A Topology-to-Therapy Map for Prodrug Nanoassemblies.

Area of Science:

• Nanomedicine
• Materials Science
• Chemical Biology

Background:

• Self-assembled prodrug nanoassemblies combine drug, response, and modification modules for cancer therapy.
• Balancing efficacy and toxicity in cancer nanomedicine is crucial, but the role of topology in nanoassembly structure-function is not well understood.

Purpose of the Study:

• To investigate how molecular topology of modification modules influences the assembly, behavior, and therapeutic outcomes of prodrug nanoassemblies.
• To establish a topological prodrug nanoassembly platform for systematic structure-function relationship studies.

Main Methods:

• Conjugation of docetaxel with linear, branched, or cyclic fatty acid-based modification modules.
• Quantum chemical and multiscale analyses to study assembly mechanisms and energetic environments.
• In vitro and in vivo evaluation of nanoassembly bioactivity and toxicity.

Main Results:

• Topology dictates nanoassembly mechanisms by modulating hydrophobic interactions and local energetic environments.
• Linear topology demonstrated superior assembly kinetics, drug release, and antitumor efficacy.
• Cyclic topology maximized safety with reduced potency, while branched topology showed intermediate performance.

Conclusions:

• Molecular topology is a critical design parameter for prodrug nanoassemblies, enabling control over assembly, drug release, and therapeutic efficacy/toxicity balance.
• This work provides systematic evidence for encoding performance into molecular topology for advanced cancer nanotherapeutics.