Conjugated Polymer Nanoparticles Research Articles

Near-Infrared Light-Responsive Nanoinhibitors for Tumor Suppression through Targeting and Regulating Anion Channels.

The gated state of anion channels is involved in the regulation of proliferation and migration of tumors. Specific regulators are urgently needed for efficacious cancer ablation. For this purpose, it is essential to understand the molecular mechanisms of interaction between the regulators and anion channels and apply this knowledge to regulate anion channels. Transmembrane 16A (TMEM16A) is the molecular basis of the calcium-activated chloride channels. It is an anion channel activated by Ca2+, and the inhibition of TMEM16A is associated with a decrease in tumorigenesis. Herein, we characterized a natural compound procyanidin (PC) as an efficacious and selective inhibitor of TMEM16A with an IC50 of 10.6 ± 0.6 μM. Our research revealed the precise sites (D383, R535, and E624) of electrostatic interactions between PC and TMEM16A. Near-infrared (NIR)-light-responsive photothermal conjugated polymer nanoparticles encapsulating PC (CPNs-PC) were established to remotely target and regulate the TMEM16A anion channel. Upon NIR irradiation, CPNs-PC downregulated the signaling pathway downstream of TMEM16A and arrested the cell cycle progression of cancer cells and improved the bioavailability of PC. The tumor inhibition ratio of CPNs-PC was superior to PC by 13.4%. Our findings enabled the development of a strategy to accurately and remotely regulate anion channels to promote tumor regression using NIR-light-responsive conjugated polymer nanoparticles containing specific inhibitors of TMEM16A.

Genetically Engineered Cell Membrane Modified Conjugated Polymer Nanoparticles for NIR‐II Photothermal Therapy

AbstractTumor‐selective near infrared‐induced photothermal therapy is a successful approach for ablation of malignant and cancerous cells. In the NIR region, tissue penetration depth in the near‐infrared second region (NIR‐II, 1000–1700 nm) is deeper than that of the traditional near‐infrared first region (NIR‐I, 700–900 nm) for the lower scattering and absorption. However, there are few photothermal conversion agents (PCAs) in the NIR‐II. And these PCAs are quickly identified by the immune system and rapidly cleared by the reticuloendothelial system (RES), leading to low accumulation in tumor, which prevents further advanced clinical practice. In this work, the conjugated polymer, PBTPBFTDPP, is prepared and assembled into nanoparticles (SPN). Then, the genetically engineered cell membranes are coated on the surface of SPN to obtain the positive targeting ability (SPN‐TF). The obtained SPN‐TF nanoparticles exhibit an excellent photothermal conversion ability, predominant targeting efficiency, and superb photothermal therapy for anticancer both in vitro and in vivo. These works will inspire more translational work on SPN for future clinical applications.

Unveiling the improved targeting migration of mesenchymal stem cells with CXC chemokine receptor 3-modification using intravital NIR-II photoacoustic imaging

BackgroundTherapy with genetically modified mesenchymal stem cells (MSCs) has clinical translation promise. Optimizing the targeting migratory ability of MSCs relies on accurate imaging of the distribution and extravasation kinetics of MSCs, and the corresponding imaging results could be used to predict therapeutic outcomes and guide the optimization of the treatment program. Among the different imaging modalities, second near-infrared (NIR-II) optical-resolution photoacoustic microscopy (OR-PAM) has merits, including a fine resolution, a deep penetration, a high sensitivity, and a large signal-to-background ratio. It would be an ideal candidate for precise monitoring of MSCs, although it has not been tested for this purpose so far.ResultsPenetrating peptide-decorated conjugated polymer nanoparticles (TAT-CPNPs) with strong NIR-II absorbance were used to label chemokine-receptor genetically modified MSCs, which were subsequently evaluated under intravital NIR-II OR-PAM regarding their targeting migratory ability. Based on the upregulation of chemokine (C-X-C motif) ligand 10 in the inflamed ears of contact hypersensitivity mice, MSCs with overexpression of corresponding receptor, chemokine (C-X-C motif) receptor 3 (Cxcr3) were successfully generated (MSCCxcr3). TAT-CPNPs labeling enabled NIR-II photoacoustic imaging to discern MSCCxcr3 covered by 1.2 cm of chicken breast tissue. Longitudinal OR-PAM imaging revealed enhanced inflammation-targeting migration of MSCCxcr3 over time attributed to Cxcr3 gene modification, which was further validated by histological analysis.ConclusionsTAT-CPNPs-assisted NIR-II PA imaging is promising for monitoring distribution and extravasation kinetics of MSCs, which would greatly facilitate optimizing MSC-based therapy.Graphical

