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

Although nanoparticle-based chemotherapeutic strategieshave gainedin popularity, the efficacy of such therapies is still limited inpart due to the different nanoparticle sizes needed to best accommodatedifferent parts of the drug delivery pathway. Herein, we describea nanogel-based nanoassembly based on the entrapment of ultrasmallstarch nanoparticles (size 10-40 nm) within disulfide-crosslinkedchondroitin sulfate-based nanogels (size 150-250 nm) to addressthis challenge. Upon exposure of the nanoassembly to the reductivetumor microenvironment, the chondroitin sulfate-based nanogel candegrade to release the doxorubicin-loaded starch nanoparticles inthe tumor to facilitate improved intratumoral penetration. CT26 coloncarcinoma spheroids could be efficiently penetrated by the nanoassembly(resulting in 1 order of magnitude higher DOX-derived fluorescenceinside the spheroid relative to free DOX), while in vivo experiments showed that doxorubicin-loaded nanoassemblies reducedtumor sizes by 6x relative to saline controls and 2x relativeto free DOX after 21 days. Together, these data suggest that nanogel-basednanoassemblies are a viable option for improving the efficacy andsafety of nanoparticle-based drug delivery vehicles treating cancer.

Automated summary

In this study, a nanogel-based nanoassembly was developed by encapsulating ultra-small starch nanoparticles within disulfide-crosslinked chondroitin sulfate-based nanogels to address the challenge of different sizes needed for drug delivery pathway. The chondroitin sulfate-based nanogel can degrade in the tumor microenvironment to release doxorubicin-loaded starch nanoparticles, thereby improving intratumoral penetration. In vitro experiments demonstrated efficient penetration of CT26 colon carcinoma spheroids by the nanoassembly, resulting in significantly higher DOX-derived fluorescence compared to free DOX. In vivo experiments showed that doxorubicin-loaded nanoassemblies reduced tumor sizes by 6 times compared to saline controls and 2 times compared to free DOX after 21 days.