Raspberry-like gold nano-conjugates of block copolymer prodrug based bicontinuous nanoparticles for cancer theranostics

Abstract

Theranostic nanoparticles like polymer conjugated gold nanoparticles are at the cutting edge of cancer therapy, offering an integrated platform for simultaneous diagnosis and treatment. In this study, we report a nanoconjugate (P2AuNPs) by combining doxorubicin (DOX) tethered polymeric prodrug based bicontinuous nanoparticles (P2NPs), developed recently by us, with gold nanoparticles (AuNPs). The AuNPs were generated by in situ reduction of HAuCl₄, where different polymer functionalities served the role of reducing and stabilizing agents. The bicontinuous morphology of P2NPs provided a unique template for the growth of gold nanoparticles, resulting in an overall raspberry-like morphology. Compared to existing small-sized theranostic AuNPs, which often trigger systematic cytotoxicity, the synthesized P2AuNPs had an ideal size of ∼90 nm for passive targeting of cancer cells through leaky tumor blood vessels. Furthermore, the embedded gold nanoparticles in P2AuNPs nanoconjugate served as a nanometal surface energy transfer (NSET) pair with the covalently attached DOX molecules, resulting in the significant quenching of DOX (turned ‘OFF’ state) fluorescence at physiological pH (7.4) as confirmed through steady-state and time-resolved fluorescence measurements. It was also possible to recover the quenched DOX fluorescence (turned ‘ON’ state) with the release of DOX selectively in cancer cell lines, plausibly due to higher glutathione (GSH) levels and acidic pH. In vitro cellular studies asserted the safe nature of P2NPs against non-cancerous cells (HEK-293T) while exhibiting significantly higher drug-induced cytotoxicity against cancerous cells (MCF-7) compared to free DOX. Moreover, when P2AuNPs were incubated with HEK-293T and MCF-7 cells, a fluorescence turn ‘ON’ for DOX was observed only in MCF-7 cells after the release of DOX, thereby providing an opportunity to improve the sensitivity of imaging and real-time monitoring of drug release. Together, this integrated theranostic system not only has the potential to enhance the precision and effectiveness of cancer therapy but also offers improved monitoring capabilities, representing a significant advancement in tailored nanomedicine.