Nano-delivery vehicle based on chlorin E6, photodynamic therapy, doxorubicin chemotherapy provides targeted treatment of HER-2 negative, ανβ3-positive breast cancer.

The prognosis for patients with HER-2 negative breast cancer is currently poor, largely due to the lack of efficacious targeted therapeutics. Photodynamic nanomaterial technologies have rapidly developed in recent years, but their anti-tumor effects are often limited by poor targeting, low transformation efficiency, toxicity, and other factors. Thus, we prepared a new type of nanoparticles (Ce6/Dox@NPs-cRGD, CDNR) with cyclo(Arg-Gly-Asp-d-Phe-Cys) (c(RGDfC)) that target the ανβ3 receptor. We loaded those nanoparticles (NPs) with a combination of the doxorubicin (Dox) and photosensitizer chlorin E6 (Ce6) to test synergy between chemotherapy and photodynamic therapy (PDT) for the treatment of ανβ3 receptor positive and HER-2 negative breast cancer. Through analysis of the Fourier transform infrared and UV-vis spectra of these NPs, we found that Ce6 and Dox were successfully loaded into the CDNR. According to dynamic light scattering (DLS) analyses, CDNR particles had a diameter of 112.6 nm (polydispersity index 0.11), which was also confirmed via TEM characterization. The zeta potential was about -21.5 mV. Stability studies showed that CDNR particle size was stable in ddH2O, PBS, and DMEM + 5 % FBS for 16 days. The drug loading content of Dox and Ce6 were 5.3 and 6.8 %, respectively. Release studies of CDNR showed that the slow release of Dox was accelerated with increasing GSH concentration, and there was no burst release effect. From studying the absorbance of 9,10-dimethylanthrancene (ABDA), we found that CDNR produces high levels of ROS after excitation with a 670 nm laser, and ROS production increased with increasing radiation time. CDNR was significantly taken up by MCF-7 cells at 6 h because of cRGD targeting. In a CCK8 test, the relative growth rate (RGR) of CDNR +670 nm laser for MCF-7 cells was less than 75 % at 20 μg/mL after 24 h treatment and 15 μg/mL after 48 h treatment. We found that CDNR's effects on RGR were concentration dependent. Live-cell staining with a DCFH-DA kit and flow cytometry assay further supported that a CDNR +670 nm laser provided the maximum chemotherapy-PDT toxicity and production of intracellular ROS, and that cell death was mainly caused by necrosis and apoptosis. In vivo experiments showed that using the cRGD-targeting strategy, CDNR had a stronger affinity and increased half-life relative to Ce6/Dox@NPs in mice with MCF-7 xenograft tumors. Further, the Cmax of CDNR in the transplanted tumor occurred 8 h post-injection (HPI) and there was still detectable signal at 24 HPI. In addition, MCF-7 bearing mice that were treated with CDNR +670 nm PDT at 8 HPI had a significantly decreased tumor volume (P < 0.05) and prolonged survival time compared to other groups. Thus, CDNR plus 670 nm PDT was associated with favorable anti-tumor activity with no appreciable impact on body weight or the major organs in mice, as determined by immunohistochemistry/immunofluorescence and hematoxylin-eosin staining. In conclusion, CDNR with 670 nm laser irradiation represents a promising new potential treatment paradigm for the management of breast cancers that are ανβ3-receptor positive and HER-2 negative.

He Z ，Jiang H ，Zhang X ，Zhang H ，Cui Z ，Sun L ，Li H ，Qian J ，Ma J ，Huang J ... -  《-》

A Redox-Activatable and Targeted Photosensitizing Agent to Deliver Doxorubicin for Combining Chemotherapy and Photodynamic Therapy.

Yin J ，Ouyang C ，Shen S ，Zhou Y ，He G ，Zhang H ，Zhou K ，Chen G ，Ren L ... -  《-》

Dual-effect liposomes encapsulated with doxorubicin and chlorin e6 augment the therapeutic effect of tumor treatment.

