Dual pH/reduction-responsive hybrid polymeric micelles for targeted chemo-photothermal combination therapy.

The combination of chemotherapy and photothermal therapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy. Herein, we designed new pH/reduction dual-responsive and folate decorated polymeric micelles (FA Co-PMs) as theranostic nanocarrier to co-encapsulate doxorubicin (DOX) and indocyanine green (ICG) for targeted NIR imaging and chemo-photothermal combination therapy. The Co-PMs exhibited nano-sized structure (∼100 nm) with good monodispersity, high encapsulation efficiency of both ICG and DOX, triggered DOX release in response to acid pH and reduction environment, and excellent temperature conversion with laser irradiation. In vitro cellular uptake study indicated FA Co-PMs achieved significant targeting to BEL-7404 cells via folate receptor-mediated endocytosis, and laser-induced hyperthermia further enhanced drug accumulation into cancer cells. In vivo biodistribution study indicated that FA Co-PMs prolonged drug circulation and enhanced drug accumulation into the tumor via EPR effect and FA targeting. Furthermore, the ICG-based photo-triggered hyperthermia combined with DOX-based chemotherapy synergistically induced the BEL-7404 cell death and apoptosis, and efficiently suppressed the BEL-7404 xenografted tumor growth while significantly reduced systemic toxicity in vivo. Therefore, the designed dual-responsive Co-PMs were promising theranostic nanocarriers for versatile antitumor drug delivery and imaging-guided cancer chemo-photothermal combination therapy. The combination of chemotherapy and photothermal therapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy. Herein, we designed novel pH/reduction dual-responsive and folate decorated polymeric micelles (FA Co-PMs) as theranostic nanocarrier to co-encapsulate doxorubicin (DOX) and indocyanine green (ICG) for targeted NIR imaging and chemo-photothermal combination therapy. The Co-PMs triggered DOX release in response to acid pH and reduction environment and exhibited excellent temperature conversion with laser irradiation. The results indicated FA Co-PMs achieved significant targeting to BEL-7404 cells in vitro and efficiently suppressed the BEL-7404 xenografted tumor growth while significantly reduced systemic toxicity in vivo. Therefore, the designed dual-responsive Co-PMs displayed great potential in imaging-guided cancer chemo-photothermal combination therapy as theranostic nanocarriers.

Zhang L ，Qin Y ，Zhang Z ，Fan F ，Huang C ，Lu L ，Wang H ，Jin X ，Zhao H ，Kong D ，Wang C ，Sun H ，Leng X ，Zhu D ... -  《-》

Bubble-generating polymersomes loaded with both indocyanine green and doxorubicin for effective chemotherapy combined with photothermal therapy.

The combination of chemotherapy and photothermaltherapy (PTT) via stimuli-responsive nanovesicles has great potential in tumor treatment. In the present study, bubble-generating polymersomes, which can generate bubbles in response to low pH or hyperthermia, were fabricated to simultaneously encapsulate chemotherapeutic drug and photosensitizing agent for the synergistic chemo-photothermal tumor therapy. Photosensitizer indocyanine green (ICG) was encapsulated into the bilayer of polymersomes formed by amphiphilic triblock copolymer PCL8000-PEG8000-PCL8000 through thin film re-hydration method, while chemotherapeutic doxorubicin (DOX) was loaded into the hydrophilic lumen using a transmembrane ammonium bicarbonate gradient loading procedure. Under acidic condition or laser irradiation, the ammonium bicarbonate (NH4HCO3) encapsulated in the bubble-generating DOX-ICG-co-delivery polymersomes (BG-DIPS) would decompose to produce CO2 bubbles, resulting in destruction of vesicle structure and rapid drug release. In vitro drug release study confirmed that acidic environment and NIR laser irradiation could accelerate DOX release from the BG-DIPS. Cellular uptake study indicated that laser-induced hyperthermia highly enhanced endocytosis of BG-DIPS into 4T1-Luc cancer cells. In vitro cytotoxicity study demonstrated that BG-DIPS exhibited much higher cytotoxicity than free drugs under laser irradiation. In vivo biodistribution study indicated that BG-DIPS could accumulate in the tumor region, prolong drug retention, and increase photothermal conversion efficiency. Furthermore, in vivo antitumor study showed that BG-DIPS with laser irradiation efficiently inhibited 4T1-Luc tumor growth with reduced systemic toxicity. Hence, the formulated bubble-generating polymersomes system was a superior multifunctional nanocarrier for stimuli-response controlled drug delivery and combination chemo-photothermal tumor therapy. The combination of chemotherapy and photothermaltherapy via stimuli-responsive nanovesicles has great potential in tumor treatment. Herein, bubble-generating polymersomes, which can generate bubbles in response to low pH or hyperthermia, were fabricated to simultaneously encapsulate chemotherapeutic drug (DOX) and photosensitizing agent (ICG) for the synergistic chemo-photothermal tumor therapy. The results in vitro and in vivo demonstrated that bubble-generating DOX-ICG-co-delivery polymersomes (BG-DIPS) would accelerate DOX release from the BG-DIPS and accumulate in the tumor region, prolong drug retention, and increase photothermal conversion efficiency. BG-DIPS with laser irradiation could efficiently inhibited 4T1-Luc tumor growth with reduced systemic toxicity. Hence, the formulated bubble-generating polymersomes system was a superior multifunctional nanocarrier for stimuli-response controlled drug delivery and combination chemo-photothermal tumor therapy.