Light-induced charge generation in polymeric nanoparticles restores vision in advanced-stage retinitis pigmentosa rats

Retinal dystrophies such as Retinitis pigmentosa are among the most prevalent causes of inherited legal blindness, for which treatments are in demand. Retinal prostheses have been developed to stimulate the inner retinal network that, initially spared by degeneration, deteriorates in the late stages of the disease. We recently reported that conjugated polymer nanoparticles persistently rescue visual activities after a single subretinal injection in the Royal College of Surgeons rat model of Retinitis pigmentosa. Here we demonstrate that conjugated polymer nanoparticles can reinstate physiological signals at the cortical level and visually driven activities when microinjected in 10-months-old Royal College of Surgeons rats bearing fully light-insensitive retinas. The extent of visual restoration positively correlates with the nanoparticle density and hybrid contacts with second-order retinal neurons. The results establish the functional role of organic photovoltaic nanoparticles in restoring visual activities in fully degenerate retinas with intense inner retina rewiring, a stage of the disease in which patients are subjected to prosthetic interventions.

π-Conjugated Copper Phthalocyanine Nanoparticles as Highly Sensitive Sensor for Colorimetric Detection of Biomarkers.

Though numerous nanomaterials with enzyme-like activities have been utilized as probes and sensors for detecting biological molecules, it is still challenging to construct highly sensitive detectors for biomarkers using polymeric materials. Benefiting from the π-d delocalization effect of electrons, excellent metal-chelating property, high electron transferability, and good chemical stability of π-conjugated phthalocyanine, the design of the copper phthalocyanine-based conjugated polymer nanoparticles (Cu-PcCP NPs) as a colorimetric sensor for a variety of biomarkers is reported. The Cu-PcCP NPs are synthesized through a simple microwave-assisted polymerization, and their chemical structures are thoroughly characterized. The colorimetric results of Cu-PcCP NPs demonstrate excellent peroxidase-like detecting activity and also great substrate selectivity than most of the reported Cu-based nanomaterials. The Cu-PcCP NPs can achieve a detection limit of 4.88 μM for the H2 O2 , 4.27 μM for the L-cysteine, and 21.10 μM for the glucose via a cascade catalytic system, which shows comparable detecting sensitivity as that of many earlier reported enzyme-like nanomaterials. Moreover, Cu-PcCP NPs present remarkable resistance to harsh conditions, including high temperature, low pH, and excessive salts. These highly specific π-conjugated copper-phthalocyanine nanoparticles not only overcome the current limitation of polymeric material-based sensors but also provide a new direction for designing next-generation enzyme-like nanomaterial-based colorimetric biosensors.

Polymer Nanoparticles Overcome Drug Resistance by a Dual-Targeting Apoptotic Signaling Pathway in Breast Cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activating therapy has received wide attention due to its capacity to precisely induce cancer cell apoptosis. However, drug resistance and the poor pharmacokinetic properties of TRAIL protein are obstacles in TRAIL-based therapy for cancer. Herein, a strategy is developed to remotely control and specifically initiate TRAIL-mediated apoptotic signaling to promote TRAIL-resistant cancer cell apoptosis using near-infrared (NIR) light-absorbing conjugated polymer nanoparticles (CPNs). Upon 808 nm laser excitation, the promoter 70 kilodalton heat shock protein (HSP70) initiates transcription of the TRAIL gene in response to heat shock, thereby expressing TRAIL protein in breast cancer cells, which activates the TRAIL-mediated apoptosis signaling pathway. Simultaneously, the CPNs locally release W-7, which targets calmodulin (CaM) and further promotes caspase-8 cleavage and enhances cancer cell apoptosis. Both in vitro and in vivo results demonstrate that CPNs/W-7/pTRAIL produces an excellent synergistic therapeutic effect on breast cancer upon near-infrared light with low toxicity. Therefore, this work provides a strategy for overcoming drug resistance through dual-targeting TRAIL-mediated apoptotic signaling in breast cancer.

