Cell-Penetrating Hyperbranched Polyprodrug Amphiphiles for Synergistic Reductive Milieu-Triggered Drug Release and Enhanced Magnetic Resonance Signals

• Published in: Journal of the American Chemical Society 2015-01, Vol.137 (1), p.362-368
• Main Authors: Hu, Xianglong, Liu, Guhuan, Li, Yang, Wang, Xiaorui, Liu, Shiyong
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Cell Membrane Permeability - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Liberation - drug effects; Guanidine - chemistry; Guanidine - metabolism; Guanidine - pharmacology; Hep G2 Cells; Humans; Magnetic Resonance Imaging; Models, Molecular; Molecular Structure; Nanoparticles - chemistry; Nanoparticles - metabolism; Oxidation-Reduction - drug effects; Polymers - chemistry; Polymers - metabolism; Polymers - pharmacology; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacology; Structure-Activity Relationship; Surface-Active Agents - chemistry; Surface-Active Agents - metabolism; Surface-Active Agents - pharmacology
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja5105848

The rational design of theranostic nanoparticles exhibiting synergistic turn-on of therapeutic potency and enhanced diagnostic imaging in response to tumor milieu is critical for efficient personalized cancer chemotherapy. We herein fabricate self-reporting theranostic drug nanocarriers based on hyperbranched polyprodrug amphiphiles (hPAs) consisting of hyperbranched cores conjugated with reduction-activatable camptothecin prodrugs and magnetic resonance (MR) imaging contrast agent (Gd complex), and hydrophilic coronas functionalized with guanidine residues. Upon cellular internalization, reductive milieu-actuated release of anticancer drug in the active form, activation of therapeutic efficacy (>70-fold enhancement in cytotoxicity), and turn-on of MR imaging (∼9.6-fold increase in T 1 relaxivity) were simultaneously achieved in the simulated cytosol milieu. In addition, guanidine-decorated hPAs exhibited extended blood circulation with a half-life up to ∼9.8 h and excellent tumor cell penetration potency. The hyperbranched chain topology thus provides a novel theranostic polyprodrug platform for synergistic imaging/chemotherapy and enhanced tumor uptake.