Cholesterol-Modified Dendrimers for Constructing a Tumor Microenvironment-Responsive Drug Delivery System

Poly(amidoamine) (PAMAM) dendrimers are widely used as templates for synthesizing small nanoparticles. Herein, the surfaces of amine-terminated generation 4 (G4-NH₂) poly(amidoamine) (PAMAM) dendrimers are modified with poly(ethylene glycol)-cholesterol to form self-assembled nanoparticles (termed DPC NPs). It is found that the cellular uptake of DPC NPs increases in a cholesterol-content-dependent manner. Benefiting from the hydrophobic cores of dendrimers, the DPC NPs are developed as drug carriers to encapsulate the photosensitizer chlorin e6 (Ce6) to obtain DPCC NPs for photodynamic therapy (PDT). To improve the PDT efficacy of the DPCC NPs in hypoxic tumor tissues, MnO₂ was synthesized in DPCC NPs in situ to obtain Ce6/MnO₂@DPC NPs (termed DPCCM NPs) based on the strong coordination between dendrimer and Mn²⁺. The as-designed DPCCM NPs behave like nanozymes, which can catalyze H₂O₂ to produce O₂ and achieve enhanced PDT effect upon 670 nm laser irradiation. The in vivo imaging experiments for cyanine7 (a near-infrared fluorescent dye)-conjugated DPCCM NPs reveal the excellent tumor accumulation performance of the nanozyme in tumor-bearing mice after intravenous administration. Finally, we have demonstrated the satisfactory in vivo antitumor therapeutic outcome and the good biosafety of the nanozyme. This work provides a new strategy for increasing the cellular uptake of drugs and proposes a method of synthesizing smart nanozymes based on dendrimers.