Glioblastoma, the most aggressive brain cancer, has a low median survival after surgery or chemotherapy. Even immunotherapy, considered a promising strategy to delay the progression of glioblastoma has not provided the expected results. The microenvironment generated by glioblastoma is per se immunosuppressive and its heterogeneity is the main cause of chemoresistance. The advent of theranostic nanomedicine, a combination of imaging and therapeutic agents, represents new road for malignant brain tumors eradication. The possibility to synergistically combine cancer therapy and detection by exploiting radio labeled biomimetic gold nanoparticles (Au NPs) with tailored thermo-optical properties, represents a new horizon in the field of drug-free cancer therapy. This goal is accomplished through the conjugation of biomimetic protein capped (Keratin) Au NPs (Ker-AuNPs) with a sugar-based radio tracer (fluorodeoxyglucose,18F-FDG). The FDG-Ker-AuNPs is used as a Trojan horse for targeting (FDG accumulates in energy-hungry cancer cells), detecting (18Fpositron emission isotope) and burning (Ker-AuNPs photo-thermal properties) glioblastoma tumour cells. Here, we propose an innovative approach based on the combination of targeting, detection, and therapy, by verifying the therapeutical biological effects of FDG-Ker-AuNPs in a 3D bioprinted model of human primary glioblastoma. Thus, FDG-Ker-AuNPs will selectively recognize the glioblastoma cells assembled in a 3D model and the 18F will detect and localize in the construct with very high precision NPs by computer and positron emission tomography technology. This strategy will allow us to investigate the physiological spatial and heterogenous distribution of glioblastoma testing the efficacy/toxicity of the drug delivered by FDG-Ker-AuNPs. The end-goal is to perform an in vitro-in vivo correlation unlocking the possibility to realize innovative studies based on an animal free glioblastoma cancer model.
Over the past 20 years the increasing knowledge of molecular and tumor biology has notably changed cancer treatment paradigms. In this scenario, conventional therapies to treat cancer such as surgery, chemotherapy or radiotherapy, have not resolved the heterogeneity of cancer cells. The utilization of gold nanoparticles (AuNPs) as photo-thermal agents represents a win-win solution because it allows to combine high-precision targeting, localization and in-situ photo-thermal ablation. In this framework, FDG-Ker-AuNPs are proposed for high-precision applications in oncology to increase both the efficiency of therapies and diagnosis. In fact, these biomimetic agents potentially introduce noteworthy advantages with respect to the traditional use of single molecules as radioactive tracers for in vivo and in vitro imaging. Furthermore, nanoradiocompounds like FDG-Ker-AuNPs increase drug concentrations at the pathological target, thereby improving the balance between the efficacy and the toxicity of systemic chemotherapeutic interventions. By utilizing the nanoscale thermal confinement of FDG-Ker-AuNPs, combined with a double functionalization strategy and a tailor-made 3D bioprinted tumor model, we aim at investigating a new methodology in the fight against cancer, bridging targeting, detection and therapy. This accomplishment can be obtained by exploiting the nanoscale properties of AuNPs: size, shape and functionality [1]. The ultra-small size (20-30nm) along with the biomimetic shield can afford a stealth surface that would moderate the reticuloendothelial system (RES) recognition of NPs leading to extended circulation time. The shape along with the surrounding keratin capping arranged in a ¿protein like corona¿ system can promote the cellular internalization (uptake). The chemical and physical functionality is a key factor for bridging NPs with a recognition system (e.g. sugar) or for remotely controlling the temperature around NPs (e.g. by using bio-transparent light) [2]. The main breakthrough idea of our project is the possibility to conjugate the Ker-AuNPs to tumor-avid biomolecules (FDG, sugar-like molecule), using a Trojan horse system to introduce a higher ratio of radioactive particles into the tumor [3]. Once in place, the selective and localized heating, arising from AuNPs after the resonant laser irradiation, will allow the photo-thermal destruction of tumor cells without (or minimally) affecting the healthy ones. Interestingly, a very innovative part of this project is the unique capability to localize the NPs, in a 3D bioprinted tumor model, with very high accuracy thanks to the presence of a radio tracer. With the use of this 3D model, that is a simple predictor of what will really happens in a tumor micro-environment (TME), we aim at creating an in vitro TME overcoming all the intrinsic limitations of 2D experiments and all the controversies of experiments on animal models. The functional information obtained by SPECT and PET will be coupled with the anatomic/morphologic information typically provided by computed tomography (CT): these approaches, named ¿hybrid imaging¿, have many advantages as well as high sensitivity and good spatial resolution. When dealing with hyperthermia-based applications, real-time assessment of thermal damage is the key to therapeutic safety and efficiency of such procedures. The lack of suitable technological options to assess the temperature of a targeted site has limited the large-scale marketing of hyperthermia treatment and thermally controlled drug delivery protocols. Breakthroughs in basic research are also expected if a noninvasive, accurate, sensitive, and robust thermometer is made available for probing cellular behaviors. Indeed, it is very hard to measure the local temperature in the human body while NPs are illuminated with an external light source. In order to overcome this issue, we will use the magnetic resonance (MR) [4] thermometry technique for dynamic monitoring the temperature increase under a laser irradiation. From a basic knowledge standpoint, this is a very important step forward in comparison with previously reported studies on similar subjects [5]. In fact, we will be able to combine therapy, detection/visualization and quantification thanks to the: photo-thermal properties (therapy); presence of a radio tracer (detection/visualization) and MR thermometry (quantification). The MR thermometry will be exploited for both in-vitro (2D cells system) and 3D bioprinted glioma model studies of plasmonic NPs combined with radiopharmaceutical drugs, representing a new avenue for the utilization of nanotechnology based thermal therapies.
References
1) Liz-Marzán, L.M. (2004) Mater. Today, 7, 26.
2) L. De Sio et al. (2015) Progr. Quant. Electr. 41, 23.
3) M. Tanasova et al. (2018) Curr. Top Med Chem. 18, 467.
4) R. Viola et al. (2008) J Magn Reson Imaging 27, 376.
5) A.M. Pouch et al. (2010) J Ultrasound Med. 29, 1595.