Multifunctional carbon nanocapsules for highly efficient neutron cancer therapy.

Overview

Project Summary

THE CHALLENGE: Neutron capture therapy (NCT) is a highly precise form of radiotherapy, that exploits specific isotopes to produce high linear energy transfer (LET) particles that can cause cancer cell death. The recent installation of accelerator in hospitals environment, advanced NCT clinical practice for treating highly aggressive cancers, namely high-grade gliomas, primaries or cerebral metastases of melanoma, and head/neck cancers, where other conventional therapies were ineffective. However, current pharmaceuticals present substantial limitations for successful clinical translation including, low chemical stability, selectivity, and persistence intracellularly during neutron irradiation, causing severe side effects.

CarboNCT presents an innovative approach to designing more efficient multifunctional nanotherapeutic NCT agents by exploring 10B, 157/155Gd, 6Li active nuclides. For that purpose, we will explore the new concept of carbon nanocapsules (CNCs), able to accommodate high concentrations of active nuclides in their internal cavity. Here, carbon nanohorns (CNHs) and carbon nanodots (CNDs) will be investigated for the first time for the synthesis of CNCs. Computer models will be applied to elucidate the strength and specificity of the interaction between the load and the different nanocarriers for improved filling yields. the high density of NCT active species in the inner cavity of the nanocarrier will provide the possibility to implement a new disruptive NCT nanotherapy. Significantly, the NCT species will be located in the inner cavity of the CNCs avoiding toxicity and degradation. 

The CNCs external surfaces will be coated with bioactive hydrogel loaded with clinically approved chemotherapeutic indocyanine greendoxorubicin (dox) by microfluidics-based fabrication. The precise control over the physicochemical features of the hydrogel coating by the microfluidic system allows modulating the CNCs physiological behaviour as well as controlling drug release profile (DOX). Furthermore, biopolymer will be conjugated with ligands that recognize receptors that are highly expressed in cancer cells or the tumor microenvironment (TME), increasing CNCs cellular uptake, tumor targeting and diffusion. The multifunctional CNCs will operate as selectively delivering nanoagents for an effective chemo-neutron therapy combination monitored by highresolution bioimaging, (ANNEX 1) while avoiding systemic side effects typical of conventional cancer therapies. CNCs present intrinsic fluorescence (CNDs and tagged DOX), that can provide relevant information regarding the real-time monitorization of the biodistribution by confocal analysis, following the vision for the 21st century of personalized medicine. To better understand the interplay between the complex TME and the delivery of the CNCs-based therapy, a head and neck tumor model will be mimicked by using 3D-bioprinted multicellular tumors. The predictive in-vitro 3D tumor models will allow the in-situ confocal bio-detection and monitorization of CNCs-based therapy to uncover the underlying transduction pathways involved in reducing malignant tumor progression. This information is critical for the therapeutic diagnosis screening and the optimization of the neutron irradiation dosage (time/fluency), to conduct highly efficient nct pre-clinical tests. 

The research teams involved in CarboNCT have high competencies and experience in the field, evidenced by the coordination of several National/European projects and publication of numerous scientific articles and patents, that is complemented by a strict collaboration of the PI with the Laboratory for Applied Nuclear Energy (LENA), with high expertise in the medical application of NCT. Therefore, the consortium will be able to generate critical knowledge for the development of novel NCT nanomedicines towards clinical application.

Main Goals

CarboNCT is a multidisciplinary scientific research proposal formed by a consortium of three research units with complementary expertise to create synergies that capitalize and optimize existing means and resources to reach the main specific goals of the project:

1) TEMA-UA, synthesis and characterization of novel CNCs filled with NCT active agents. 

2) CICECO-UA, applied computer modelling to support the chemical synthesis, and controlled bioactive hydrogel coating of CNCs.

3) ICBR-UC and TEMA-UA, In vitro biocompatibility analysis of CNCs and the development of predictive models using bioprinted 3D multicellular head/neck tumor.

Project Details