1. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
2. Cancer center, University of Virginia, Charlottesville, VA, USA.
3. Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA, USA.
4. Department of Pathology, University of Virginia, Charlottesville, VA, USA.
5. Department of Microbiology, University of Virginia, Charlottesville, VA, USA.
† Laboratory of Drug and Gene Delivery System, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan. (Current address)
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.
Keywords: genomics, proteomics, plectin, poly(ADP-ribose) polymerase, targeted drug delivery, epithelial ovarian cancer, pharmacokinetics, pharmacodynamics