Semiconducting polymer nanotheranostics for NIR-II/Photoacoustic imaging-guided photothermal initiated nitric oxide/photothermal therapy.

Gasotransmitters with their cytotoxicity in high concentration have become the focus of attention. For such concentration depended therapy, how to effectively deliver gases and precisely control gases release to the lesion as well as combine them with other therapy to achieve precise therapeutics is still a big challenge. Herein, we realize single near-infrared (NIR) laser-initiated nitric oxide (NO) therapy/photothermal therapy (PTT) using semiconducting polymer nanoparticles (SPNs, PFTDPP) combing s-nitrosothiol groups (the NO donor, SNAP). By the good photothermal conversion effect of SPNs, NIR laser energy can be spatio-temporally controlled to convert into heat to decompose s-nitrosothiol. Meanwhile, considering the accompanied PTT produced by photothermal, we can easily and precisely conduct a dual therapy (NO therapy/PTT) under single NIR laser irradiation. Additionally, semiconducting polymer with its structural modifiability and spectral adjustability can provide a second NIR window & photoacoustic (NIR II/PA) imaging for guiding photothermal initiated NO/photothermal therapy. PFTDPP showed a high photothermal conversion efficiency of 48% and good dual-mode imaging signals (NIR-II/photoacoustic). Cellular test illustrated that NO combined photothermal presented more prominent cytotoxicity than any one of them individually. As the tumor pinpointed in vivo by dual-mode imaging (NIR II/PA), this nanotheranostics provided a tumor inhibition of 77%. Consequently, such phototheranostics produced a new design thought for effectively deliver and precisely controlled release of drugs for oncology. And also, it expanded the application range of gasotransmitters combined therapy that shall have a promising application foreground.

Hyaluronic Acid Nanoparticles Based on a Conjugated Oligomer Photosensitizer: Target-Specific Two-Photon Imaging, Redox-Sensitive Drug Delivery, and Synergistic Chemo-Photodynamic Therapy.

Self-assembled hyaluronic acid (HA) nanoparticles have been extensively investigated as anticancer therapeutic agents due to the biocompatibility, biodegradability, and active targeting characteristics of HA. However, many HA nanoparticles are restricted to the applications in drug delivery for chemotherapy or lack effective imaging agents. Hence, we developed the camptothecin (CPT)-loaded HA-SS-BFVPBT nanoparticles (HSBNPs) as a multifunctional platform for two-photon imaging and synergistic chemo-photodynamic therapy at the same time. A novel conjugated oligomer photosensitizer, BFVPBT, which was conjugated onto HA through the redox-responsive disulfide linkage (SS), could not only provide a hydrophobic domain for the formation of nanoparticles and drug entrapment but also act as a two-photon photosensitizer that can be directly excited and simultaneously used in two-photon imaging and photodynamic therapy (PDT). HeLa cells overexpressing the HA receptor (CD44) were used for in vitro studies, which proved the specific cellular uptake of CPT-loaded HSBNPs and excellent two-photon PDT/chemotherapy synergistic effect. The nanoparticles have also been shown to realize tumor-targeting in vivo imaging in HeLa-tumor-bearing mice. Moreover, the fluorescence of CPT-loaded HSBNPs could be activated due to the degradation by the reductive glutathione (GSH) and overexpressed hyaluronidases (Hyal-1) in cancer cells, and the intracellular drug release rate was quickened, thus improving the probability of precise cancer diagnosis and therapy. Accordingly, this HSBNPs system is also anticipated to be a precise nanocarrier for other imaging and therapeutic agents besides CPT, offering a promising new avenue for imaging-guided efficient cancer therapy.

A perylene diimide zwitterionic polymer for photoacoustic imaging guided photothermal/photodynamic synergistic therapy with single near-infrared irradiation.

Phototherapy has great promise for precise cancer diagnosis and effective therapy, but the development of one multifunctional nanoplatform for synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) at a single excitation wavelength remains a challenge. In this work, a perylene diimide zwitterionic polymer PDS-PDI was synthesized via atom transfer radical polymerization (ATRP). This polymer was designed for photoacoustic imaging (PAI) guided synergistic PDT and PTT with single 660 nm near-infrared (NIR) light irradiation. The prepared PDS-PDI polymer presents high photothermal conversion efficiency (η≈ 40%) and efficient singlet oxygen quantum yield (ΦΔ≈ 16.7%) under 660 nm laser irradiation. Polymer PDS-PDI also acts as a contrast agent for PAI, offering real-time monitoring in tumor sites. Additionally, in vitro and in vivo assays indicate that polymer PDS-PDI has good biocompatibility and effective tumor destruction ability under 660 nm laser irradiation. In brief, polymer PDS-PDI prepared in this study could be applied as a dual-mode phototherapeutic agent under single laser irradiation.

Conjugated Polymer Brush Based on Poly(l-lysine) with Efficient Ovalbumin Delivery for Dendritic Cell Vaccine.

