An Intelligent Vascular Disrupting Dendritic Nanodevice Incorporating Copper Sulfide Nanoparticles for Immune Modulation‐Mediated Combination Tumor Therapy

Abstract

Development of intelligent nanoplatforms that can simultaneously target multiple factors associated with tumor growth and metastasis remains an extreme challenge. Here, an intelligent dendritic nanodevice incorporating both copper sulfide nanoparticles (CuS NPs) and 5,6‐dimethylxanthenone‐4‐acetic acid (DMXAA, a vascular disrupting agent) within the dendrimer internal cavities and surface modified with a targeting agent LyP‐1 peptide is reported. The resulting generation 5 (G5) dendrimer‐based nanodevice, known as G5‐PEG‐LyP‐1‐CuS‐DMXAA NPs (GLCD NPs), possess good colloidal stability, pH‐sensitive drug release kinetics, and high photothermal conversion efficiency (59.3%). These functional GLCD NPs exert a LyP‐1‐targeted killing effect on breast tumors by combining CuS‐mediated photothermal therapy (PTT) and DMXAA‐induced vascular disruption, while also triggering antitumor immune responses through PTT‐induced immunogenic cell death and DMXAA‐mediated immune regulation via M1 polarization of tumor‐associated macrophages and dendritic cell maturation. In addition, with the LyP‐1‐mediated proapoptotic activity, the GLCD NPs can specifically kill tumor lymphatic endothelial cells. The simultaneous disruption of tumor blood vessels and lymphatic vessels cuts off the two main pathways of tumor metastasis, which plays a two‐pronged role in inhibiting lung metastasis of the breast cancer model. Thus, the developed GLCD NPs represent an advanced intelligent nanoformulation for immune modulation‐mediated combination tumor therapy with potential for clinical translations.

Dendritic nanoparticles for immune modulation: a potential next-generation nanocarrier for cancer immunotherapy

“…5A). 75 The dendrimer core contained the CuS NPs and an anti-vascular drug, DMXAA. Additionally, the external surface was functionalized with a cancer-targeting peptide, LyP-1.…”

Nanomaterial‐Based Strategies for Preventing Tumor Metastasis by Interrupting the Metastatic Biological Processes

“…[45] An intelligent dendritic nanodevice prepared by Zhang et al combined photothermal therapy to block the two most common pathways of tumor metastasis by destroying the capillaries and lymphatic capillaries around the tumor, thereby preventing tumor metastasis. [46] In addition to destroying capillary lymphatic vessels, eliminating cancer cells in the lymph nodes is also a crucial method for preventing lymph node metastasis. Cabral et al found that smaller NPs (≈30 nm) had better lymph nodetargeting efficiency than larger ones (70-80 nm).…”

Near-Infrared Titania Nanoparticle-Based Photoimmunotherapy via Tumor-Microenvironment-Responsive Gene Editing of SerpinB9 for Triple-Negative Breast Cancer

“…By elevating the temperature of tumor tissues, PTT can selectively target and eliminate primary tumors . PDT is a targeted therapeutic approach that utilizes photosensitizers, which are activated by specific wavelengths of light to produce ROS, ultimately leading to tumor cell death. , PTT and PDT have been employed for the treatment of diverse cancers, including melanoma, lung cancer, breast cancer, etc. ,− However, tumor cells may produce SerpinB9 to suppress granzyme B activity, thereby reducing the efficacy of phototherapy. Therefore, overcoming SerpinB9-mediated resistance is the key to improving the effectiveness of phototherapy.…”