Recombinant nanocapsid for targeted theranostic delivery
Julkaistu sarjassa
Jyväskylä studies in biological and environmental scienceTekijät
Päivämäärä
2017Oppiaine
Solu- ja molekyylibiologiaDevelopments in diagnostic and therapeutic delivery are trending towards
molecular level targeting with nano-platforms. Targeted delivery reduces
generalized distribution by localizing diagnostic and/or therapeutic
(theranostic) molecules to an intended target site. The first section of this thesis
proposes Hepatitis E Virus (HEV) nanocapsids as a vector to stabilize and
target theranostic delivery. Derived from the capsid protein of HEV, a feco-orally transmitted virus, HEV-like particles self-assemble in to non-infectious,
nanocapsids that can withstand harsh protease and pH conditions in the
mucosal system. The flexible nanocapsid surface protrusion domain is
amenable to substantial modification. Chemical modulation of nanocapsids was
achieved through surface conjugation to single solvent exposed cysteine sites.
In this thesis, nanocapsids chemically modulated with tumor-targeting ligands
exhibit cancer cell-specific binding and internalization, as well as in vivo tumor
detection. We also used cysteine sites to conjugate thiolate-protected gold
nanoclusters (AuNCs), which have molecule like qualities distinct from
colloidal gold nanoparticles (AuNPs). Specifically, Au102(pMBA)44 (Au102) and
maleimide-linked Au102 (Au102_C6MI) were conjugated to nanocapsid cysteine
through place exchange and maleimide-thiol coupling, respectively.
Au102_C6MI-bound nanocapsids were imaged in cryoEM and a 3D structure
was determined. The resolved structure of AuNC-bound nanocapsid revealed a
5-fold ring density attributable to AuNC densities. Rigid modelling supported
this finding. In the last section of this thesis, a recombinant enterovirus was
engineered to distinguish the role of structural vs. non-structural proteins in
Enterovirus B infection kinetics, replication and infection persistency. The
results indicated cell-receptor binding likely triggered lytic vs. non-lytic
infection, providing insight in to adaptive mechanisms of native virus cell
delivery.
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Julkaisija
University of JyväskyläISBN
978-951-39-7118-2ISSN Hae Julkaisufoorumista
1456-9701Asiasanat
Metadata
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- Väitöskirjat [3499]
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