Local multi-drug delivery and osteogenesis in bone metastasis of prostate cancer by a core-shell 3D printed scaffold

Prostate cancer is the most common cancer in men. Approximately 80 % of people with advanced prostate cancer reportedly develop bone metastasis. Common treatments of bone metastasis of prostate cancer (BM -PC) cause severe adverse effects. Besides, there is a high probability of metastatic bone tumor recurrence after tumor resection surgery. Thus, local drug delivery is an alternative way to prevent the difficulties as mentioned earlier. In this study, a bilayer core -shell 3D -printed scaffold was prepared. The outer layer of the scaffold serves as the drug delivery vehicle, and the internal layer creates a platform for preosteoblasts' migration to substitute the resected tumor with healthy bone in BM -PC. First, PLGA microspheres of triptorelin (TRP-PLGA microsphere) and albumin -bound paclitaxel nanoparticles (NAB-PTX) were prepared for the assessment of their synergistic effect against DU -145 cells. To obtain the optimal combination, both microspheres and nanoparticles were loaded in the outer layer of a scaffold based on Gelatin MethAcryloyl (GelMA) hydrogel using the 3D printing method. The inner layer of the scaffold was based on GelMA and alginate containing hydroxyapatite nanoparticles (nHA). The effect of nHA in the internal layer of the scaffold was assessed through osteogenesis in vitro analyses. The 75 % inhibitory concentrations (IC75) for TRP and PTX combination were 58.75 mu M and 1.94 nM, respectively, while this value was obtained at 235 mu M and 39 nM for TRP and PTX, respectively, which indicates a synergistic effect and reduction in the required dose of two drugs. The outer layer of the scaffold had a mechanical strength of 25 kPa and a suitable pore size for drug delivery in 21 days. On top of that, the inner layer showed an enhanced mechanical strength of 190 kPa, which is ideal for osteogenesis. Furthermore, biodegradation of the outer layer in 3 weeks and the inner layer in 10 weeks is proportional to their objective. The presence of nHA in the internal layer of the scaffold enhanced bone regeneration (146 %), increased ALP activity (150 %), and doubled the calcium deposition within 14 days. It also led to the upregulation of RUNX2, COL1A1, and OPN genes about 86, 60, and 14 fold, respectively, within 21 days, indicating osteogenic differentiation. In conclusion, this scaffold will successfully prevent bone tumor recurrence and then enhance bone regeneration at the site.