Mild-Temperature Photothermal Effect Enhanced by Functional Conjugated Polymer Nanoparticles through Enzyme-Mediated Starvation.

Mild-temperature photothermal therapy (PTT) is being extensively explored because it causes less injury to normal cells. However, the effect of mild-temperature PTT is decreased because of heat shock protein (HSP) overexpression. To solve this problem, we designed functional conjugated polymer nanoparticles (CPNs-G) that enhance the mild-temperature photothermal effect. Upon near-infrared (NIR) light irradiation, CPNs-G generate local heat to realize the photothermal effect. Meanwhile, the increased temperature enhances the catalytic activity of GOx, thus impeding the generation of adenosine triphosphate (ATP) and inhibiting HSP expression. Therefore, this work provides a strategy for overcoming thermoresistance through an enzyme-mediated starvation effect regulated by NIR light.

Non-metallic T2-MRI agents based on conjugated polymers

Developing non-metallic contrast agents of clinically applied magnetic resonance imaging (MRI) is an alternative strategy to reduce the toxicity of heavy metal elements in current MRI agents. These non-metallic MRI agents usually generate contrasts by unpaired electrons, which are prone to be deactivated by in vivo radical scavenging pathways. Since the unpaired electrons in conjugated polymers exhibit satisfying stability for in vivo imaging, developing conjugated polymers based MRI agents may solve the in vivo stability problem of current non-metallic agents. However, MRI-active properties have not been reported in existing conjugated polymers yet. Herein we report on MRI-active conjugated polymer nanoparticles based on polypyrrole (PPy), which can be used for in vivo imaging. Our method not only introduce a kind of non-metallic MRI agents but extends the applications of conjugated polymers from optical imagings to MRI.

Conjugated Polymer Nanoparticles as a Fluorescence Probe for Amplified Detection of Human Serum Bilirubin

Conjugated Polymer Nanoparticles as a Fluorescence Probe for Amplified Detection of Human Serum Bilirubin

Potentially tunable ratiometric electrochemiluminescence sensing based on conjugated polymer nanoparticle for organophosphorus pesticides detection

In general, suitable double luminophores and their coreactants are necessary for constructing electrochemiluminescence (ECL) ratio strategy. However, the complexity of matching double luminophores and the stability and repeatability problem suffered by introducing exogenous coreactant would greatly limit the application of ratio detection. An original single-luminophore-based ECL ratio sensing was developed excluding any exogenous coreactants in this work. The poly [9,9-bis(3'-(N,N-dimethylamino)propyl)− 2,7-fluorene]-alt-2,7-(9,9-dioctylfluorene)] nanoparticles (PFN NPs) were explored to emit two anodic ECL signals. One centered at + 1.25 V (ECL-1) with the scanning potential of 0 ~ + 1.25 V and the other at + 1.95 V (ECL-2) with the scanning potential of 0 ~ + 1.95 V. ECL-1 showed a very strong emission without any exogenous coreactant. Importantly, hydrogen peroxide (H2O2) was able to efficiently weaken ECL-1 but strengthen ECL-2. When organophosphorus pesticides (OPs) were absent, the immobilized acetylcholinesterase-choline oxidase (AChE-ChOx) would catalyze the substrate acetylthiocholine chloride (ATCl) to produce H2O2, resulting in a quenched ECL-1 and an enhanced ECL-2. With the introduction of OPs, ECL-1 increased while ECL-2 accordingly decreased as OPs prohibited production of H2O2 by inhibiting activity of AChE. Highly sensitive ECL ratio detection for OPs was realized based on the change of the ratio of two signals. The dual anode emission properties of PFN NPs coupled with the opposite regulation of H2O2 on the two signals paved a new avenue for potentially tunable ECL ratio sensing strategy, and showed enormous potential applications for OPs analysis

