Folate-targeted polymersomes loaded with both paclitaxel and doxorubicin for the combination chemotherapy of hepatocellular carcinoma.

Combination chemotherapy is a promising method of improving cancer treatment, but the distinct pharmacokinetics of combined drugs and non-specific drug distribution slow down the development in the clinic. In this study, folate (FA) receptor-targeted polymersomes with apparent bilayered lamellar structure were successfully developed to co-encapsulate a hydrophobic-hydrophilic chemotherapeutic drug pair (PTX and DOX) in a single vesicle for enhancing the combination chemotherapeutic effect. Hydrophobic PTX was loaded into the thick hydrophobic lamellar membrane by the self-assembly of triblock copolymer PCL8000-PEG8000-PCL8000, while hydrophilic DOX was encapsulated into the hydrophilic reservoir using a trans-membrane ammonium sulfate gradient method. In vitro release study indicated that the drugs were released from the polymersomes in a controlled and sustained manner. Cellular uptake study indicated that FA-targeted Co-PS had higher internalization efficiency in FA receptor-overexpressing BEL-7404 cells than non-targeted Co-PS. In vitro cytotoxicity assay demonstrated that FA-targeted Co-PS exhibited less cytotoxic effect than free drug cocktail, but suppressed the growth of tumor cells more efficiently than non-targeted Co-PS. Ex vivo imaging biodistribution studies revealed that FA-targeted Co-PS led to highly efficient targeting and accumulation in the BEL-7404 xenograft tumor. Furthermore, the in vivo antitumor study showed that the combination chemotherapy of polymersomes to BEL-7404 tumor via intravenous injection was superior to free drug cocktail treatment, and the FA-targeted Co-PS exhibited significantly higher tumor growth inhibition than non-targeted Co-PS group. Therefore, the newly developed FA-targeted co-delivery polymersomes hold great promise for simultaneous delivery of multiple chemotherapeutics and would have great potential in tumor-targeting and combination chemotherapy. Combination chemotherapy is a promising method of improving cancer treatment, but the distinct pharmacokinetics of combined drugs and non-specific drug distribution slow down the development in the clinic. In our study, novel folate-targeted co-delivery polymersomes (Co-PS) were successfully developed to encapsulate a hydrophobic-hydrophilic chemotherapeutic drug pair (paclitaxel and doxorubicin) into the different compartments of the vesicle. In vivo studies revealed that the combination chemotherapy of polymersomes to BEL-7404 xenograft tumor via intravenous injection was superior to free drug cocktail treatment, and the FA-targeted Co-PS exhibited significantly higher tumor growth inhibition than non-targeted Co-PS group. Therefore, the newly developed FA-targeted co-delivery polymersomes hold great promise for simultaneous delivery of multiple chemotherapeutics and would have great potential in tumor-targeting and combination chemotherapy.

Zhu D ，Wu S ，Hu C ，Chen Z ，Wang H ，Fan F ，Qin Y ，Wang C ，Sun H ，Leng X ，Kong D ，Zhang L ... -  《-》

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 ... -  《-》

Construction of a biodegradable, versatile nanocarrier for optional combination cancer therapy.

A novel biodegradable versatile nanocarrier (FA-CM) was fabricated based on the self-assembly of delaminated CoAl-layered double hydroxides (LDHs) and manganese dioxide (MnO2) for optional combination cancer therapy. Biodegradation, versatility, targeting, bioimaging, in vitro cytotoxicity and in vivo antitumor efficacy were evaluated. The results showed that FA-CM could not only be effectively degraded into Co2+, Al3+ and Mn2+ to overcome the long-term toxic side effects, but also successfully load any positive-charged, negative-charged, hydrophilic, and hydrophobic drug, meeting the critical requirement of versatile nanocarrier. Meanwhile, the presence of FA led to the higher uptake efficiency, cytotoxicity, and excellent fluorescence imaging of FA-CM toward cancerous cells. In particular, FA-CM exhibited glutathione and pH dual-response drug release, avoiding any premature leakage and side effects. The applicability of the FA-CM was determined by co-loading hydrophilic (doxorubicin (DOX)) and hydrophobic drug (paclitaxel (PTX)) for synergistic combination chemotherapy. In vitro cytotoxicity evaluation and a xenograft tumor model of hepatoma showed that this combination exhibited more efficient anticancer effects compared with either free drug alone or the corresponding cocktail solutions. Especially, the ratios of DOX and PTX loaded on FA-CM could be tuned as needed. A powerful approach is provided for the design and preparation of a biodegradable versatile nanocarrier with targeted ability and excellent biocompatibility, which can be potentially applied in clinical practice and medical imaging. STATEMENT OF SIGNIFICANCE: Drug delivery nanocarriers that can transport an effective dosage of drug molecules to targeted cells and tissues have been extensively designed to overcome the adverse side effects and low effectiveness of conventional chemotherapy. However, lack of biodegradability and versatility existing in majority of nanocarriers limit their further clinical applications. Thus, constructing a novel biodegradable versatile nanocarrier that can carry various types of drugs, is in urgent need and more suitable for commercial production and clinical use. In this study, we developed a novel biodegradable versatile nanocarrier (FA-CM) based on the self-assembly of delaminated CoAl-layered double hydroxides (LDHs) and manganese dioxide (MnO2) for optional combination cancer therapy. This work provides a new strategy for constructing versatile biodegradable platform for targeted drug delivery, which would have broad applications in cancer theranostics.

Wen J ，Lv Y ，Xu Y ，Zhang P ，Li H ，Chen X ，Li X ，Zhang L ，Liu F ，Zeng W ，Sun S ... -  《-》

Synergistic antitumor effect of folate-targeted Pluronic™ F-127/poly(lactic acid) polymersomes for codelivery of doxorubicin and paclitaxel.

Wu TY ，Li ZL ，Gong YC ，Xiong XY ... -  《-》

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 ... -  《-》