Penetration-promoting polymeric micelles for the treatment of fibrotic cancers
Fibrotic tumors have a poor prognosis and are very difficult to treat. They are typically characterized by a dense stroma, in which the excessive deposition of extracellular matrix (ECM) components such as collagen prevents drugs and drug delivery systems from efficiently accumulating, penetrating and distributing at the pathological site. We aim to improve the treatment of fibrotic tumors and metastases via a combinatorial approach, encompassing very small-sized polymeric micelles co-loaded with a chemotherapeutic drug and with a microenvironment modulator. Specific aims include:
- development of π-π stacking stabilized polymeric micelles with a size of 30-40 nm and with very high drug co-loading capacity;
- evaluation of the therapeutic and priming potential of combining paclitaxel and dexamethasone in micelles, to debulk tumors and metastases and to suppress production of ECM components;
- analysis of the effect of double-drug-loaded micelle treatment on the tumor accumulation and distribution of subsequent micelle doses; and
- assessment of the therapeutic efficacy of double-drug-loaded micelles in monotherapy setups as well as in clinically relevant combination regimens.
Experiments will be performed in two established fibrotic mouse models (subcutaneous BxPC3 human pancreatic and 4T1 murine breast cancer) and findings will be validated in three more advanced models (spontaneous KPC murine pancreatic, 4T1 murine metastatic breast, and human patient-derived breast cancer xenografts (PDX)). Multimodal and multiscale imaging tools will be employed to study the accumulation, penetration, distribution and efficacy of the size-optimized double-drug-loaded polymeric micelles. Our efforts will contribute to a better understanding of the biological barriers limiting drug delivery to and into tumors and metastases, and they will assist in identifying novel chemical and pharmaceutical entities that can help to improve the treatment of fibrotic cancers.