The leading cause of death among cancer patients is tumor metastasis. Tumor-derived exosomes are emerging as mediators of metastasis. In the present study, we demonstrated that exosomes play a pivotal role in the metastatic progression of colorectal cancer. First, a nude mouse model of colorectal cancer liver metastasis was established and characterized. Then, we demonstrated that exosomes from a highly liver metastatic colorectal cancer cell line (HT-29) could significantly increase the metastatic tumor burden and distribution in the mouse liver of Caco-2 colorectal cancer cells, which ordinarily exhibit poor liver metastatic potential. We further investigated the mechanisms by which HT-29-derived-exosomes influence the liver metastasis of colorectal cancer and found that mice treated with HT-29-derived exosomes had a relatively higher level of CXCR4 in the metastatic microenvironment, indicating that exosomes may promote colorectal cancer metastasis by recruiting CXCR4-expressing stromal cells to develop a permissive metastatic microenvironment. Finally, the migration of Caco-2 cells was significantly increased following treatment with HT-29-derived exosomes in vitro, further supporting a role for exosomes in modulating colorectal tumor-derived liver metastasis. The data from the present study may facilitate further translational medicine research into the prevention and treatment of colorectal cancer liver metastasis.
The application of nano drug delivery systems (NDDSs) may enhance the effectiveness of chemotherapeutic drugs in vivo. However, the short blood circulation time and poor drug release profile in vivo are still two problems with them. Herein, by using red blood cell membrane (RBCm) wrapping and pH sensitive technology, we prepared RBCm wrapped pH sensitive poly(l-γ-glutamylcarbocistein)-paclitaxel (PGSC-PTX) nanoparticles (PGSC-PTX@RBCm NPs), to prolong the circulation time in blood and release PTX timely and adequately in acidic tumor environment. The PGSC-PTX NPs and PGSC-PTX@RBCm NPs showed spherical morphology with average sizes about 50 and 100 nm, respectively. The cytotoxicity of PGSC-PTX@RBCm NPs was considerably decreased compared with that of PGSC-PTX NPs. PTX release from PGSC-PTX and PGSC-PTX@RBCm NPs at pH 6.5 was remarkably higher than those at pH 7.4, respectively. The PGSC-PTX@RBCm NPs exhibited remarkably decreased uptake by macrophages than PGSC-PTX NPs. The area under the curve within 72 h (AUC) for is significantly higher than PGSC-PTX NPs. The PGSC-PTX@RBCm NPs also showed significantly stronger growth-inhibiting effect on tumor than PGSC-PTX NPs. These results indicated that PGSC-PTX@RBCm NPs have acidic drug release sensitivity, the characteristics of long circulation, and remarkable tumor growth inhibiting effect. This study may provide an effective strategy for improving the antitumor effect of NDDS.
To enhance the tumor-penetrating ability and targeting therapeutic effect of polymer-drug conjugates (PDCs), tumor-penetrating peptide RGERPPR (RGE) modified and PEGylated poly(l-γ-glutamylglutamine)-paclitaxel (PGG-PTX) nanoparticles (RGE-PEG/PGG-PTX NPs) were prepared by using a so-called "modular" design strategy. In brief, a RGERPPR-conjugated targeting material, DSPE-PEG-RGERPPR, was first synthesized and assembled with PGG-PTX into RGE-PEG/PGG-PTX NPs based on the hydrophobic interaction between the groups of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) and PTX. The NPs exhibited a uniform spherical morphology with particle size of around 90 nm, as shown by the dynamic light scattering and transmission electron microscopy results. The NPs showed good in vitro stability at 4 °C for over 3 weeks, sustained drug release within 120 h, and good hemocompatibility. The cellular-uptake study displayed that the NPs showed increased uptake by U87 MG cells and human umbilical vein endothelial cells (HUVECs) compared to the unmodified PGG-PTX. The cytotoxicity test demonstrated that RGE-PEG/PGG-PTX NPs produced a stronger growth inhibitory effect against U87 MG cells and HUVECs than PGG-PTX, which was consistent with the cellular uptake results. Finally, the pharmacodynamic study proved that RGE-PEG/PGG-PTX NPs significantly prolonged the median survival time of nude mice bearing intracranial glioblastoma. The results indicated the effectiveness of RGE-PEG/PGG-PTX NPs in the treatment of glioblastoma as well as the feasibility of the "modular" design strategy in the preparation of active-targeting PDCs.
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