Radiolabeled polymeric nanoconstructs loaded with docetaxel and curcumin for cancer combinatorial therapy and nuclear imaging

Growing evidence suggests that multifaceted diseases as cancer can be effectively tackled by hitting simultaneously different biological targets and monitoring patient-specific responses. Combinatorial therapies, relying on the administration of two or more molecules with different cytotoxic mechanisms, are rapidly progressing in the clinic. Here, 100 nm spherical polymeric nanoconstructs (SPNs) are proposed for the combinatorial treatment of tumors by codelivering a potent antimitotic drug - docetaxel (DTXL) - and a broad spectrum anti-inflammatory molecule - curcumin (CURC). In vitro, SPNs loaded with DTXL and CURC induce a threefold decrease in IC<inf>50</inf> as compared to DTXL-loaded SPNs. This synergic antitumor effect is also significant in mouse models of glioblastoma multiforme, where, after 22 d of treatment, the combinatorial approach leads to complete disease regression. At 90 d post-treatment initiation, mice injected with DTXL + CURC SPNs have a 100% survival, whereas only 50% of the DTXL SPN treated mice survive. SPNs are also labeled with radioactive ⁶⁴Cu(DOTA) molecules to document, via PET imaging, the progressive tumor mass shrinkage. Sensitization of DTXL by CURC is associated with NF-κB downregulation and increased apoptosis. These theranostic nanoconstructs could be used for combinatorial treatment and assessment of therapeutic efficacy in other malignancies. Spherical polymeric nanoconstructs (SPNs) are multifunctional nanoparticles designed for combinatorial therapy and disease management. The platform presented here is used to codeliver docetaxel, a strong antitumor drug, with curcumin as sensitizing agent. SPNs are labeled with ⁶⁴Cu for PET imaging to detect the delivery of SPNs and follow the therapy efficacy over time. This combinatorial approach is successful in glioblastoma xenograft mouse model.