title: Supramolecular nanoparticles that target phosphoinositide-3-kinase overcome insulin resistance and exert pronounced antitumor efficacy.
abstract: The centrality of phosphoinositide-3-kinase (PI3K) in cancer etiology is well established, but clinical translation of PI3K inhibitors has been limited by feedback signaling, suboptimal intratumoral concentration, and an insulin resistance "class effect." This study was designed to explore the use of supramolecular nanochemistry for targeting PI3K to enhance antitumor efficacy and potentially overcome these limitations. PI3K inhibitor structures were rationally modified using a cholesterol-based derivative, facilitating supramolecular nanoassembly with L-α-phosphatidylcholine and DSPE-PEG [1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polythylene glycol)]. The supramolecular nanoparticles (SNP) that were assembled were physicochemically characterized and functionally evaluated in vitro. Antitumor efficacy was quantified in vivo using 4T1 breast cancer and K-Ras(LSL/+)/Pten(fl/fl) ovarian cancer models, with effects on glucose homeostasis evaluated using an insulin sensitivity test. The use of PI103 and PI828 as surrogate molecules to engineer the SNPs highlighted the need to keep design principles in perspective; specifically, potency of the active molecule and the linker chemistry were critical principles for efficacy, similar to antibody-drug conjugates. We found that the SNPs exerted a temporally sustained inhibition of phosphorylation of Akt, mTOR, S6K, and 4EBP in vivo. These effects were associated with increased antitumor efficacy and survival as compared with PI103 and PI828. Efficacy was further increased by decorating the nanoparticle surface with tumor-homing peptides. Notably, the use of SNPs abrogated the insulin resistance that has been associated widely with other PI3K inhibitors. This study provides a preclinical foundation for the use of supramolecular nanochemistry to overcome current challenges associated with PI3K inhibitors, offering a paradigm for extension to other molecularly targeted therapeutics being explored for cancer treatment.
authors.affiliation: Authors' Affiliations: Laboratory for Nanomedicine, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital; Harvard-MIT Division of Health Sciences and Technology; Indo-US Joint Center for Nanobiotechnology, Cambridge; Department of Pathology, Brigham and Women's Hospital; Harvard Medical School, Boston; Dana Farber Cancer Institute, Brookline, Massachusetts; Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, San Diego; Center for Nanomedicine, Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, California; Indian Institute for Science Education Research (IISER); and National Chemical Laboratories, Pune, India.
authors.forename: Ashish A
authors.initials: AA
authors.lastname: Kulkarni
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Roy
authors.forename: Poornima S
authors.initials: PS
authors.lastname: Rao
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wyant
authors.forename: Ayaat
authors.initials: A
authors.lastname: Mahmoud
authors.forename: Madhumitha
authors.initials: M
authors.lastname: Ramachandran
authors.forename: Poulomi
authors.initials: P
authors.lastname: Sengupta
authors.forename: Aaron
authors.initials: A
authors.lastname: Goldman
authors.forename: Venkata Ramana
authors.initials: VR
authors.lastname: Kotamraju
authors.forename: Sudipta
authors.initials: S
authors.lastname: Basu
authors.forename: Raghunath A
authors.initials: RA
authors.lastname: Mashelkar
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Dinulescu
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D008970:Molecular Weight; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors