Plectin-targeted liposomes enhance the therapeutic efficacy of a PARP inhibitor in the treatment of ovarian cancer

Abstract

Advances in genomics and proteomics drive precision medicine by providing actionable genetic alterations and molecularly targeted therapies, respectively. While genomic analysis and medicinal chemistry have advanced patient stratification with treatments tailored to the genetic profile of a patient's tumor, proteomic targeting has the potential to enhance the therapeutic index of drugs like poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors in breast and ovarian cancer patients with BRCA1/2 mutations have shown promise. About 10% of the patients who received Olaparib (PARP inhibitor) showed adverse side effects including neutropenia, thrombocytopenia and in some cases resulted in myelodysplastic syndrome, indicating that off-target effects were substantial in these patients. Through proteomic analysis, our lab previously identified plectin, a cytolinker protein that mislocalized onto the cell surface during malignant transformation of healthy ovarian tissue. This cancer specific phenotype allowed us to image pancreatic cancer successfully using plectin targeted peptide (PTP) conjugated to nanoparticles or displayed on capsid protein of adeno-associated virus (AAV) particles.Objective: The goal of this study was to integrate the available pharmacogenomics and proteomic data to develop effective anti-tumor therapies using a targeted drug delivery approach.Methods: Plectin expression and localization in human ovarian tumor specimens were analyzed followed by in vitro confirmation of cell surface plectin localization in healthy and ovarian cancer cell lines. PTP-conjugated liposomes were prepared and their specificity for plectin+ cells was determined in vitro and in vivo. A remote loading method was employed to encapsulate a PARP inhibitor (AZ7379) into liposomes. An ideal buffer exchange method and remote loading conditions were determined based on the amount of lipid and drug recovered at the end of a remote loading process. Finally, in vivo tumor growth studies were performed to determine the efficacy of PTP liposomes in preventing PARP activity in mice bearing OVCAR8 (high grade epithelial ovarian cancer (EOC)) tumors.Results: PTP liposomal AZ7379 delivery not only enhanced PARP inhibition but also resulted in decelerated tumor growth in mice bearing subcutaneous and intraperitoneal OVCAR8 tumors. In mice bearing subcutaneous or intraperitoneal tumors, treatment with PTP liposomes resulted in a 3- and 1.7-fold decrease in tumor volume, respectively, compared to systemic drug treatment.Conclusion: Targeted drug delivery assisted by genomic and proteomic data provides an adaptable model system that can be extended to effectively treat other cancers and diseases.

A nano-liposome formulation of the PARP inhibitor Talazoparib enhances treatment efficacy and modulates immune cell populations in mammary tumors of BRCA-deficient mice

“…Tumor specific proteins can also be conjugated onto liposomes to enhance targeted drug delivery. For example, plectin-targeted liposomes enhance the therapeutic efficacy of a PARP inhibitor (AZ7379) in the treatment of ovarian cancer in animal models 53. Recently, a solid lipid nanoparticle formulation of Talazoparib was reported and has been tested in BRCA1 mutant triple negative breast cancer cell lines in vitro .…”

Application of Phage-Displayed Peptides in Tumor Imaging Diagnosis and Targeting Therapy

“…Syp-1 is a stable and effective tumor targeting ligand and may strongly support the validity of peptide-mediated drug targeting therapy (Li et al 2013a ). Kelly et al designed PTP liposomal AZ7379 (a PARP inhibitor) delivery apparently decreased tumor growth and volume of ovarian cancer, which provides new opportunity to extend the treat efficiency of diseases (Dasa et al 2018 ).…”

The Expressions and Mechanisms of Sarcomeric Proteins in Cancers

“…For example, radiation alone can be used for treating patients with low plectin levels, while a combination of radiation with chemotherapy is used for patients with high plectin levels [131]. The use of liposome chemotherapeutics targeting plectin has improved the treatment of ovarian cancer [136]. Experimental evidence supporting the plectin in animal models suggests that some human cancers could also be related to plectin and hence could be treated by targeting plectin.…”

“…Pancreatic intraductal papillary mucinous neoplasm [127] ↑ NR Lung cancer [128] ↑ NR Colon carcinoma [129] ↑ Isoform-specific Prostate cancer [130] ↑ Nyalwidhe HNSCC [131] ↑ Erk 1/2 kinase Breast cancer [132] ↑ Periplakin Ovarian cancer [136] ↑ PARP Nesprin-1…”