Active targeting of rhabdomyosarcoma cells using helenalin-loaded functionalised cubosomes

Thesis

Rhabdomyosarcoma (RMS) is the most frequent paediatric soft tissue sarcoma and affects ~55 young patients in the UK every year. Even though multidisciplinary treatments such as chemotherapy, surgical resection and radiation therapy can be employed, the clinical outcomes for patients with metastatic or released/refractory RMS remains poor. In this study, helenalin was chosen as a candidate anti-tumour compound for RMS treatment, since it showed the highest anti-tumour efficacy towards paediatric tumour cells among numerous natural products from a previous high-throughput assessment. Nanoparticle encapsulation of drugs can improve the pharmacokinetics and anti-tumour potency of cargos, while at the same time decreasing off-target impact on healthy cells. Herein, helenalin was designed to be loaded into next-generation lipid nanoparticles, i.e., cubosomes. These cubic phase nanoparticles are self-assembled liquid crystalline nanoparticles possessing a honey-combed structure and have been reported to have high drug-loading capacity, biocompatibility, bio-adhesive and permeation capacity, and thermodynamic stability. The aim of this thesis was to evaluate the anti-tumour potential and mechanism of action of helenalin towards RMS cells and then to target the tumour cells in an active manner using multifunctional cubosomes carrying helenalin. It was found that helenalin suppressed the proliferation, cell cycle, migration, and colony formation of RMS cells, while inducing a relatively lower toxicity towards healthy control cells. The pivotal mechanism of anticancer action of helenalin was revealed to be ROS generation and oxidative stress in RMS cell death, while mitochondrial depolarisation, endoplasmic reticulum stress, and NF-𝛋B deactivation might also contribute to the cytotoxicity on a small scale. The cubosomes were fabricated using a top-down approach and further functionalised with hyaluronic acid, antibodies, and/or iron oxide nanoparticles. CD44 and CD221-directed magnetic cubosomes carrying helenalin showed active targeting towards RMS cells in vitro by enhancing the anti-tumour capacity of helenalin without causing additional side-effects.

Authors: Mun, HM

• DOI: 10.5287/ora-xo2dv0ggo
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: cancer therapy; active targeting; cubosome; nanomedicine
• Subjects: Cancer biology