Long circulating doxorubicin (Dox)-loaded PEGylated liposomes are clinically safer than the free form due to the significant reduction of cardiac toxicity. However, the therapeutic efficacy of the PEGylated liposome could further be improved if poor diffusivity and slow drug release of the liposome in tumor interstitium can be overcome. In this study, a dual-effect liposome triggered by photodynamic effect was developed to improve the therapeutic efficacy of Dox-loaded PEGylated liposomes. Dox and chlorin e6 (Ce6) were co-encapsulated in PEGylated liposomes (named as PL-Dox-Ce6). To induce the drug release, photodynamic effect was triggered by the light irradiation of a 662 nm diode laser. The cellular distribution of Dox and Ce6 was examined under confocal microscope. The in vitro and in vivo cytotoxicity of PL-Dox-Ce6 was determined via the colony formation assay and the synergistic C26 tumor model, respectively. The cellular distribution of PL-Dox-Ce6 was in the cytoplasmic area; while under light irradiation, Dox was co-localized with nuclear staining positive signals. The cellular cytotoxicity of PL-Dox-Ce6 was significantly higher than the controls including liposomes encapsulating either Dox (PL-Dox) or Ce6 (PL-Ce6). The in vivo treatment efficacy of PL-Dox-Ce6 determined in the C26 tumor model reveals a significant therapeutic effect compared to that of PL-Ce6 and PL-Dox alone or in combination. This study indicates that this dual-effect PEGylated liposome could provide clinical advantages in the combination regimen of photodynamic therapy and chemotherapy.

Peng PC ，Hong RL ，Tsai YJ ，Li PT ，Tsai T ，Chen CT ... -  《-》

Self-Amplified pH/ROS Dual-Responsive Co-Delivery Nano-System with Chemo-Photodynamic Combination Therapy in Hepatic Carcinoma Treatment.

Huang Y ，Wu S ，Li J ，He C ，Cheng Y ，Li N ，Wang Y ，Wu Y ，Zhang J ... -  《International Journal of Nanomedicine》

Folic acid-modified bovine serum albumin nanoparticles with doxorubicin and chlorin e6 for effective combinational chemo-photodynamic therapy.

We herein describe a facile method to synthesize stable bovine serum albumin-based nanoparticles (BNPs) loaded with two anticancer therapeutics, doxorubicin (DOX) and a photosensitizer, chlorin e6 (Ce6), in combination with folic acid (FA) as a target cancer cell receptor for the development of an effective combined chemo and photodynamic (FA-Ce6/DOX/BNPs) therapy against cervical cancer. FA-Ce6/DOX/BNPs exhibited excellent monodispersity with an average diameter of 103.5 ± 3.8 nm, a negative zeta potential of approximately -30.44 ± 0.35 mV, and long-term stability. As a result, FA-Ce6/DOX/BNPs exhibited severe toxicity to cervical HeLa cancer cells. Also, a higher drug release rate was observed under acidic pH conditions (pH 5.0). Moreover, FA-Ce6/DOX/BNPs potentiated mitochondrial reactive oxygen species (ROS) production in HeLa cells under 671-nm laser exposure, leading to activation of key regulator proteins of apoptosis such as BH3 interacting-domain death agonist (BID), B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X (BAX), as well as induction of the caspase cascade and mitochondrial ROS-mediated cell death. Confocal microscopy analysis further validated cellular uptake of FA-Ce6/DOX/BNPs by HeLa cells. Furthermore, results of real-time quantitative PCR (RT-qPCR) and western blot analysis further validated the anticancer effect of FA-Ce6/DOX/BNPs, as evidenced by elevated gene/protein expression levels of apoptotic biomarkers p53, BID, caspase-3, cleaved poly(ADP-ribose) polymerase 1 (PARP-1), and BAX, contrary to levels of the anti-apoptotic marker Bcl-2. Moreover, in vivo toxicity results of FA-Ce6/DOX/BNPs using laser irradiation in zebrafish larvae, as a chemo-photodynamic therapy confirmed that it does not affect the larval development without causing any adverse toxic effect in zebrafish larvae. Altogether these findings strongly support the anticancer effect of FA-Ce6/DOX/BNPs combinational chemo-photodynamic therapy, which could be a promising candidate for cervical cancer therapy.

Lee H ，Kim S ，Oh C ，Khan I ，Shukla S ，Bajpai VK ，Han YK ，Huh YS ... -  《-》