Glutathione-Responsive Multifunctional “Trojan Horse” Nanogel as a Nanotheranostic for Combined Chemotherapy and Photodynamic Anticancer Therapy

It remains a great challenge to design a multifunctional and robust nanoplatform for stimuli-responsive drug delivery toward a lesion, which tactfully integrates multiple molecules with therapeutic and diagnostic characteristics. Herein, we reported a facile and ingenious cross-linked nanogel (DSA) based on the chemical cross-link of drugs as a straightforward strategy to overcome the instability of the assembly. In DSA, doxorubicin (DOX) and 5-aminolevulinic acid (ALA) were cross-linked with a disulfide linker for realizing synergistic anticancer therapy. The stability of DSA was adjusted via balancing the hydrophobic/hydrophilic property with hydrophilic NH2-PEG1k. After regulating the coordination of the DOX part and ALA moiety, the drug-loaded nanogel exhibited superior chemotherapeutic efficacies. Additionally, the DSA could selectively biosynthesize fluorescent protoporphyrin IX (PpIX) in tumor cells, which could be applied for a real-time imaging probe of accurate cancer diagnosis. Besides, the in situ synthesized PpIX in mitochondria could serve as a photosensitizer to convert oxygen into toxic reactive oxygen species under a near infrared ray at 660 nm irradiation, leading to an excellent tumor-killing efficacy. This work proposed a unique strategy for designing a series of prodrug nanogels as a universal drug delivery platform for realizing precise disease therapy and diagnostics.