title: Bioengineered vaults: self-assembling protein shell-lipophilic core nanoparticles for drug delivery.
abstract: We report a novel approach to a new class of bioengineered, monodispersed, self-assembling vault nanoparticles consisting of a protein shell exterior with a lipophilic core interior designed for drug and probe delivery. Recombinant vaults were engineered to contain a small amphipathic α-helix derived from the nonstructural protein 5A of hepatitis C virus, thereby creating within the vault lumen a lipophilic microenvironment into which lipophilic compounds could be reversibly encapsulated. Multiple types of electron microscopy showed that attachment of this peptide resulted in larger than expected additional mass internalized within the vault lumen attributable to incorporation of host lipid membrane constituents spanning the vault waist (>35 nm). These bioengineered lipophilic vaults reversibly associate with a sample set of therapeutic compounds, including all-trans retinoic acid, amphotericin B, and bryostatin 1, incorporating hundreds to thousands of drug molecules per vault nanoparticle. Bryostatin 1 is of particular therapeutic interest because of its ability to potently induce expression of latent HIV, thus representing a preclinical lead in efforts to eradicate HIV/AIDS. Vaults loaded with bryostatin 1 released free drug, resulting in activation of HIV from provirus latency in vitro and induction of CD69 biomarker expression following intravenous injection into mice. The ability to preferentially and reversibly encapsulate lipophilic compounds into these novel bioengineered vault nanoparticles greatly advances their potential use as drug delivery systems.
authors: Department of Biological Chemistry, David Geffen School of Medicine at University of California Los Angeles , Los Angeles, California 90095, United States.
authors: Daniel C
authors: DC
authors: Buehler
authors: Matthew D
authors: MD
authors: Marsden
authors: Sean
authors: S
authors: Shen
authors: Daniel B
authors: DB
authors: Toso
authors: Xiaomeng
authors: X
authors: Wu
authors: Joseph A
authors: JA
authors: Loo
authors: Z Hong
authors: ZH
authors: Zhou
authors: Valerie A
authors: VA
authors: Kickhoefer
authors: Paul A
authors: PA
authors: Wender
authors: Jerome A
authors: JA
authors: Zack
authors: Leonard H
authors: LH
authors: Rome
mesh_terms: D000818:Animals; D057005:Bioengineering; D054713:Bryostatins / Q000737:chemistry; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry*; D017433:Protein Structure, Secondary; D020394:Vault Ribonucleoprotein Particles / Q000737:chemistry*
chemical_list: D054713:Bryostatins; D004337:Drug Carriers; D020394:Vault Ribonucleoprotein Particles; C046785:bryostatin 1