellular drug delivery can also be traced. Moreover, the Cur-loaded micelles also show great tumor inhibition ability and minimal side effects in vivo compared with free drug. These novel polymeric micelles are expected to be potential candidates for cancer theranostics.

Dual-Responsive Doxorubicin-Conjugated Polymeric Micelles with Aggregation-Induced Emission Active Bioimaging and Charge Conversion for Cancer Therapy.

In recent years, intelligent polymeric micelles with multifunctions are in urgent demand for cancer diagnosis and therapy. Herein, pH and redox dual-responsive prodrug micelles with aggregation-induced emission (AIE) active cellular imaging and charge conversion have been prepared for combined chemotherapy and bioimaging based on a novel doxorubicin-conjugated amphiphilic PMPC-PAEMA-P (TPE- co-HD)-ss-P (TPE- co-HD)-PAEMA-PMPC copolymer. The doxorubicin is conjugated via a pH cleavable imine linkage and can be packed in the hydrophobic core along with the glutathione (GSH)-sensitive disulfide bond. The DOX-conjugated inner core is sealed with a pH-responsive PAEMA as the "gate", which would rapidly open in the acidic condition, following the drug release and charge conversion-mediated acceleration of endocytosis. After an efficient internalization, the disulfide bond can be cleaved by the high concentration of GSH causing the further accelerated drug release. Meanwhile, intracellular drug delivery can be traced due to the AIE behavior of micelles. Moreover, great tumor inhibition in vitro and in vivo has been demonstrated for these DOX-conjugated micelles. This smart prodrug micelle system would be a desirable drug carrier for cancer therapy and bioimaging.

Redox and pH Dual-Responsive Polymeric Micelles with Aggregation-Induced Emission Feature for Cellular Imaging and Chemotherapy.

Intelligent polymeric micelles for antitumor drug delivery and tumor bioimaging have drawn a broad attention because of their reduced systemic toxicity, enhanced efficacy of drugs, and potential application of tumor diagnosis. Herein, we developed a multifunctional polymeric micelle system based on a pH and redox dual-responsive mPEG-P(TPE- co-AEMA) copolymer for stimuli-triggered drug release and aggregation-induced emission (AIE) active imaging. These mPEG-P(TPE- co-AEMA)-based micelles showed excellent biocompatibility and emission property, exhibiting great potential application for cellular imaging. Furthermore, the antitumor drug doxorubicin (DOX) could be encapsulated during self-assembly process with high loading efficiency, and a DOX-loaded micelle system with a size of 68.2 nm and narrow size distribution could be obtained. DOX-loaded micelles demonstrated great tumor suppression ability in vitro, and the dual-responsive triggered intracellular drug release could be further traced. Moreover, DOX-loaded micelles could efficiently accumulate at the tumor site because of enhanced permeability and retention effect and long circulation of micelles. Compared with free DOX, DOX-loaded micelles exhibited better antitumor effect and significantly reduced adverse effects. Given the efficient accumulation targeting to tumor tissue, dual-responsive drug release, and excellent AIE property, this polymeric micelle would be a potential candidate for cancer therapy and diagnosis.

Redox-Responsive Biomimetic Polymeric Micelle for Simultaneous Anticancer Drug Delivery and Aggregation-Induced Emission Active Imaging.

Intelligent polymeric micelles have been developed as potential nanoplatforms for efficient drug delivery and diagnosis. Herein, we successfully prepared redox-sensitive polymeric micelles combined aggregation-induced emission (AIE) imaging as an outstanding anticancer drug carrier system for simultaneous chemotherapy and bioimaging. The amphiphilic copolymer TPE-SS-PLAsp- b-PMPC could self-assemble into spherical micelles, and these biomimetic micelles exhibited great biocompatibility and remarkable ability in antiprotein adsorption, showing great potential for biomedical application. Anticancer drug doxorubicin (DOX) could be encapsulated during the self-assembly process, and these drug-loaded micelles showed intelligent drug release and improved antitumor efficacy due to the quick disassembly in response to high levels of glutathione (GSH) in the environment. Moreover, the intracellular DOX release could be traced through the fluorescent imaging of these AIE micelles. As expected, the in vivo antitumor study exhibited that these DOX-carried micelles showed better antitumor efficacy and less adverse effects than that of free DOX. These results strongly indicated that this smart biomimetic micelle system would be a prominent candidate for chemotherapy and bioimaging.

