Vinča institute of nuclear sciences, University of Belgrade, Belgrade, Serbia
Effective heating of the super-paramagnetic nanoparticles (MNPs) by alternating magnetic field (AMF) serves as a base for development of AMF-generated hyperthermia for tumor therapy. Despite being thoroughly investigated by years and the basic idea confirmed in vitro, it is sparsely used in clinics. The limitations arising from basic laws of physics, nature of the material and interaction with biological systems hamper the applicability in vivo. Namely, resembling some properties of viruses and bacteria, most of the MNPs encounter biological barriers and immune system components when applied in vivo, leaving relatively small amounts of MNPs capable of reaching the tumor. An opposite process, enhanced permeability and retention (EPR), allows MNPs to reach the tumor and retain there. However, it is frequently not sufficient to accumulate enough MNPs to effectively heat large volume of the tumor, hampering the use of therapy. Also, nature of MNP-mediated hyperthermia limits the cells damage to short distance only.
Combining our expertise in magnetism, radioisotopes, pharmacology and cancer biology in project MagBioVin, we focused on improving all phases of the approach, aiming to generate material and therapeutic approaches suitable for in vivo application. Aiming that goal, we have been optimizing the preparation of MNPs and their coating by various compounds (citrate, PEG, DOTA, dopamine, lysine etc…) to improves their circulation half-life, help avoiding immune system, lower the toxicity and serve as a linker for radioisotopes, drugs and bio-macromolecules. The produced material is screened for cytotoxicity and hyperthermia-induced cell death on mouse and human cancer cell lines in vitro. Material with suitable characteristic serves as a base for in vivo application.
Potential for tumor therapy of coated and derivatized MNPs have been tested in vitro measuring its impact on cancer cells in tissue culture and in vivo on the impact on growth of mouse and human tumor xenografts on immune-competent and immune compromised mice. The data confirmed the basic mode of action but facing the same limitations as reported earlier. To overcome them, we have been focused on developing combined therapies, by linking the MNPs to agents complementing or synergizing hyperthermia, as radionuclides (131I, 90Y, 177Lu, 99mTc…), anticancer drugs (camptothecins), signal molecules (IL12), antibodies (CC49/Tag72) and enzymes (beta-Glucuronidase). The mechanism of action of the obtain material may have better pharmacological and therapeutic effects, surpassing hyperthermia alone, justifying their further development for eventual therapeutic approach.