Abstract 1950: LHRH Peptide decorated cross-linked micelles for the targeted drug delivery to breast cancer

Abstract

Abstract We have recently developed a series of micellar nanoparticles (NPs) based on linear polyethylene glycol (PEG) and dendritic cholic acids (CA) block copolymer (telodendrimer), for the targeted delivery of chemotherapeutic drugs in the treatment of cancers. The tumor targeting specificity and efficiency of drug-loaded NPs might be further improved by the decoration of cancer cell surface targeting ligands. LHRH (Luteinizing hormone releasing hormone), a natural hormone peptide, is able to bind specifically to the LHRH receptor, which has been reported to be over-expressed in more than 50% breast cancer patients. In the present study, we incorporated the passive targeting of our micellar NPs and the active targeting of LHRH peptide into a single platform with an attempt to further improve the therapeutic index of NPs delivered drugs in the treatment of breast cancer. We synthesized the LHRH peptide on the tentagel resin bead via the solid-phase peptide synthesis method, and demonstrated that human breast cancer cell lines MDA-MB-231 and MDA-MB-435 were able to bind strongly with LHRH peptide beads. Besides breast cancer cell lines, immunohistochemistry staining further demonstrated LHRH peptide was able to specifically bind to human breast tumor tissue as well as transgenic murine mammary carcinoma tissue, but not to normal breast tissue. Alkyne-containing LHRH peptides were successfully conjugated to the azide group at the distal PEG terminus of PEG5k-Cys4-L8-CA8 telodendrimer (cross-linked micelle forming unit) via the “click chemistry”. LHRH peptide ligand significantly enhanced the intracellular delivery of cross-linked micelles in both MDA-MB-231 and MDA-MB-435 breast cancer cells. In addition, the enhanced uptake of LHRH-targeted micelles in those cells can be inhibited by the addition of access of LHRH antibody, indicating the LHRH receptor-medicated internalization. The co-localization of internalized FITC-labeled LHRH-micelles with lysosomal compartment in human breast cancer cells were also observed, suggesting that the endocytosis pathway is likely to be involved in the internalization process. Furthermore, when loaded with paclitaxel (PTX), LHRH-micelles had significantly higher in vitro cellular toxicities against breast cancer cells as compared with the non-targeted micelles. The in vivo biodistribution, tumor targeting specificity and therapeutic efficacies of LHRH targeted micelles in MDA-MB-231 xenograft mouse model are currently under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1950. doi:1538-7445.AM2012-1950