Selective Photo-Assisted Eradication of Triple-Negative Breast Cancer Cells through Aptamer Decoration of Doped Conjugated Polymer Nanoparticles.

Photodynamic therapy (PDT) may be an excellent alternative in the treatment of breast cancer, mainly for the most aggressive type with limited targeted therapies such as triple-negative breast cancer (TNBC). We recently generated conjugated polymer nanoparticles (CPNs) as efficient photosensitizers for the photo-eradication of different cancer cells. With the aim of improving the selectivity of PDT with CPNs, the nanoparticle surface conjugation with unique 2’-Fluoropyrimidines-RNA-aptamers that act as effective recognition elements for functional surface signatures of TNBC cells was proposed and designed. A coupling reaction with carbodiimide was used to covalently bind NH2-modified aptamers with CPNs synthetized with two polystyrene-based polymer donors of COOH groups for the amide reaction. The selectivity of recognition for TNBC membrane receptors and PDT efficacy were assayed in TNBC cells and compared with non-TNBC cells by flow cytometry and cell viability assays. Furthermore, in vitro PDT efficacy was assayed in different TNBC cells with significant improvement results using CL4, sTN29 and sTN58 aptamers compared to unconjugated CPNs and SCR non-specific aptamer. In a chemoresistance TNBC cell model, sTN58 was the candidate for improving labelling and PDT efficacy with CPNs. We proposed sTN58, sTN29 and CL4 aptamers as valuable tools for selective TNBC targeting, cell internalization and therapeutic improvements for CPNs in PDT protocols.

A Perspective on Polythiophenes as Conformation Dependent Optical Reporters for Label-Free Bioanalytics.

Poly(3-alkylthiophene) (PT)-based conjugated polyelectrolytes (CPEs) constitute an important class of responsive polymers with excellent optical properties. The electrostatic interactions between PTs and target analytes trigger complexation and concomitant conformational changes of the PT backbones that produce distinct optical responses. These conformation-induced optical responses of the PTs enable them to be utilized as reporters for detection of various analytes by employing simple UV-vis spectrophotometry or the naked eye. Numerous PTs with unique pendant groups have been synthesized to tailor their interactions with analytes such as nucleotides, ions, surfactants, proteins, and bacterial and viral pathogens. In this perspective, we discuss PT-target analyte complexation for bioanalytical applications and highlight recent advancements in point-of-care and field deployable assays. Subsequently, we highlight a few areas of critical importance for future applications of PTs as reporters, including (i) design and synthesis of specific PTs to advance the understanding of the mechanisms of interaction with target analytes, (ii) using arrays of PTs and linear discriminant analysis for selective and specific detection of target analytes, (iii) translation of conventional homogeneous solution-based assays into heterogeneous membrane-based assay formats, and finally (iv) the potential of using PT as an alternative to conjugated polymer nanoparticles and dots in bioimaging.

Conjugated polymer nanoparticles and their nanohybrids as smart photoluminescent and photoresponsive material for biosensing, imaging, and theranostics.

