Although oral formulations of anticancer chemotherapies are clinically available, the therapeutic action relies on drug absorption, being inevitably accompanied with systemic side effects. It is thus desirable to develop oral therapy systems for the local treatment of colon cancers featured with highly selective delivery and minimized systemic drug absorption. The present study demonstrates the effective accumulation and cell uptake of the doxorubicin and superparamagnetic iron oxide nanoparticles-loaded solid lipid nanoparticles (SLNs) delivery system for chemo/magnetothermal combination therapy at tumors by hierarchical targeting of folate (FA) and dextran coated on SLN surfaces in a sequential layer-by-layer manner. Both the in vitro and in vivo characterizations strongly confirmed that the dextran shells on SLN surfaces not only retarded the cellular transport of the FA-coated SLNs by the proton-coupled FA transporter in small intestine, but also enhanced the particle residence in colon by specific association with dextranase. The evaluation of the in vivo antitumor efficacy of this SLN therapy system by oral administration showed the effective inhibition of colon tumors.1 The SLNs were prepared by emulsion method and sequentially coated with folate-modified D-a-tocopheryl polyethylene glycol succinate and octadecanol-conjugated dextran by hydrophobic interaction. The enzymatic degradability of dextran was demonstrated by the incubation with dextranase, a bacteria-produced glucanohydrolase present exclusively in colon. The cellular uptake examinations were performed by FA receptor (FAR) overexpressing CT26 colon cancer cells. An orthotropic CT26 colon tumor model was established with BALB/c mice. For in vivo distribution in gastrointestinal tract (GI tract), SLNs were labeled with NIR probe to facilitate IVIS fluorescence detection (Xenogen). For in vivo tumor inhibition study, mice were treated with drugs by gavage at a daily DOX dosage of 12 mg/kg for total three doses. To generate hyperthermia effect, the high-frequency magnetic field (HFMF) treatment was performed for 7 minutes. The dextran/FA-modified SLNs (DFSLNs) exhibited the average particle sizes of 132.1 nm and the DOX loading content of 9.27 wt%. The incubation of DFSLNs with dextranase led to the reduction of sizes to 97 nm, similar to the sizes of FA-modified SLNs (FSLNs). The in vitro targeting efficiency of the FA-decorated SLNs to FAR overexpressing CT26 cells substantially enhanced compared to SLNs and DFSLNs. The reduction of cellular uptake of DFSLNs was caused by the shielding effect with dextran that impaired the FA-mediated interactions between the NPs and the cells. As a consequence, after the removal of dextran coating with the enzymatic action of dextranase, the DFSLNs showed comparable uptake to FSLNs. The in vivo distribution of DFSLNs in GI tract shows reduced retention in intestine than that of FSLNs due to the FA residues sequestered by dextran coating. Moreover, DFSLNs promoted colon tumor region accumulation for about 2.8-folds compared to FSLNs in part by evading the undesired biorecognition. In particular, the effective tumor growth inhibition of the orthotopic colon tumor for the tumor-bearing mice receiving the DFSLNs and DFSLNs/HFMF treatments, respectively, clearly demonstrated the prominent therapeutic efficacy of DFSLNs for local treatment by oral administration.
1. Shen, M.Y. et al., Biomaterials 197, 86-100 (2019).