A Mannose 6-Phosphate Decorated Transformable Nanoplatform for Targeted Uptake in HER2+ Tumors

点击翻译按钮获取中文摘要

Abstract Human epidermal growth factor receptor 2 (HER2) is overexpressed in over 20% breast cancers, and to a lesser degree in gastric cancers, colorectal cancer, ovarian cancers and bladder cancers. In HER2+ tumors, HER2s are massively overexpressed and constitutively dimerized, leading to unrelenting activation of down-stream proliferation and survival pathways and malignant phenotype. Because of the high expression level of HER2, trastuzumab and pertuzumab, the two anti-HER2 monoclonal antibodies are ineffective as monotherapy against these tumors. They need to be given in combinations with other HER2-targeted therapy, chemotherapy or hormonal therapy. Here we will optimize and further improve a novel HER2-mediated, peptide-based, and non-toxic transformable nano-agent that has been proven to be highly efficacious as a monotherapy against HER2+ breast cancer xenograft models. This receptor- mediated transformable nanotherapy is comprised of a peptide with unique domains that allow self- assembly forming micelles under aqueous conditions and transformation into nanofibrils at the tumor site, where HER2 is encountered. The resulting nanofibrillar network effectively suppresses HER2 dimerization, and downstream signaling leading to increased tumor cell death and complete remission of the HER2+ tumors in xenograft models. Protein modulation has been a goal of drug designers since the development of tissue specific targets and is crucial to the advancement and improvement of patient care. Several strategies have recently been developed including PROTACs, PHOTACs, and LYTACs. These new classes of compounds employ normal cellular machinery to degrade specific therapeutic target proteins. Currently, LYTACs employ mannose 6-phosphate (M6P) receptors to act as carriers for endocytosis of extracellular protein/receptors to the lysosome. These carriers have demonstrated to be powerful enough to internalize macromolecules decorated with mannose 6-phosphate, such as antibodies. For this supplement, we will modify our nanoplatform to generate a novel HER2-targeting transformable cancer targeting nanoplatform (TCTN) that not only can directly suppress HER2 dimerization and signaling leading to tumor cell death, but can also sequester and degrade HER2 in the lysosome. Additionally we will investigate the potential of TCTN to deliver paclitaxel to the tumor site To achieve this, we will incorporate to the transformable nanoplatform HER2 binding ligands, mannose 6- phosphate and paclitaxel. Specific Aims: 1) to explore TCTN as a targeted drug carrier 2) to design, synthesize, and characterize mannose 6-phosphate decorated TCTN to induce lysosomal based degradation of HER2 and increase uptake of paclitaxel 3) to evaluate the biodistribution and therapeutic efficacy of paclitaxel containing and M6P decorated nanoparticles