title: Algorithm for Designing Nanoscale Supramolecular Therapeutics with Increased Anticancer Efficacy.
abstract: In the chemical world, evolution is mirrored in the origin of nanoscale supramolecular structures from molecular subunits. The complexity of function acquired in a supramolecular system over a molecular subunit can be harnessed in the treatment of cancer. However, the design of supramolecular nanostructures is hindered by a limited atomistic level understanding of interactions between building blocks. Here, we report the development of a computational algorithm, which we term Volvox after the first multicellular organism, that sequentially integrates quantum mechanical energy-state- and force-field-based models with large-scale all-atomistic explicit water molecular dynamics simulations to design stable nanoscale lipidic supramolecular structures. In one example, we demonstrate that Volvox enables the design of a nanoscale taxane supramolecular therapeutic. In another example, we demonstrate that Volvox can be extended to optimizing the ratio of excipients to form a stable nanoscale supramolecular therapeutic. The nanoscale taxane supramolecular therapeutic exerts greater antitumor efficacy than a clinically used taxane in vivo. Volvox can emerge as a powerful tool in the design of nanoscale supramolecular therapeutics for effective treatment of cancer.
authors.affiliation: Department of Medicine, Harvard Medical School , Boston, Massachusetts 02115, United States.|Harvard-MIT Division of Health Sciences and Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: India Innovation Research Center , Invictus Oncology, New Delhi 110092, India.
authors.forename: Prithvi
authors.initials: P
authors.lastname: Pandey
authors.forename: Poornima
authors.initials: P
authors.lastname: Rao
authors.forename: Ayaat
authors.initials: A
authors.lastname: Mahmoud
authors.affiliation: Department of Medicine, Harvard Medical School , Boston, Massachusetts 02115, United States.|Harvard-MIT Division of Health Sciences and Technology , Cambridge, Massachusetts 02139, United States.|Harvard Digestive Diseases Center , Boston, Massachusetts 02115, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Goldman
authors.affiliation: Department of Medicine, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Venkata
authors.initials: V
authors.lastname: Sabbisetti
authors.forename: Shashikanth
authors.initials: S
authors.lastname: Parcha
authors.forename: Siva Kumar
authors.initials: SK
authors.lastname: Natarajan
authors.forename: Vineethkrishna
authors.initials: V
authors.lastname: Chandrasekar
authors.forename: Daniela
authors.initials: D
authors.lastname: Dinulescu
authors.affiliation: India Innovation Research Center , Invictus Oncology, New Delhi 110092, India.
authors.forename: Sudip
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Medicine, Harvard Medical School , Boston, Massachusetts 02115, United States.|Harvard-MIT Division of Health Sciences and Technology , Cambridge, Massachusetts 02139, United States.|Dana Farber Cancer Institute , Boston, Massachusetts 02115, United States.
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D000465:Algorithms; D056004:Molecular Dynamics Simulation; D053758:Nanoparticles; D049329:Nanostructures; D009369:Neoplasms / Q000628:therapy*
keywords: cancer; drug delivery; molecular dynamics simulations; supramolecular nanoparticles; taxanes