Novel approaches for osteosarcoma treatment: drug combination, nanotechnology and cell therapy

Abstract

Osteosarcoma is one of the most common malignant tumours of bone, primarily affecting children and adolescents. Although the implementation of chemotherapy and radiotherapy has substantially improved survival of patients with localized disease, patients with metastatic sarcomas still have a very low survival rate. For this reason, novel therapeutic approaches are needed. The first strategy of this thesis evaluated the potential of oridonin to act in combination with doxorubicin for osteosarcoma treatment. The results show that oridonin and doxorubicin have a synergistic effect, increasing osteosarcoma cells death through increased levels of reactive oxygen species (ROS), alteration of mitochondria membrane potential and a higher rate of apoptosis. A pilot in vivo experiment could not prove this effect, due to dosing problems, but it revealed a certain hepatoprotective effect of oridonin against doxorubicin. The second strategy attempted a more complex approach, where drug repositioning, nanoencapsulation and cell therapy were combined. The goals were to evaluate the feasibility of: i) repositioning paclitaxel to treat osteosarcoma; ii) vehicularizing paclitaxel within a thermo-responsive polymer (PNIPAM), and iii) using mesenchymal stem cells (MSC) as vector for paclitaxel-loaded PNIPAM nanoparticles, based on the ability of MSC to home to tumours. The results showed that paclitaxel can reduce the viability of different osteosarcoma cell lines, in both 2D and 3D cultures. PNIPAM-vehicularized paclitaxel was as efficient to induce osteosarcoma cell death, presenting a better outcome in 3D cultures, while empty (control) PNIPAM-nanoparticles were found cytocompatible. MSC stayed viable after exposure to both presentations of paclitaxel and, although its morphology and proliferation were a bit affected, they could still migrate towards osteosarcoma sites, as shown by scratch assays.