Overcoming the Tumor Collagen Barriers: A Multistage Drug Delivery Strategy for DDR1-Mediated Resistant Colorectal Cancer Therapy.

The extracellular matrix (ECM) is critical for drug resistance in colorectal cancer (CRC). The abundant collagen within the ECM significantly influences tumor progression and matrix-mediated drug resistance (MMDR) by binding to discoidin domain receptor 1 (DDR1), but the specific mechanisms by which tumor cells modulate ECM via DDR1 and ultimately regulate TME remain poorly understand. Furthermore, overcoming drug resistance by modulating the tumor ECM remains a challenge in CRC treatment. In this study, a novel mechanism is elucidated by which DDR1 mediates the interactions between tumor cells and collagen, enhances collagen barriers, inhibits immune infiltration, promotes drug efflux, and leads to MMDR in CRC. To address this issue, a multistage drug delivery system carrying DDR1-siRNA and chemotherapeutic agents is employed to disrupt collagen barriers by silencing DDR1 in tumor, enhancing chemotherapy drugs diffusion and facilitating immune infiltration. These findings not only revealed a novel role for collagen-rich matrix mediated by DDR1 in tumor resistance, but also introduced a promising CRC treatment strategy.

Graphene-based nanomaterials for breast cancer treatment: promising therapeutic strategies.

Breast cancer is the most common malignancy in women, and its incidence increases annually. Traditional therapies have several side effects, leading to the urgent need to explore new smart drug-delivery systems and find new therapeutic strategies. Graphene-based nanomaterials (GBNs) are potential drug carriers due to their target selectivity, easy functionalization, chemosensitization and high drug-loading capacity. Previous studies have revealed that GBNs play an important role in fighting breast cancer. Here, we have summarized the superior properties of GBNs and modifications to shape GBNs for improved function. Then, we focus on the applications of GBNs in breast cancer treatment, including drug delivery, gene therapy, phototherapy, and magnetothermal therapy (MTT), and as a platform to combine multiple therapies. Their advantages in enhancing therapeutic effects, reducing the toxicity of chemotherapeutic drugs, overcoming multidrug resistance (MDR) and inhibiting tumor metastasis are highlighted. This review aims to help evaluate GBNs as therapeutic strategies and provide additional novel ideas for their application in breast cancer therapy.

Dual effects of JNK activation in blood-milk barrier damage induced by zinc oxide nanoparticles.

Zinc oxide nanoparticles (ZnO-NPs) have been extensively applied in our daily life. Humans are at high risk of being exposed to ZnO-NPs, which induce potentially adverse health effects. Although a growing number of studies have investigated the toxic effects of ZnO-NPs, the available data concerning ZnO-NP interactions with the blood-milk barrier (BMB) remain highly limited. Herein, we systematically investigated the damage to BMB integrity induced by ZnO-NPs and the mechanisms involved. ZnO-NPs that were intravenously injected into lactating dams accumulated in the mammary gland and entered into the breast milk, inducing disruption to BMB integrity and changes in the tight junction (TJ) and adherens junction (AJ) components. Furthermore, using an in vitro BMB model composed of EpH4-Ev cells, we verified that ZnO-NP-triggered ROS generation and the activation of MKK4 and JNK are the main mechanism of cell-cell junction damage. More interestingly, JNK activation played different roles in inducing changes in the TJ and AJ complex, and these effects did not need to activate the downstream c-Jun. These data provide more information for understanding ZnO-NP interactions with the BMB and raise concern for the daily use and the intravenous use of ZnO-NPs by lactating mothers.

Oxygen self-enriched nanoplatform combined with US imaging and chemo/photothermal therapy for breast cancer.

Oxygen-saturated perfluorohexane-cored, cisplatin (Pt)-decorated hollow gold nanospheres (Pt-HAuNS-PFH@O2) have been synthesized for ultrasound (US) imaging-guided tumor treatment depending on chemo/photothermal therapy, relief of hypoxia, and photothermal induced US contrast signal. Both NIR laser-induced hyperthermia generation by gold nanospheres and acidity triggered release of Pt resulted in high toxicity after internalization by breast cancer cells. According to ex vivo immunofluorescence investigation and in vivo pharmacodynamic studies on MDA-MB-231 tumor bearing mice, the susceptibility of tumors to Pt-HAuNS-PFH@O2 was improved by the relief of hypoxia. In addition, US imaging under different conditions verified the amplified US contrast property of Pt-HAuNS-PFH@O2 by the heat-dependent liquid-gas conversion of PFH. Overall, Pt-HAuNS-PFH@O2 can be promisingly used as an oxygen self-enriched nanoplatform for US imaging-guided chemo/photothermal therapy.

Endothelial Barrier Dysfunction Induced by Zinc Oxide Nanoparticles In Vivo and In Vitro and Their Mechanism of Crossing the Endothelial Barrier.

In this study, the effects of zinc oxide nanoparticle (ZnO-NP) exposure on the endothelial barrier and the pathway of ZnO-NPs to cross the endothelial barrier were examined. C57 mice were exposed to ZnO-NPs (1.2 mg/kg and 6 mg/kg body weight) and ZnSO4 (3.6 mg/kg). Zinc biodistribution and toxicity tests, including H&E staining, TUNEL and 8-OHdG IHC staining of highly vascularized organs (liver, kidney and spleen), were assessed. Endothelial barrier disruption was assessed by interendothelial junction IHC staining of the thoracic aorta, and was further studied in human umbilical vein endothelial cells (HUVECs). Four different kinds of endocytosis inhibitors were also used to study the endocytosis effects of the ZnO-NPs on the HUVECs. We found that a significantly increased concentration of zinc was detected in the highly vascularized organs from the ZnO-NP exposure groups, together with histopathologic changes such as higher apoptotic death and oxidative status. Interendothelial junction disruption and increased endothelial barrier permeability were found in both the in vivo and in vitro experiments. All four endocytosis inhibitors were able to reduce the uptake and transport of ZnO-NPs in the HUVECs. We concluded that ZnO-NPs may impair endothelial cells and induce endothelial barrier dysfunction and are able to cross the endothelial barrier through paracellular and transcellular routes.