Biomedical Engineering Reference
In-Depth Information
been delivered successfully to the nucleus. Several nanoparticles are already in
clinical trials for metastatic and solid tumors, though delivery of therapeutics to the
cytosol is just as effective, though dependent on the properties of the therapeutic
itself. Gene therapy is a novel and upcoming field as nanoparticle payloads can
include DNA, RNA, RNAi and siRNA, all of which mediate specific therapeutic
effects depending on their individual properties (Hart
2010
; Lares et al.
2010
).
5
Multi-Site Targeting
Targeting therapeutics toward a specific organelle is in vogue. One step further is
manipulating the numerous signaling elements of available proteins to design novel
carriers capable of targeting multiple organelles (Lim
2007
). With the discovery of
specific intracellular targets for advanced therapeutics we can envision systems
programmed for simultaneously delivery of agents to various subcellular locations,
providing a paradigm shift in our approach to disease management. Bearing this in
mind, we have recently introduced a concept of advanced nanovectors called Logic-
Embedded Vectors (LEVs) (Ferrari
2010
), which describe a nanoassembly responsi-
ble for the the co-delivery of multiple nanoparticles that cooperate with biomolecules
and intracellular organelles to target multiple subcelluar locations simultaneously or
sequentially. These LEVs are designed to overcome biological barriers to transport
and distribute therapeutic agents to unique sites. A prominent example of LEV is the
multistage delivery systems comprised of stage-one porous silicon microparticles
loaded with second stage nanoparticles (Serda et al.
2010b
). Each stage of the system
is formulated to overcome a biological barrier such as enzyme degradation, transport
through the vascular endothelium and molecular efflux pumps. As an example, stage
one components target afflicted endothelia surface moieties through attachment of
ligands, such as antibodies, peptides and aptamers, to the surface of the particles.
Second-stage components, concentrated within the stage one vector, target at a sec-
ond level, leading to delivery of a large quantity of therapeutic and/or imaging agents.
LEVs that incorporate superparamagnetic iron oxide nanoparticles into porous silicon
have recently been demonstrated (Ferrati et al.
2010
; Serda et al.
2010b
).
Aminosilylation of the nanoparticles creates functional sites for conjugation of target-
ing ligands, such as antibodies specific for VEGFR-2 and PECAM (Platelet
Endothelial Cell Adhesion Molecule) which facilitate endothelial association.
Intracelluar trafficking of the LEVs have been demonstrated in transmission electron
microscopy images using J774 mouse macrophages (Fig.
6
; Serda et al.
2010a, b
).
We have demonstrated that intracellular trafficking of LEVs can be designed to
target several organelles simultaneously as a function of surface modifications of
each of the components (Serda et al.
2010b
). LEVs loaded surface-modified iron
oxide nanoparticles have been shown to deliver nanoparticles to specific organelles,
specifically the endosome and cytoplasm in one case, and in another case, endo-
somes and novel membrane-bound vesicles that are candidates for exocytosis.
Silicon microparticles were transported along the endosomal pathway while
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