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A Tandem-Responsive and Multifunctional Dendritic Dot for Acid and γ-Glutamyl Transpeptidase-Activated Cancer
Yuji Sun1, Yihuan Zheng1, Zhehao Wang1
1Zhejiang Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Key Laboratory of Smart Biomaterials, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, P. R. China.
Abstract:
Stimuli-responsive "off-on" theranostic nanoprobes enable precise cancer diagnosis and treatment by activating functions within the tumor microenvironment. Current challenges include selectivity, multi-functionality, and structural definition. Here, we report a tandem-responsive multiple-functional (TRIPLE) dendritic dot (DD) synthesized via a single-molecule all-in-one (SMALL) strategy. This TRIPLE DD integrates tumor-responsive drug release, fluorescence activation for imaging, and transcytosis for deep tumor penetration. Utilizing a polylysine dendrimer with a Cy5 core and covalently conjugated camptothecin (CPT), Cy5 fluorescence is initially quenched by CPT via photoinduced electron transfer (PET) ("off" state). A surface β-carboxylic amide-linked γ-glutamylglycine motif enables sequential cleavage by acidic pH and γ-glutamyl transpeptidase (GGT), exposing amines. These amines catalyze CPT release and activate Cy5 fluorescence. The resulting cationic DD induces cellular transcytosis, enhancing drug infiltration. We demonstrate pH/GGT tandem-responsive drug release, fluorescence activation, and potent antitumor activity in vitro and in vivo, notably against hepatocellular carcinoma. This work represents a rational design of multifunctional stimuli-responsive off-on nanoprobes, paving the way for advanced precision theranostics.
Insights
This study introduces a TRIPLE dendritic dot (DD) nanoprobe for precise cancer theranostics. It offers tumor-responsive drug release and fluorescence imaging, enhancing treatment efficacy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Stimuli-responsive nanoprobes are crucial for targeted cancer diagnosis and treatment.
- Challenges remain in achieving selectivity, multifunctionality, and defined structures in current nanoprobes.
Purpose of the Study:
- To develop a tandem-responsive, multifunctional dendritic dot (TRIPLE DD) nanoprobe.
- To integrate tumor-specific drug release, fluorescence imaging, and enhanced tumor penetration.
Main Methods:
- Synthesized a TRIPLE DD using a single-molecule all-in-one (SMALL) strategy, featuring a polylysine dendrimer with a Cy5 core and camptothecin (CPT).
- Incorporated a sequential pH and γ-glutamyl transpeptidase (GGT) cleavable motif for controlled CPT release and Cy5 fluorescence activation.
- Evaluated the nanoprobe's performance in vitro and in vivo, focusing on drug release, fluorescence, and antitumor activity.
Main Results:
- Demonstrated sequential pH/GGT-responsive drug release and fluorescence activation.
- Achieved enhanced deep tumor penetration via induced transcytosis.
- Showcased potent antitumor activity against hepatocellular carcinoma in vitro and in vivo.
Conclusions:
- The TRIPLE DD nanoprobe represents a rational design for multifunctional, stimuli-responsive theranostics.
- This approach offers a promising strategy for advanced precision cancer therapy.
