Disulfide-Cross-Linked Nanogel-Based Nanoassemblies for Chemotherapeutic Drug Delivery

Although nanoparticle-based chemotherapeutic strategies have gained in popularity, the efficacy of such therapies is still limited in part due to the different nanoparticle sizes needed to best accommodate different parts of the drug delivery pathway. Herein, we describe a nanogel-based nanoassembly based on the entrapment of ultrasmall starch nanoparticles (size 10–40 nm) within disulfide-crosslinked chondroitin sulfate-based nanogels (size 150–250 nm) to address this challenge. Upon exposure of the nanoassembly to the reductive tumor microenvironment, the chondroitin sulfate-based nanogel can degrade to release the doxorubicin-loaded starch nanoparticles in the tumor to facilitate improved intratumoral penetration. CT26 colon carcinoma spheroids could be efficiently penetrated by the nanoassembly (resulting in 1 order of magnitude higher DOX-derived fluorescence inside the spheroid relative to free DOX), while in vivo experiments showed that doxorubicin-loaded nanoassemblies reduced tumor sizes by 6× relative to saline controls and 2× relative to free DOX after 21 days. Together, these data suggest that nanogel-based nanoassemblies are a viable option for improving the efficacy and safety of nanoparticle-based drug delivery vehicles treating cancer.