insu ciently e ective for the majority of patients
insuﬃciently eﬀective for the majority of patients. In recent years sig-nificant research eﬀorts have been made in mouse models to use magnetic nanoparticles for improving loco-regional cancer treatment. Some studies have focused on targeting drug loaded particles to the vicinity of the tumor with the use of an external magnetic field  while others target the particles to the tumor tissue using for example a monoclonal antibody like Cet and subsequently apply an alternating magnetic field to induce hyperthermia in the tumor area . How-ever, the traditional loco-regional treatments cannot be used to treat micro-metastases or circulating cancer Uridine diphosphate glucose that cannot be detected by existing imaging techniques. These micrometastases and circulating tumor cells lead to a high rate of cancer treatment failure and the eﬀect of existing systemic treatments on the cure rate of NSCLC patients is, so far, regrettably poor.
It is therefore, in the present work, not our only goal to develop nanocarriers for the improvement of loco-regional treatments. On the contrary we developed a versatile platform with the potential to also treat minimal residual disease, after local treatments have been applied. We demonstrated that our carriers can be used for targeted drug de-livery and in view of their superparamagnetic nature and their ability to be magnetically manipulated they can also be used for guidance by a magnetic field and for hyperthermia. In this respect our co-conjugates of Cet and Dox loaded on dextran-coated Fe3O4 magnetic nanoparticles oﬀer a significant advantage as compared with Cet conjugated and dox loaded silica nanoparticles .
The capacity to magnetically manipulate the co-conjugates is also highly important for testing their capacity to prohibit or delay growth of micro-metastases in animal models. After injection of cancer cells in the tail vein of laboratory animals, micro-metastases will develop first in the lungs . Treatment with the Cet and Dox loaded dextran-coated Fe3O4 magnetic nanoparticles is expected to delay this devel-opment. Magnetic manipulation of the co-conjugates to another part of the body of the animal during administration, forms an important control experiment needed for demonstrating that the therapeutic benefit obtained is related to the local action of the co-conjugate on the micro-metastases.
Our results clearly demonstrate that dextran coated Fe3O4 nano-particles can be eﬃciently conjugated with both a cytostatic drug and a targeting monoclonal antibody. The nanocarriers are taken up by the cells and the bound chemotherapeutic is released after which it reduces the viability of the tumor cells. Our nanocarriers form versatile tools that can be used for improving loco regional control by application of a magnetic field for increasing the drug concentration in the tumor vi-cinity or of an alternating magnetic field for inducing hyperthermia. They will, more importantly, also facilitate research aiming at evalu-ating their capacity to influence cancer progression at the level of mi-crometastases. While Cetuximab forms an eﬃcient monoclonal anti-body for targeting EGFR expressing tumors, future research may lead to even more eﬃcient antibodies, for example with a higher binding af-finity for the EGFR . Such monoclonal antibodies may in the future be used for more eﬃciently targeting potent drugs like Doxorubicin or Cisplatin to NSCLC cells in order to further increase the specific toxicity to the tumor cells thereby limiting side eﬀects in other tissues.
This work was supported by the Science and Technology Research and Development Program of the Shaanxi Province of the P.R. China with grant numbers 2014K13-11 and 2017ZDXM-SF-056.
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