Dendritic cell (DC)-based vaccines consist of antigens and antigen-presenting cells, such as DCs, that can induce antitumor immune response and extend the lives of patients. In this research, a water-soluble conjugated polymer brush (WSCPB) made of poly(l-lysine) (PLL) and poly(p-phenyleneethynylene) (PPE) was applied to an antigen delivery system for the development of a DC vaccine. We synthesized the WSCPB with a lower proportion of the rigid PPE polymer backbone and a large amount of PLL side chains. The rigid backbone retained a stable optical performance within the experimental range, which enabled the visualization of the payload and cellular imaging as a reporter. Because of the unique brushlike structure, PPE-PLL exhibited not only excellent water solubility but also outstanding antigen-loading capacity. Ovalbumin (OVA), a model antigen in different research, could be adsorbed onto PPE-PLL and then taken up by DCs. Subsequently, DC maturation and cytokine release would be induced by the antigen. In vivo, strong immune responses were induced after the injection of antigen-pulsed DCs, and the level of cytokines in the serum was significantly increased. In addition, the study of the in vivo tumor-suppressor activity of these antigen-pulsed DCs revealed that the DC vaccine induced strong immune responses and thereby effectively inhibited tumor development.

Inner salt-shaped small molecular photosensitizer with extremely enhanced two-photon absorption for mitochondrial-targeted photodynamic therapy.

Herein, we experimentally and theoretically demonstrate an unprecedentedly enhanced two-photon absorption in a small organic molecule by a simple introduction of an inner salt-shaped structure. Moreover, such an inner salt-shaped small molecule also exhibits superior singlet oxygen quantum yield and fascinating structure-inherent mitochondrial-targeting ability for highly efficient two-photon photodynamic therapy via a mitochondrial apoptosis pathway.

Engineering Lysosome-Targeting BODIPY Nanoparticles for Photoacoustic Imaging and Photodynamic Therapy under Near-Infrared Light.

Developing lysosome-targeting organic nanoparticles combined with photoacoustic imaging (PAI) and photodynamic therapy (PDT) functions toward personalized medicine are highly desired yet challenging. Here, for the first time, lysosome-targeting BODIPY nanoparticles were engineered by encapsulating near-infrared (NIR) absorbed BODIPY dye within amphiphilic DSPE-mPEG5000 for high-performing lysosomal PAI and acid-activatable PDT against cancer cells under NIR light.

Cationic Conjugated Polymer/Hyaluronan-Doxorubicin Complex for Sensitive Fluorescence Detection of Hyaluronidase and Tumor-Targeting Drug Delivery and Imaging.

Hyaluronidase (HAase) is becoming a new type of tumor marker since it has been demonstrated to be overexpressed in various kinds of cancer cells. In this study, we described a novel fluorescence method for sensitive, rapid, and convenient HAase detection and tumor-targeting drug delivery and imaging, using a probe prepared by electrostatic assembly of a cationic conjugated polymer (CCP) and anionic hyaluronan (HA) conjugated with the anticancer drug doxorubicin (Dox). The CCP we used was poly{[9,9-bis(6'-(N,N,N-diethylmethylammonium)hexyl)-2,7-fluorenylene ethynylene]-alt-co-[2,5-bis(3'-(N,N,N-diethylmethylammonium)-1'-oxapropyl)-1,4-phenylene]} tetraiodide (PFEP). HA is a natural mucopolysaccharide that can be hydrolyzed by HAase into fragments with low molecular weights. In the PFEP/HA-Dox complex, the fluorescence of PFEP was efficiently quenched due to electron transfer from PFEP to Dox. After the PFEP/HA-Dox complex was exposed to HAase or was taken up by cancer cells through the specific binding between HA and CD44 receptor, HA was degraded by HAase to release the Dox, leading to the recovery of PFEP fluorescence to the "turn-on" state. Moreover, the degree of fluorescence recovery was quantitatively correlated with the concentrations of HAase. Compared with many previously reported methods, our work did not require laborious multiple modifications of HA that may affect the activity of HAase. This point, combined with the excellent optoelectronic property of conjugated polymer, endowed this method with high sensitivity (detection limit: 0.075 U/mL), high specificity, and rapid response, making it applicable for reliable and routine detection of HAase. This fluorescent probe was successfully utilized to detect HAase levels in human urine samples; furthermore, it can also be employed as a multifunctional system by realizing tumor-targeting drug delivery and cell imaging simultaneously. The development of this fluorescence method showed promising potential for early tumor diagnosis and therapy based on HAase detection.

Cationic conjugated polymer/fluoresceinamine-hyaluronan complex for sensitive fluorescence detection of CD44 and tumor-targeted cell imaging.