Zhu D ，Fan F ，Huang C ，Zhang Z ，Qin Y ，Lu L ，Wang H ，Jin X ，Zhao H ，Yang H ，Zhang C ，Yang J ，Liu Z ，Sun H ，Leng X ，Kong D ，Zhang L ... -  《-》

Near-infrared light triggered drug delivery system for higher efficacy of combined chemo-photothermal treatment.

The combination of chemotherapy and photothermal therapy is a promising strategy for cancer treatment. In the present study, indocyanine green (ICG), a widely used near-infrared (NIR) dye in photothermal therapy, and chemotherapeutic drug-doxorubicin (DOX) were loaded within the nanoparticles of novel designed arylboronic ester and cholesterol modified hyaluronic acid (PPE-Chol1-HA), denoted as PCH-DI. We take advantage of reactive oxygen species (ROS) production capability of ICG and ROS-sensitivity of arylboronic ester to realize controllable drug release. It was confirmed that PCH-DI exhibited remarkable photothermal effect and light-triggered faster release of DOX with NIR laser irradiation. DOX in PCH-DI/Laser group exhibited the most efficient nucleus binding toward HCT-116 colon cells in vitro. Furthermore, enhanced cytotoxicity and promoted tumor growth suppression effect of PCH-DI on HCT-116 tumor xenograft nude mice and AOM-induced murine orthotopic colorectal cancer model was achieved under NIR laser irradiation. Thus, the co-delivery system based on PCH appears to be a promising platform for the combined chemo-photothermal therapy in tumor treatment. In case of chemo-photothermal combination therapy, the synchronism of treatments plays an important role in achieving expected antitumor efficiency. In this study, a light triggered ROS mediated drug delivery system was developed with the help of ROS-sensitive moieties of arylboronic ester and ROS producer of ICG. We innovatively make use of the ROS production capability of ICG under NIR laser irradiation to promote a faster release of DOX resulting from swelling of PCH-DI due to the presence of arylboronic ester. Intracellular ROS detection demonstrated that ROS level of PCH-I increased under irradiation. Moreover, the faster release behavior of DOX from PCH-DI with NIR laser irradiation was confirmed by the in vitro drug release and cellular uptake study. Meanwhile, local hyperthermia was verified by photothermal effect tests. Therefore, the synchronism of the combination therapy was achieved via light triggered faster release of DOX (chemo-therapy) and local hyperthermia (thermal-therapy) using PCH-DI under irradiation. It was reasonable to attribute the efficient anti-tumor efficiency of PCH-DI both in vitro and in vivo to the enhanced synergistic effect of chemo-photothermal combination therapy with realization of synchronism. To this end, this novel co-delivery system has provided a promising solution for achieving the synchronism of treatment to strengthen the efficiency of combination therapy.

Chen Y ，Li H ，Deng Y ，Sun H ，Ke X ，Ci T ... -  《-》

NIR-Light-Triggered Anticancer Strategy for Dual-Modality Imaging-Guided Combination Therapy via a Bioinspired Hybrid PLGA Nanoplatform.

Shen X ，Li T ，Chen Z ，Xie X ，Zhang H ，Feng Y ，Li S ，Qin X ，Yang H ，Wu C ，Zheng C ，Zhu J ，You F ，Liu Y ... -  《-》

Chemotherapeutic drug-photothermal agent co-self-assembling nanoparticles for near-infrared fluorescence and photoacoustic dual-modal imaging-guided chemo-photothermal synergistic therapy.

Multimodal imaging-guided synergistic combination therapy has shown great potential for cancer treatment. However, the nanocarrier-based theranostic systems suffer from batch-to-batch variation, complexity of multicomponent, poor drug loading, and carrier-related toxicity issues. To address these issues, herein we developed a novel carrier-free theranostic system with nanoscale characteristics for near-infrared fluorescence (NIRF) and photoacoustic (PA) dual-modal imaging-guided synergistic chemo-photothermal therapy (PTT). Indocyanine green (ICG) and epirubicin (EPI) could co-self-assemble into small molecular nanoparticles (NPs) in aqueous solution without any molecular precursor or excipient via collaborative interactions (electrostatic, π-π stacking, and hydrophobic interactions). The exceptionally high dual-drug loading (∼92wt%) ICG-EPI NPs showed good physiological stability, preferable photothermal response, excellent NIRF/PA imaging properties, pH-/photo-responsive drug release behavior, and promoted cellular endocytosis compared with free ICG or EPI. Importantly, the ICG-EPI NPs showed excellent tumor targeting ability with high spatial resolution and deep penetration via in vivo NIRF/PA dual-modal imaging. Moreover, in comparison with individual chemotherapy or PTT, the combinational chemo-PTT therapy of ICG-EPI NPs with NIR laser irradiation synergistically induced apoptosis and death of cancer cells in vitro, and showed synergistic chemo-PTT efficiency in vivo as evidenced by highly efficient tumor ablation. Furthermore, the ICG-EPI NPs exhibited inappreciable toxicity. This co-self-assembly of both FDA-approved agents provides a safe and "Molecular economical" strategy in the rational design of multifunctional nano-theranostic systems for real-time self-monitoring intracellular drug delivery and targeting multimodal imaging-guided synergistic combination therapy.

Li Y ，Liu G ，Ma J ，Lin J ，Lin H ，Su G ，Chen D ，Ye S ，Chen X ，Zhu X ，Hou Z ... -  《-》