Conjugated Polymeric Materials in Biological Imaging and Cancer Therapy.

Conjugated polymers (CPs) have attracted much attention in the fields of chemistry, medicine, life science, and material science. Researchers have carried out a series of innovative researches and have made significant research progress regarding the unique photochemical and photophysical properties of CPs, expanding the application range of polymers. CPs are polymers formed by the conjugation of multiple repeating light-emitting units. Through precise control of their structure, functional molecules with different properties can be obtained. Fluorescence probes with different absorption and emission wavelengths can be obtained by changing the main chain structure. By modifying the side chain structure with water-soluble groups or selective recognition molecules, electrostatic interaction or specific binding with specific targets can be achieved; subsequently, the purpose of selective recognition can be achieved. This article reviews the research work of CPs in cell imaging, tumor diagnosis, and treatment in recent years, summarizes the latest progress in the application of CPs in imaging, tumor diagnosis, and treatment, and discusses the future development direction of CPs in cell imaging, tumor diagnosis, and treatment.

Incorporation of Porphyrin to π-Conjugated Backbone for Polymer-Dot-Sensitized Photodynamic Therapy.

The photosensitizers used in photodynamic therapy are mainly based on porphyrin derivatives. However, clinical applications encounter several limitations regarding photosensitizers such as their low absorption coefficients, poor water-solubility, and leaching from delivery carriers. Here, we describe covalent incorporation of porphyrin in conjugated polymer backbone for development of efficient polymer-dot photosensitizer. Spectroscopic characterizations revealed that the light-harvesting polymer dominantly transfer the excitation energy to the porphyrin unit, yielding efficient singlet oxygen generation for photodynamic therapy. The polymer dots (Pdots) also possess excellent stability that overcomes the photosensitizer leaching problem as encountered in other nanoparticle carriers. In vitro cytotoxicity and photodynamic efficacy of the Pdots were evaluated in MCF-7 cells by in vitro assay, indicating that the Pdots can efficiently damage cancer cells. In vivo photodynamic therapy by using the Pdots was further investigated with xenograft tumors in Balb/c nude mice, which show that the tumors were significantly inhibited or eradicated in certain cases. The high-yield singlet oxygen generation and excellent stability of porphyrin-incorporated Pdots are promising for photodynamic treatment of malignant tumors.

H2O2-triggered controllable carbon monoxide delivery for photothermally augmented gas therapy.

Carbon monoxide (CO) gas therapy has shown great potential as a very promising approach in the ongoing fight against tumors. However, delivering unstable CO to the tumor site and safely releasing it for maximum efficacy still have unsatisfactory outcomes. In this study, we've developed nanotheranostics (IN-DPPCO NPs) based on conjugated polymer IN-DPP and carbon monoxide (CO) carrier polymer mPEG(CO) for photothermal augmented gas therapy. The IN-DPPCO NPs can release CO with the hydrogen peroxide (H2O2) overexpressed in the tumor microenvironment. Meanwhile, IN-DPPCO NPs exhibit strong absorption in the near-infrared window, showing a high photothermal conversion efficiency of up to 41.5% under 808 nm laser irradiation. In vitro and in vivo experiments demonstrate that these nanotheranostics exhibit good biocompatibility. Furthermore, the synergistic CO/photothermal therapy shows enhanced therapeutic efficacy compared to gas therapy alone. This work highlights the great promise of conjugated polymer nanoparticles as versatile nanocarriers for spatiotemporally controlled and on-demand delivery of gaseous messengers to achieve precision cancer theranostics.

NIR-II Absorbing Conjugated Polymer Nanotheranostics for Thermal Initiated NO Enhanced Photothermal Therapy.

Photothermal therapy (PTT) has received constant attention as a promising cancer treatment. However, PTT-induced inflammation can limit its effectiveness. To address this shortcoming, we developed second near-infrared (NIR-II) light-activated nanotheranostics (CPNPBs), which include a thermosensitive nitric oxide (NO) donor (BNN6) to enhance PTT. Under a 1064 nm laser irradiation, the conjugated polymer in CPNPBs serves as a photothermal agent for photothermal conversion, and the generated heat triggers the decomposition of BNN6 to release NO. The combination of hyperthermia and NO generation under single NIR-II laser irradiation allows enhanced thermal ablation of tumors. Consequently, CPNPBs can be exploited as potential candidates for NO-enhanced PTT, holding great promise for their clinical translational development.

Sodium fluoride activates the extrinsic apoptosis via regulating NOX4/ROS-mediated p53/DR5 signaling pathway in lung cells both in vitro and in vivo.

