RESUMO
Stimulating the release of small nanoparticles (NPs) from a larger NP via the application of an exogenous stimulus offers the potential to address the different size requirements for circulation versus penetration that hinder chemotherapeutic drug delivery. Herein, we report a size-switching nanoassembly-based drug delivery system comprised of ultrasmall starch nanoparticles (SNPs, â¼20-50 nm major size fraction) encapsulated in a poly(oligo(ethylene glycol) methyl ether methacrylate) nanogel (POEGMA, â¼150 nm major size fraction) cross-linked via supramolecular PEG/α-cyclodextrin (α-CD) interactions. Upon heating the nanogel using a non-invasive, high-intensity focused ultrasound (HIFU) trigger, the thermoresponsive POEGMA-CD nanoassemblies are locally de-cross-linked, inducing in situ release of the highly penetrative drug-loaded SNPs. HIFU triggering increased the release of nanoassembly-loaded DOX from 17 to 37% after 3 h, a result correlated with significantly more effective tumor killing relative to nanoassemblies in the absence of HIFU or drug alone. Furthermore, 1.5× more total fluorescence was observed inside a tumor spheroid when nanoassemblies prepared with fluorophore-labeled SNPs were triggered with HIFU relative to the absence of HIFU. We anticipate this strategy holds promise for delivering tunable doses of chemotherapeutic drugs both at and within a tumor site using a non-invasive triggering approach.
RESUMO
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.