Simple, rapid, and sensitive detection of CD44 is of paramount importance since it plays pivotal roles in tumor initiation, growth and metastasis. Herein, we describe a novel method for sensitive, visual and facile fluorescence detection of CD44 and CD44-mediated cancer cell imaging, using a probe based on cationic conjugated polymer (CCP)-PFEP and fluoresceinamine-hyaluronan (FA-HA). HA is an anionic natural glycosaminoglycan that can specifically bind to the overexpressed CD44 on various kinds of cancer cells. PFEP and FA-HA formed a complex through electronic interactions, resulting in a highly efficient fluorescence resonance energy transfer (FRET) from PFEP to FA-HA; moreover, the efficiencies of FRET correlated with the concentrations of CD44 because the specific binding of HA-CD44 would separate FA-HA away from PFEP. This method did not require laborious and expensive dual-labeling or protein-labeling needed in previously reported detection methods of CD44. Just mix the sample and test solution containing the PFEP/FA-HA complex, and the results allowed naked-eye detection by observing fluorescent color of solutions with the assistance of a UV lamp. Most importantly, the use of a conjugated polymer with excellent amplification property as well as the specific binding of HA-CD44 endowed this method with high sensitivity and specificity, making it applicable for reliable quantitative detection of CD44. Furthermore, the PFEP/FA-HA complex formed nanoparticles in aqueous solution, and the nanoparticles can be selectively taken up by MCF-7 cells (cancer cell) through the HA-CD44 interaction, thereby giving rise to a dual-color tumor-targeted imaging probe with good photostability. The development of this fluorescent probe showed promising potential to make a reliable and routine method available for early diagnosis of cancer.

Monodispersed grafted conjugated polyelectrolyte-stabilized magnetic nanoparticles as multifunctional platform for cellular imaging and drug delivery.

An anionic grafted conjugated polyelectrolyte was synthesized, and then magnetic nanoparticles stabilized with this material were successfully prepared by a convenient method and used for bioimaging and drug delivery. Grafted conjugated polymer (PFPAA) containing abundant carboxyl groups was attached to the surface of Fe3O4 nanoparticles through ligand exchange with oleic acid and anionic grafted conjugated polyelectrolyte-stabilized magnetic nanoparticles (MNPs@PFPANa) were then obtained by ionization with sodium carbonate. These as-synthesized nanoparticles showed good water solubility and stability, with no precipitation observed in 8 months, and had a narrow size distribution with a mean hydrodynamic diameter of 26 ± 2.4 nm. In addition, these nanoparticles exhibited superparamagnetic properties with a saturation magnetization (Ms) of 20 emu g-1, which sufficient for bioapplications. Upon 48 h incubation with macrophage cells, the obtained nanoparticles showed good biocompatibility of 2 pg Fe per cell as measured by ICP-OES. Furthermore, MNPs@PFPANa were low toxicity as confirmed by an MTT assay using NIH-3T3 fibroblasts. Confocal microscopy results revealed that MNPs@PFPANa can be retained in cytoplasm with high fluorescence. MNPs@PFPANa exhibited good DOX drug loading efficiency of about 10 wt% and showed good therapeutic efficiency for BGC-823 cancer cells. These results indicated such multifunctional nanoparticles would be useful in bioimaging and as drug carriers for cancer treatment.

Monodispersed brush-like conjugated polyelectrolyte nanoparticles with efficient and visualized siRNA delivery for gene silencing.

RNA interference is supposed to be one of the most powerful technologies for suppression of genes and treatment of diverse human diseases while the safe delivery and visualization of siRNA were still challenging. In this text, a novel type of monodispersed conjugated polymer nanoparticles PFNBr with brush-like molecular structure was introduced into siRNA delivery system. The nanoparticles exhibited dual functions conveniently in the delivery system which can not only carry high amount of siRNA to penetrate intracellularly for knocking down targeted mRNA but also act as signal agents for siRNA tracking and cellular imaging. Due to the high density side chains with positive charges and more extended conformation of the spatial structure, PFNBr nanoparticles as nanocarrier for siRNA provided outstanding capture ability (1 mol polymer to more than 32.5 mol siRNA) and enhanced protection capability of siRNA molecules from degradation. Here, it should be noted that the concentration of carrier in the working platform was lowered from the level of µmol/L to nmol/L compared with other conjugated polymer delivery systems due to the outstanding carrying capacity of PFNBr. And meanwhile, this system acquired high gene silence efficiency and good biocompatibility. The proposed complex nanoparticles efficiently transfected siPlk1 into PANC-1 cells and induced high knockdown efficiency for targeted Plk1 mRNA to 23.9% and no significant cytotoxicity of the PFNBr/siRNA complexes was shown. Therefore, this working platform provides a solution to most of the common problems associated with the siRNA delivery, visualization, and therapeutic applications, and keeps a bright outlook for the development of new nucleic acid-based therapeutics and simultaneously for fluorescent bioimaging.

Water-soluble conjugated polyelectrolyte brush encapsulated rare-earth ion doped nanoparticles with dual-upconversion properties for multicolor cell imaging.

A concise route to prepare water-soluble rare-earth ion doped upconversion nanoparticles (UCNPs) by encapsulation of grafted cationic conjugated polyelectrolyte brushes (PFNBr) is reported. Integrating two kinds of upconversion materials effectively addresses multicolor fluorescence by introducing the concept of dual-upconversion.