Search

Precise delivery and release of therapeutics in the subcellular targets are critical for tumor‐selective chemotherapy. Self‐immolative structures are sophisticatedly designed to achieve stimuli‐responsive drug delivery. Herein, the facile fabrication of self‐immolative peptide‐camptothecin (CPT) nanoassemblies is reported for cancer‐selective drug delivery by utilizing the dual‐mode peptide targeting design and amine‐catalyzed intramolecular hydrolysis. The dual‐mode peptide targeting design is realized by co‐assembly of tumor targeting and nuclei‐localizing peptide‐CPT prodrugs, rendering the nanoassemblies with efficient cancer cell‐selective capability. When the nanoassemblies enter cancer cell, the overexpressed endonuclear histone deacetylases (HDACs) cleave the acetyl group to generate primary amines, triggers amine‐catalyzed intramolecular hydrolysis, and fast‐release drug in the cell nuclei. The peptide‐CPT prodrugs release up to 68% CPT in 1 h in the presence of HDACs, while no detectable CPT release is observed in the absence of HDACs at the same time. The peptide‐CPT prodrugs selectively kill cancer cells with high HDACs levels. The dual targeting peptide‐CPT nanoassemblies exhibit extended blood circulation, excellent tumor accumulation, and potent antitumor activity by inhibiting tumor progression and metastasis in mice bearing 4T1 aggressive breast tumors. Overall, the HDAC‐triggered self‐immolative strategy is promising for developing cancer‐selective drug delivery systems. [ABSTRACT FROM AUTHOR]

Liver is the most common metastatic site for colorectal cancer (CRC), there is no satisfied approach to treat CRC liver metastasis (CRCLM). Here, we investigated the role of a polycomb protein BMI-1 in CRCLM. Immunohistochemical analysis showed that BMI-1 expression in liver metastases was upregulated and associated with T4 stage, invasion depth and right-sided primary tumor. Knockdown BMI-1 in high metastatic HCT116 and LOVO cells repressed the migratory/invasive phenotype and reversed epithelial–mesenchymal transition (EMT), while BMI-1 overexpression in low metastatic Ls174T and DLD1 cells enhanced invasiveness and EMT. The effects of BMI-1 in CRC cells were related to upregulating snail via AKT/GSK-3 β pathway. Furthermore, knockdown BMI-1 in HCT116 and LOVO cells reduced CRCLM using experimental liver metastasis mice model. Meanwhile, BMI-1 overexpression in Ls174T and DLD1 significantly increased CRCLM. Moreover, sodium butyrate, a histone deacetylase and BMI-1 inhibitor, reduced HCT116 and LOVO liver metastasis in immunodeficient mice. Our results suggest that BMI-1 is a major regulator of CRCLM and provide a potent molecular target for CRCLM treatment. [ABSTRACT FROM AUTHOR]

Colorectal liver metastasis (CRLM) is the leading cause of death in patients with colorectal cancer (CRC). MiR-30b-5p can function as an oncogene or tumor suppressor in cancers, but its role in CRLM is still unknown. Here, we found that miR-30b-5p overexpression suppressed the invasion, migration, adhesion, and motility of HCT116 and LoVo cells. The expression of EMT (Zeb1, Snail, and vimentin) and adhesion-related proteins (p-paxillin and p-Src) was decreased. We validated Rap1b, a Ras family small GTPase that regulates cell adhesion and mobility, as the direct and functional target of miR-30b-5p. Rap1b overexpression rescued the aggressive characteristics of CRC cells that were inhibited by miR-30b-5p. Rap1b knockdown suppressed invasion and migration and decreased CRC cell-matrix adhesion and spreading, which was consistent with the results of miR-30b-5p overexpression. Further in vivo experiments demonstrated that miR-30b-5p overexpression inhibited CRLM, but Rap1b rescue attenuated the inhibitory effect of miR-30b-5p. In addition, miR-30b-5p was downregulated in CRC specimens, and Rap1b showed a negative correlation with miR-30b-5p expression in primary CRC and LM tissues. These results indicate that miR-30b-5p functions as a metastasis suppressor by targeting Rap1b and may provide a new target for the treatment of CRLM. [ABSTRACT FROM AUTHOR]

Background/aims: There are many studies on immune cell infiltration in colorectal cancer, including FoxP3+-regulatory T cells, CD66b+ tumorassociated neutrophils, and CD163+ tumor-associated macrophages. These studies mainly focus on the relationship between cell infiltration and tumor progression, prognosis, and so on, while the relationship between tumor cell differentiation and cell infiltration is poorly understood. We aimed to explore the relationship between cell infiltration and tumor cell differentiation., Materials and Methods: The tissue microarray and immunohistochemistry were used to determine the infiltration of FoxP3+-regulatory T cells, CD66b+ tumor-associated neutrophils, and CD163+ tumor-associated macrophages in 673 colorectal cancer samples from the Second Affiliated Hospital, Wenzhou Medical University (2001-2009). Kruskal-Wallis test was used to assess the positive cell infiltration in colorectal cancer tissues with tumor cells of varying degrees of differentiation., Results: The number of CD163+ tumor-associated macrophages, FoxP3+-regulatory T cells, and CD66b+ tumor-associated neutrophils in colorectal cancer tissues was different, and the level of CD163+ tumor-associated macrophages was the highest while the level of FoxP3+-regulatory T cells was the least. There were significant differences in the cell infiltration of colorectal cancer tissue cells with different levels of differentiation (P < .05). The highest infiltration of CD163+ tumor-associated macrophages (154.07 ± 6.95) and FoxP3+-regulatory T cells (20.14 ± 2.07) were in the poorly differentiated colorectal cancer tissues, while the higher infiltration of CD66b+ tumor-associated neutrophils was in the moderately or well-differentiated colorectal cancer tissues (36.70 ± 1.10 and 36.09 ± 1.06, respectively)., Conclusion: Infiltration of CD163+ tumor-associated macrophages, FoxP3+-regulatory T cells, and CD66b+ tumor-associated neutrophils in colorectal cancer tissues may be related to the differentiation of tumor cells.

Specific labeling of biomarkers with bright and high photostable fluorophores is vital in fluorescent imaging applications. Here, we report a general strategy to develop single-molecule dendritic nanodots with finely tunable optical properties for in vivo fluorescent imaging. The well-defined nanodots are based on the divergent growth of biodegradable polylysine dendrimers with a fluorophore as the core. By tuning the size and surface chemistry, we obtained fluorescent nanodots with excellent brightness and photostability, favorable pharmacokinetics, and multivalent tumor-targeting capability. The nanodots provided robust, stable, long-lasting, and specific fluorescence enhancement in tumor tissue with an in situ tumor-to-normal ratio (TNR) of ∼3 and lasting over 5 days and an ex vivo TNR up to ∼17, holding considerable promise for cancer imaging and image-guided surgery. This strategy significantly improves the in vivo performance of fluorophores and can be applied to other modality imaging probes.