Stimuli-responsive metal-loaded vesicular nanoparticles for therapeutic and diagnostic applications

Abstract

The rising demand for precision drug delivery in cancer therapy has led to the development of stimuli-responsive nanocarriers such as thermosensitive liposomes (TSLs). These systems offer spatiotemporal control over drug release, aiming to maximise therapeutic efficacy while minimising systemic toxicity. In this study, dual- triggered TSLs incorporating gold (Au) and silver (Ag) nanoparticles were developed for enhanced delivery of the chemotherapeutic agent doxorubicin (Dox). Liposomes composed of DPPC/Chol were fabricated using the thin-film hydration method followed by extrusion to achieve uniform vesicle size. Au and Ag nanoparticles were synthesised separately and incorporated into the lipid bilayer during hydration. Active loading of Dox was achieved via a pH gradient technique, resulting in high encapsulation efficiency (~90%). The hybrid liposomes demonstrated effective temperature-sensitive release, with up to 80% Dox release observed at the lipid phase transition temperature (Tm ~42 °C). Including metallic nanoparticles further enabled light-triggered release: near-infrared (NIR) irradiation induced localised surface plasmon resonance (LSPR), producing localised heating and an additional 30% increase in Dox release. The optimised DPPC/Chol/Au/Ag/Dox formulation exhibited excellent colloidal stability, with less than 5% drug leakage at 37 °C over 24 hours. Upon external stimulation, rapid drug release was observed, achieving near-complete release within 15 minutes of heating or 3 minutes of light exposure. In vitro cytotoxicity assays were performed on MCF-7 and SKBR-3 breast cancer cell lines to assess therapeutic efficacy. The TSLs showed minimal cytotoxicity under physiological conditions, confirming low off-target effects. Upon activation by temperature or NIR light, a significant increase in cytotoxicity was noted. The dual-metallic TSLs outperformed single-metallic counterparts, achieving 20% and 15% greater cytotoxicity than Au- and Ag-only formulations. Notably, up to 97% cell death was observed compared to 65–85% for free Dox. These results demonstrate that the dual- metallic hybrid TSL system offers highly efficient, spatiotemporally controlled drug delivery. Its enhanced release profile, superior cytotoxicity, and excellent stability position it as a strong candidate for clinical translation in targeted cancer therapy.

Date of Award	2024
Original language	English
Awarding Institution	University of Brighton
Supervisor	Dipak Sarker (Supervisor), Laila Kudsiova (Supervisor) & Irina Savina (Supervisor)