An extensive body of research has demonstrated that pulmonary toxicity induced by fluoride is related to cell apoptosis. Although induction of death receptor-initiated extrinsic apoptosis by sodium fluoride (NaF) has been reported, its mechanism of action is still not clearly defined. Herein, we found that NaF treatment induced activation of caspase-8 in BEAS-2B cells, resulting in apoptosis, which was markedly reduced by blocking caspase-8 using small interfering RNA (siRNA). In this study, we report that death receptor 5 (DR5), a major component of the extrinsic apoptotic pathway, is markedly induced upon NaF stimulation. Enhanced DR5 induction was necessary for the apoptotic effects of NaF, inasmuch as transfected BEAS-2B cells with DR5 siRNA attenuated NaF-induced caspase-8 activation in lung cells. Mechanism investigation indicated that the induction of DR5, following NaF exposure, was mediated by tumor protein 53 (p53)-dependent transcriptional activation. Notably, we demonstrated that NaF could induce a significant increase in intracellular reactive oxygen species (ROS) level derived from nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). Specifically, NOX4 knockdown inhibited NaF-induced the activation of p53/DR5 axis by reducing NOX4-derived ROS production. Further in vivo investigation demonstrated that NOX4 deficiency markedly attenuates NaF-induced lung injury, apoptosis, and ROS levels in the lung. Moreover, the expressions of p53 and DR5 were significantly reduced after NaF treatment in NOX4 knockout mice compared with the wild type mice. Taken together, our findings provide a novel insight into for the pulmonary apoptosis in response to NaF exposure.

Engineering biocompatible benzodithiophene-based polymer dots with tunable absorptions as high-efficiency theranostic agents for multiscale photoacoustic imaging-guided photothermal therapy.

To date, photoacoustic imaging (PAI) and PAI-guided photothermal therapy (PTT) have been performed for noninvasive cancer diagnosis and precise ablation of tumors. To conduct concurrent PAI and PTT, it is essential to develop theranostic agents with strong optical absorption and high photothermal transfer efficiency. In this study, we have engineered theranostic agents with tunable absorptions based on conjugated polymer dots (Pdots) with different structures via the simple precipitation method. The as-synthesized Pdots exhibit strong absorption, high biocompatibility, and superior stability. In addition, the Pdots demonstrate that they can serve as contrast agents for multiscale PAI in vitro and in vivo. More importantly, a high photothermal conversion efficiency up to 40% is reached under irradiation with LED light, resulting in effective cancer treatment with extremely low light dose. Consequently, they show the potential as imaging-guided therapeutic agents for clinical cancer treatment and various biomedical applications.

Highly Stable Conjugated Polymer Dots as Multifunctional Agents for Photoacoustic Imaging-Guided Photothermal Therapy.

Theranostic nanomedicines involved in photothermal therapy (PTT) have received constant attention as promising alternatives to traditional therapies in clinic. However, most photothermal agents are limited by their instability and low photothermal conversion efficiency. In this study, we report new conjugated polymer dots (Pdots) as multifunctional agents for photoacoustic (PA) imaging-guided PTT. The novel 4,8-bis[5-(2-ethylhexyl)thiophen-2-yl]-2,6-bis(trimethylstannyl)benzo[1,2-b:4,5-b']dithiophene-6,6'-dibromo-N,N'-(2-ethylhexyl)isoindigo (BDT-IID) Pdots are readily fabricated though nanoreprecipitation and can absorb strongly in the 650-700 nm region. Furthermore, the BDT-IID Pdots possess a stable nanostructure and an extremely low biotoxicity. In particular, its photothermal conversion efficiency can be up to 45%. More importantly, our in vivo results exhibit that the BDT-IID Pdots are able to offer concurrently enhanced PA contrast and sufficient photothermal effect. Consequently, the BDT-IID Pdots can be exploited as a unique theranostic nanoplatform for PA imaging-guided PTT of tumors, holding great promise for their clinical translational development.

Photo-Cross-Linkable Polymer Dots with Stable Sensitizer Loading and Amplified Singlet Oxygen Generation for Photodynamic Therapy.

Photodynamic therapy (PDT) is a promising treatment modality for clinical cancer therapy. However, the therapeutic effect of PDT is strongly dependent on the property of photosensitizer. Here, we developed photo-cross-linkable semiconductor polymer dots doped with photosensitizer Chlorin e6 (Ce6) to construct a nanoparticle platform for photodynamic therapy. Photoreactive oxetane groups were attached to the side chains of the semiconductor polymer. After photo-cross-linking reaction, the Ce6-doped Pdots formed an interpenetrated structure to prevent Ce6 leaching out from the Pdot matrix. Spectroscopic characterizations revealed an efficient energy transfer from the polymer to Ce6 molecules, resulting in amplified generation of singlet oxygen. We evaluated the cellular uptake, cytotoxicity, and photodynamic effect of the Pdots in gastric adenocarcinoma cells. In vitro photodynamic experiments indicated that the Ce6-doped Pdots (∼10 µg/mL) effectively killed the cancer cells under low dose of light irradiation (∼60 J/cm2). Furthermore, in vivo photodynamic experiments were carried out in tumor-bearing nude mice, which indicated that the Pdot photosensitizer apparently suppressed the growth of solid tumors. Our results demonstrate that the photo-cross-linkable Pdots doped with photosensitizer are promising for photodynamic cancer treatment.