Title : Notch-targeted tumor microenvironment-responsive drug delivery for efficient treatment of metastatic colorectal cancer by remodeling its signal dynamics
Abstract:
The incidence of colorectal cancer has been rising steadily, with the Notch signaling pathway playing a crucial oncogenic role in its pathogenesis. Targeted modulation of this pathway represents a promising therapeutic strategy. However, current Notch pathway inhibitors frequently elicit severe toxicities due to insufficient targeting and specificity in monotherapy regimens, underscoring the urgent need for novel intervention strategies with enhanced precision. To address targeting limitations, we developed a tumor-acidic microenvironment-responsive nanocarrier, PEG-b(HEMA-co-DM(A), which enables pH-sensitive carrier-mediated precise accumulation of Notch inhibitors at the tumor site. Regarding specificity challenges, we systematically analyzed the dynamic regulatory mechanisms underlying abnormally activated Notch signaling nodes in colorectal cancer based on the different activation states and biological effects of Notch receptors in malignant tumors. Leveraging the non-equivalent inhibitory effects of various γ-secretase inhibitors on different Notch receptors, we identified a dual-functional molecule MK-0752 that selectively inhibits Notch1 while preserving Notch4 activity. This approach amplifies cascade effects within tumor-suppressive signaling networks to achieve pathway-specific blockade. Through the synergistic integration of "microenvironment-targeted delivery" and "signaling node-specific intervention", this strategy significantly enhances antitumor efficacy while minimizing off-target toxicity in healthy tissues. Our findings establish an innovative research paradigm with substantial clinical translational potential for precision-targeted therapy.