Micelles prepared from poly(N-isopropylacrylamide-co-tetraphenylethene acrylate)-b-poly[oligo(ethylene glycol) methacrylate] double hydrophilic block copolymer as hydrophilic drug carrier.

Self-assembled micelles obtained from a double hydrophilic block copolymer (DHBC) based on poly(N-isopropylacrylamide) (PNIPAAm) are a facile and green strategy compared to the conventional solvent exchange method. However, hydrophobic drug encapsulation in micelles from PNIPAAm-based DHBC has relatively low drug loading (DL) and encapsulation efficiency (EE). Intermolecular and intramolecular hydrogen bondings of PNIPAAm chains are formed to exclude hydrophobic drugs. Nevertheless, hydrogen bonding can be used for hydrophilic drug delivery. Therefore, we report micelles prepared from a poly(N-isopropylacrylamide-co-tetraphenylethene acrylate)-b-poly[oligo(ethylene glycol) methacrylate] [P(NIPAAm-co-TPE)-b-POEGMA] double hydrophilic block copolymer as a hydrophilic drug (thymopentin, TP5) carrier. The FTIR results confirm hydrogen bond formation between PNIPAAm chain and TP5. Micelles are obtained by simply increasing the temperature above the critical micelle temperature (CMT). The self-assembly behaviour of polymeric micelles is investigated by DLS, TEM and aggregation-induced emission (AIE) phenomenon. Cytotoxicity results indicate that the micelles are biocompatible. The in vitro prolonged drug release (from 6 min to several hours) and in vivo immunity enhancement indicate that the micelles formed by P(NIPAAm-co-TPE)-b-POEGMA DHBC are promising candidates as hydrophilic drug carriers, where hydrogen bonding is formed between PNIPAAm and drug.

Redox-Sensitive Polymeric Micelles Based on Tetraphenylethylene-Conjugated Copolymer for Aggregation-Induced Emission Active Imaging and Drug Delivery.

Intelligent nanocarriers for efficient drug delivery and bioimaging application are urgently demand. Herein, paclitaxel (PTX)-encapsulated redox-sensitive polymeric micelles based on tetraphenylethylene (TPE)-conjugated poly(D, L-lactide)-disulfide-poly(methacryloyloxyethyl phosphorylcholine) (TPE-PLA-SS-PMPC) copolymer has been developed for combined cancer therapy and aggregation induced emission (AIE) imaging. These biomimetic TPE-PLA-SS-PMPC micelles exhibit great biocompatibility and remarkable AIE features, showing great potential for bioimaging applications. PTX is loaded during the self-assembly process, and these drug-loaded micelles can disassemble quickly in the medium containing 10 mM glutathione to trigger rapid drug release and great growth inhibition of tumor cells. Moreover, these micelles can also be traced via fluorescent imaging of these AIE micelles. AIE active imaging and tumor cell growth inhibition, as well as excellent biocompatibility make these smart biomimetic micelles highly attractive as a prominent candidate for chemotherapy and bioimaging.

Unparalleled Ease of Access to a Library of Biheteroaryl Fluorophores via Oxidative Cross-Coupling Reactions: Discovery of Photostable NIR Probe for Mitochondria.

The development of straightforward accesses to organic functional materials through C-H activation is a revolutionary trend in organic synthesis. In this article, we propose a concise strategy to construct a large library of donor-acceptor-type biheteroaryl fluorophores via the palladium-catalyzed oxidative C-H/C-H cross-coupling of electron-deficient 2H-indazoles with electron-rich heteroarenes. The directly coupled biheteroaryl fluorophores, named Indazo-Fluors, exhibit continuously tunable full-color emissions with quantum yields up to 93% and large Stokes shifts up to 8705 cm(-1) in CH2Cl2. By further fine-tuning of the substituent on the core skeleton, Indazo-Fluor 3l (FW = 274; λem = 725 nm) is obtained as the lowest molecular weight near-infrared (NIR) fluorophore with emission wavelength over 720 nm in the solid state. The NIR dye 5h specifically lights up mitochondria in living cells with bright red luminescence. Typically, commercially available mitochondria trackers suffer from poor photostability. Indazo-Fluor 5h exhibits superior photostability and very low cytotoxicity, which would be a prominent reagent for in vivo mitochondria imaging.