The emergence of conjugated polymers (CPs) has provided a pathway to attain smart multifunctional conjugated polymer nanoparticles (CPNs) with enhanced properties and diverse applications. CPNs based on π-extended CPs exhibit high fluorescence brightness, low cytotoxicity, excellent photostability, reactive oxygen species (ROS) generation ability, high photothermal conversion efficiency (PCE), etc. which endorse them as an excellent theranostic tool. Furthermore, the unique light-harvesting and energy transfer properties of CPNs enables their transformation into smart functional nanohybrids with augmented performance. Owing to such numerous features, simple preparation method and an easy separation process, the CPNs and their hybrids have been constantly rising as a frontrunner in the domain of medicine and much work has been done in the respective research area. This review summarizes the recent progress that has been made in the field of CPNs for biological and biomedical applications with special emphasis on biosensing, imaging, and theranostics. Following an introduction into the field, a first large section provides overview of the conventional as well as recently established synthetic methods for various types of CPNs. Then, the CPNs-based fluorometric assays for biomolecules based on different detection strategies have been described. Later on, examples of CPNs-based probes for imaging, both in vitro and in vivo using cancer cells and animal models have been explored. The next section highlighted the vital theranostic applications of CPNs and corresponding nanohybrids, mainly via imaging-guided photodynamic therapy (PDT), photothermal therapy (PTT) and drug delivery. The last section summarizes the current challenges and gives an outlook on the potential future trends on CPNs as advanced healthcare material.

Photothermal Conjugated Polymer Nanoparticles for Suppressing Breast Tumor Growth by Regulating TRPA1 Ion Channels.

Cancer cells survive by relying on oxidative stress defense against the accumulation of reactive oxygen species (ROS) during tumor formation. ROS-sensitive TRPA1 ion channels are overexpressed in breast cancer cells and induce a large influx of Ca2+ which upregulates the anti-apoptotic pathway to lead breast cancer cells to produce oxidative stress defense and enhance the resistance to ROS related chemotherapy. Targeting and inhibiting the TRPA1 ion channels are critical for breaking down the oxidative stress defense system and overcoming cellular resistance. Here, near-infrared (NIR) light-responsive conjugated polymer nanoparticles are designed and prepared to promote apoptosis of breast cancer cells, reduce cell drug resistance and suppress tumor growth through the remote and precise regulation of TRPA1 ion channels. Upon 808nm laser irradiation, the nanoparticles block the formation of Ca2+ /CaM complex and regulate the content of MCL-1 protein. Especially, the nanoparticles overcome drug resistance of cancer cells, therefore accelerating apoptosis of cancer cells and suppressing tumor growth in mice. Compared with carboplatin, the volume of tumor induced by NPs-H decreases by 54.1%. This work provides a strategy to disrupt the oxidative stress defense system and downregulate the antiapoptotic signaling pathway in cancer cells.

Facile and wide-range size tuning of conjugated polymer nanoparticles for biomedical applications as a fluorescent probe.

Conjugated polymer nanoparticles (Pdots) are expected to be novel bioimaging and sensing probes. However, the size tuning required to control biological interactions has not been well established. Herein, we achieved a size-tunable synthesis of Pdots ranging from 30 to 200 nm by controlling the hydrolysis rate of the stabilising agent and evaluated their cellular imaging properties.

An Amplified Fluorescence Biosensor for Intracellular Telomerase Determination and in Situ Imaging Based on Thioflavin T and Conjugated Polymer Nanoparticles

An Amplified Fluorescence Biosensor for Intracellular Telomerase Determination and in Situ Imaging Based on Thioflavin T and Conjugated Polymer Nanoparticles

Cellulose mediated conjugated polymer nanoparticles with enhanced fluorescence efficiency for bioimaging

Conjugated polymers (CPs) attract a lot of attention in sensing, imaging, and biomedical applications by taking advantage of their extraordinary characteristics. However, most of them inevitably aggregate at higher concentrations, leading to attenuated fluorescence efficiency. Herein, we report a fluorescence enhancement strategy for conjugated polymers by using cellulose as a mediator. The composite nanoparticles CMC@PFE-1-NPs are prepared based on carboxymethyl cellulose (CMC) and poly(fluorene-co-phenylene ethynylene) derivative (PFE-1) via self-assembly through electrostatic and hydrophobic interactions. This spatial confinement effectively restricts π-π stacking effects and other nonradiative channels, leading to high luminescent efficiency of isolated PFE-1. A 5-fold enhancement in fluorescence quantum yield for CMC@PFE-1-NPs is obtained compared with conjugated polymers themselves. Furthermore, the nanoparticles realize more sensitive cell imaging. Therefore, this simple and effective method provides a new way for reducing the aggregation between rigid fluorescent molecules and improving their photophysical properties and biological application.

