Breaching the protective cancer stroma with radiotherapy-responsive liposomes – REMOTECONTROL

Liposomes have been the most successful type of nanomedicine for cancer patients, playing a leading role in improving the tolerability of chemotherapeutics. However, to advance the success of liposomal drug delivery and cancer treatment, new approaches to physically trigger drug release in cancer tissues and increase the permeability of the protective cancer stroma are needed. This project will investigate whether radiocatalytic nanomaterials can be integrated in liposomes for spatiotemporal-controlled drug release, the alleviation of cancer desmoplasia, and improved efficacy of co-encapsulated drugs.

Liposomes will be composed of oxidation-susceptible phospholipids that encapsulate hydrophilic drugs in their aqueous core. Radiation-absorbing nanomaterials will be included in the liposomes to produce high levels of reactive oxygen species when activated by X-rays. This will oxidize the liposomes and facilitate the release of the encapsulated drugs. Simultaneously, the cytotoxicity of the oxidants is expected to reduce the high cell densities in the tumor periphery, enabling the therapeutics to deeply permeate the cancer tissues following their release. This customizable strategy will be developed in the context of pancreatic cancer, a chemoresistant form of cancer with poor survival rates. This project develops a multidisciplinary approach that includes the use of monochromatic synchrotron radiation to investigate radiation-induced drug release, adaptive optics microscopy and ex vivo mass spectrometry to study tissue permeability in 3D cultures and mouse models of desmoplastic pancreatic cancer.

Radiotherapy-controlled drug release from liposomes is a ground-breaking novel concept, and its capacity to increase cancer tissue permeability has never before been demonstrated. When successful, new avenues for controlled liposomal drug delivery will emerge that can significantly advance the standard-of-care for many cancer patients.