Bridging the Gap between Macroscale Drug Delivery Systems and Nanomedicines: A Nanoparticle-assembled Thermosensitive Hydrogel for Peritumoral Chemotherapy.

The objective of this study was to investigate the spatiotemporal delivery of nanomedicines by an injectable, thermosensitive and nanoparticle self-aggregated hydrogel for peritumoral chemotherapy. Doxorubicin (Dox) was taken as the model medicine, which was encapsulated into poly(ε-caprolactone-co- 1,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(ε-caprolactone-co -1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) nanoparticles (PECT/Dox NPs). Macroscale hydrogel was formed by thermosensitive self-aggregation of PECT/Dox NPs in aqueous solution. Drug release from the hydrogel formulation was dominated by sustained shedding of PECT/Dox NPs and the following drug diffusion from these NPs. The hydrogel retention and release pattern of NPs in vivo was further confirmed by fluorescence resonance energy transfer (FRET) imaging. A single treatment with the hydrogel formulation possessed similar cytotoxicity against HepG2 cells compared to triple administrations of free Dox or PECT/Dox NPs in vitro due to enhanced uptake of PECT/Dox NPs and sustained intracellular drug release. Importantly, single peritumoral injection of drug-encapsulated hydrogel in vivo showed advantages over multiple intravenous administrations of PECT/Dox NPs and free Dox, including preferential and prolonged local drug accumulation and retention in tumors, resulting in superior cancer chemotherapy efficiency. Collectively, such a unique thermosensitive and nanoparticle-shedding hydrogel could effectively combine the advantages of nanomedicines and macroscale drug delivery systems, demonstrating great potential in the local nanodrugs delivery. It will open a new promising path for cancer chemotherapy with enhanced treatment efficacy and minimized side effects.