Solar-Driven Producing of Value-Added Chemicals with Organic Semiconductor-Bacteria Biohybrid System.

Photosynthetic biohybrid systems exhibit promising performance in biosynthesis; however, these systems can only produce a single metabolite and cannot further transform carbon sources into highly valuable chemical production. Herein, a photosynthetic biohybrid system integrating biological and chemical cascade synthesis was developed for solar-driven conversion of glucose to value-added chemicals. A new ternary cooperative biohybrid system, namely bacterial factory, was constructed by self-assembling of enzyme-modified light-harvesting donor-acceptor conjugated polymer nanoparticles (D-A CPNs) and genetically engineered Escherichia coli (E. coli). The D-A CPNs coating on E. coli could effectively generate electrons under light irradiation, which were transferred into E. coli to promote the 37% increment of threonine production by increasing the ratio of nicotinamide adenine dinucleotide phosphate (NADPH). Subsequently, the metabolized threonine was catalyzed by threonine deaminase covalently linking with D-A CPNs to obtain 2-oxobutyrate, which is an important precursor of drugs and chemicals. The 2-oxobutyrate yield under light irradiation is increased by 58% in comparison to that in dark. This work provides a new organic semiconductor-microorganism photosynthetic biohybrid system for biological and chemical cascade synthesis of highly valuable chemicals by taking advantage of renewable carbon sources and solar energy.

Nearly monodispersed, emission-tuneable conjugated polymer nanoparticles

We describe the synthesis of monodispersed, silica encapsulated conjugated polymer nanoparticles, their colour tunability and use in imaging HeLa cells.

Miniemulsion polymerization-formulated poly(fluorene-alt-6-(2-ethylhexyl)-[1,2,5]thiadiazole[3,4-f]benzotriazole) for cancer cell imaging

Near-infrared (NIR) conjugated polymer nanoparticles (CPNPs) possesses advantages for bioimaging because of their merits in low autofluorescence interference, good biocompatibility, large light extinction coefficient, improved photostability, and facile functionalization capability. Different from conventional post-polymerization methods for fabricating NIR CPNPs, like nanoprecipitation, emulsion and solvent evaporation/miniemulsion, and self-assembly, herein, an efficient one-pot strategy by in-situ miniemulsion polymerization is demonstrated to synthesize CPNPs for NIR fluorescence imaging of cancer cells. Via adjusting the donor-acceptor strength, the new CP, poly(fluorene-alt-6-(2-ethylhexyl)-[1,2,5]thiadiazole[3,4-f]benzotriazole) (PFTA), show absorption and emission maximum at 648 nm and 730 nm, respectively, which is much more red-shifted than its counterpart, poly(fluorene-alt-benzo-2,1,3-thiadiazole) (PFBT). DFT calculation demonstrates that the repeating unit of PFTA has a smaller dihedral angel to 33.2° and much reduced energy gap to 2.46 eV, as compared to that of PFBT NPs. Importantly, through controlling surfactant concentrations from 40 g·L−1 to 2.5 g·L−1 during the miniemulsion polymerization, the particles size can be accordingly changed from even 88 to 210 nm. Furthermore, the particles show extinction coefficient of 2.82 × 104 M−1·cm−1at 648 nm, photoluminescence quantum yields c.a. 2.4% and fluorescence lifetime c.a. 1.26 ns, respectively. Moreover, the PFTA NPs exhibit biocompatibility, good colloidal stability and bright fluorescence signals to clearly pinpoint breast cancer cells, with a trend that smaller NP size, higher cellular uptake. This work demonstrates the promise of miniemulsion polymerization as a facile method to fabricate NIR CPNPs for bioimaging.