Targeted liposomal drug delivery to pediatric sarcomas: beyond the EPR effect
Dzhangar Dzhumashev, MSc (PhD fellow sponsored by the PRC) - Department of BioMedical Research, University of Bern, Switzerland (firstname.lastname@example.org)
Pediatric sarcomas account for about 15% of pediatric cancers. These sarcomas often display a highly aggressive behavior with early tendency for development of metastasis. Although current treatment regimens, including surgery and chemotherapy, can achieve good response rates, the relapse rate is generally high, with an extremely poor prognosis. The aggressive chemotherapies needed to fight relapsed tumors have a significant toxicity generating late side effects, a major complication in pediatric oncology.
Liposomal formulations can decrease systemic side effects by passive accumulation through the enhanced permeability and retention (EPR) effect. In this project, we aim to investigate the possibility to further increase local drug concentration by targeting liposomes to the tumor site.
Selected ligands (peptides, nanobodies) showing high affinity for diseased cells or tissue can indeed be conjugated to drugs, macromolecules, or colloidal particles and bring their cargo to the tumor in a relatively selective fashion.1)2)3) In the past years, our group has identified peptides and nanobodies with strong affinity for rhabdomyosarcoma4) (RMS) the most common soft tissue sarcoma in children. Moreover, we have optimized the formulation of peptide- and nanobody-targeted liposomes loaded with vincristine (VCR). Here, we want to identify the optimal liposomal formulation for targeted drug delivery to rhabdomyosarcoma.
Benefit for the community
The development of targeted therapies for pediatric sarcomas is our priority to improve existing therapies and reduce long-term side effects. We have invested considerable efforts and have achieved promising results in the identification of specific targeting ligands for rhabdomyosarcoma and development of targeted liposomes. Now we want to take our commitment a step closer to the clinical application. This project is focused on rhabdomyosarcoma, because we have a long-standing experience with this disease, but we plan to broaden our approach to treat other significant pediatric malignancies such as Ewing’s sarcoma and osteosarcoma.
More efficient and less toxic therapies for pediatric sarcomas will hopefully increase survival rates and have a profound positive impact on the quality of life of pediatric sarcomas survivors.
Prolonged circulation and increased tumor accumulation of liposomal vincristine in a mouse model of rhabdomyosarcoma
Nanomedicine (Lond.) 12, 1135-1151
Peptides for tumor-specific drug targeting: state of the art and beyond
J. Mater. Chem. B 5, 4348-4364
Furin Targeted Drug Delivery for Treatment of Rhabdomyosarcoma in a Mouse Model
PLoS One 5, e10445
Nat. Rev. Dis. Primers 5, 1