Novel theranostics based on hybrid nanoparticles for early cancer detection and treatment

Abstract

Nanoscience and nanotechnology have advanced rapidly in recent years and have made a profound impact in the medical field. Nanoparticles have attracted great attention for their potential as diagnostic and/or therapeutic tools in oncology owing to their unique properties. Theranostics are nanodevices with diagnostic, therapeutic and possibly treatment-monitoring functions for treating cancers. Different noble metal nanoparticles can provide the basic unit for theranostics. Suitably designed and developed noble metal nanoparticle-based theranostics will have multiple functions. In this project, the design, fabrication and performance of novel multifunctional nanodevices for cancer detection and treatment were investigated. The foundation of this project was laid by investigating different types of hybrid nanoparticles for novel theranostics. Different approaches were developed for fabricating core-shell structured hybrid nanoparticles. Highly branched gold and gold-silver bimetallic nanoparticles were firstly made. pH-sensitive folic acid-chitosan (CS-FA) conjugate was then introduced on these nanoparticles to form hybrid nanoparticles with a metal core (Au@CS-FA and Au-Ag@CS-FA). Poly(lactide-co-glycolide) (PLGA) and chitosan (CS) micro- or nanoparticles were also produced to serve as the polymer core for forming hybrid particles with a gold or gold-silver nanoshell (PLGA@Au, CS@Au and PLGA@Ag-Au). Furthermore, Fe3O4@Au nanoparticles having both magnetic and plasmonic properties were investigated. Thermo-sensitive poly(N-isopropylacrylamide) (pNIPAm) polymer or pH-sensitive CS-FA was then coated on Fe3O4@Au nanoparticles, forming new hybrid nanoparticles. The formation mechanisms of nanoparticles and hybrid nanoparticles were studied.

Raman reporters (Rhodamine B or 4-mercaptobenzoic acid) and anti-cancer drugs (paclitaxel or 5-fluorouracil) were loaded into the polymer core or shell of hybrid nanoparticles to form multifunctional nanodevices. While the noble metal unit in the nanodevices provided high light-scattering enhancement for achieving photothermal effect, the polymer component encapsulated Raman reporter molecules and put them close to the metal nanoparticles for generating high surface enhanced Raman scattering (SERS) signals. These nanodevices could also serve as excellent drug carriers, and the stimulus-triggered release of incorporated drug was studied. It was shown in this project that the conjugation of targeting ligand (e.g. folic acid) or antibody (e.g. anti-HER2 monoclonal antibody) on hybrid nanoparticles had formed novel theranostics which allowed selective detection, continuous imaging of intracellular behavior and killing of targeted cancer cells. These theranostics could be taken up by specific cancer cells through receptor-mediated endocytosis and internalized into cytoplasma of the cell. These theranostics as stable SERS-active tags and imaging agents for HeLa cells, SK-BR-3 cancer cells or MCF-7 cancer cells were demonstrated. The targeting ability and intracellular uptake of these theranostics were studied. The photothermal effect of the theranostics was investigated using different laser irradiation powers. The anti-cancer treatment could be significantly improved by the synergistic effects of chemo- and photothermal therapy when these theranostics were also tasked as the carrier of anti-cancer drugs. Therefore, combining plasmonic metal nanoparticles with targeting ligand or antibody, magnetic nanoparticles, polymer shell or core, and anti-cancer drug has created advanced theranostics for the early detection and effective treatment of cancers. These novel theranostics have greatly improved capability for cancer detection and can provide multifunctions for cancer cell targeting, sensing/imaging and combined therapy.