title: Sequential application of a cytotoxic nanoparticle and a PI3K inhibitor enhances antitumor efficacy.
abstract: Nanomedicines that preferentially deploy cytotoxic agents to tumors and molecular targeted therapeutics that inhibit specific aberrant oncogenic drivers are emerging as the new paradigm for the management of cancer. While combination therapies are a mainstay of cancer chemotherapy, few studies have addressed the combination of nanomedicines and molecular targeted therapeutics. Furthermore, limited knowledge exists on the impact of sequencing of such therapeutics and nanomedicines on the antitumor outcome. Here, we engineered a supramolecular cis-platinum nanoparticle, which induced apoptosis in breast cancer cells but also elicited prosurvival signaling via an EGF receptor/phosphoinositide 3-kinase (PI3K) pathway. A combination of mathematical modeling and in vitro and in vivo validation using a pharmacologic inhibitor of PI3K, PI828, demonstrate that administration of PI828 following treatment with the supramolecular cis-platinum nanoparticle results in enhanced antitumor efficacy in breast cancer as compared with when the sequence is reversed or when the two treatments are administered simultaneously. This study addresses, for the first time, the impact of drug sequencing in the case of a combination of a nanomedicine and a targeted therapeutic. Furthermore, our results indicate that a rational combination of cis-platinum nanoparticles and a PI3K-targeted therapeutic can emerge as a potential therapy for breast cancer.
authors.affiliation: Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA.
authors.forename: Ambarish
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Roy
authors.affiliation: Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Goldman
authors.affiliation: Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA.
authors.forename: Sasmit
authors.initials: S
authors.lastname: Sarangi
authors.affiliation: Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA.
authors.forename: Poulomi
authors.initials: P
authors.lastname: Sengupta
authors.affiliation: Department of Applied Mathematics, University of Waterloo, Waterloo, ON, N2L 3G1, Canada.|Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, ON, N2L 3G1, Canada.
authors.forename: Colin
authors.initials: C
authors.lastname: Phipps
authors.affiliation: Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA.
authors.forename: Jawahar
authors.initials: J
authors.lastname: Kopparam
authors.affiliation: Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Oh
authors.affiliation: Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Basu
authors.affiliation: Department of Applied Mathematics, University of Waterloo, Waterloo, ON, N2L 3G1, Canada.|Center for Mathematical Medicine, Fields Institute for Research in Mathematical Sciences, Toronto, ON, M5T 3J1, Canada.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Kohandel
authors.affiliation: Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital. Department of Medicine, Harvard Medical School. Boston, MA, USA.
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt