Biomedical Engineering Reference
In-Depth Information
In the majority of cases the intracellular internalization of nanocarriers involves
enodocytosis (Prokop and Davidson
2008
). Endosomes are naturally designed to
start the degradation process of the substances invading the cell membrane, and as
a result have much lower pH than that of the cytoplasm. Thus, endosomal escape is
one of the most important processes to prevent the deactivation of pharmaceutics
and enable their efficient action. A variety of strategies to enhance endosomal
escape are discussed in the literature, including pH-sensitive carriers (Park et al.
2010a
; Kakimoto et al.
2010
; Torchilin
2006
), photochemical activation (Selbo
et al.
2010
) and the use of endosome-disruptive agents (Nakase et al.
2010
). As an
example, surface charge of nanoparticles plays a vital role in determining their
destination. Transition from pH 7 to an endosomal acidic pH resulted in the
release of the particles from the endosome into the cytoplasm (Panyam et al.
2003
;
Panyam and Labhasetwar
2004
). Cationic quantum dots (QDs) conjugated with
polyethylenimine (PEI) have been demonstrated to be suitable siRNA carriers to
silence specific target genes and also to study intracellular trafficking pathways
(Lee et al.
2010b
). Cell Penetrating Peptides have been used to deliver therapeutic
agents to intracellular sites using nanoparticles. Mitochondria are characteristic of
possessing a high membrane potential and so attract positively charged particles
like oligoguanidines organelle (Rothbard et al.
2005
). Nanocarriers modified with
mitochondriotropic triphenylphosphonium have shown effective delivery of a
model lipophilic molecule, ceramide, to mammalian mitochondria, increasing its
therapeutic efficiency both
in vitro
and
in vivo
(Sarathi et al.
2008
). Localization
signals specific to organelles need to be incorporated on the nanovector surface
to be directed to specific organelles (Prokop and Davidson
2008
). NLS (nuclear
localization signal) peptides interact with cytosolic agents and facilitate targeted
delivery to the nucleus. Low molecular weight protamine, which is structurally
similar to HIV-TAT (Human Immunodeficiency Virus Trans-Activator of
Transcription) peptide, has been coupled to plasmid DNA, permitting nuclear
specific delivery (Park et al.
2003
). Viral proteins and combinations of organelle
targeting peptides and cell penetrating peptides are being investigated for intra-
cellular targeting (Tkachenko et al.
2003
; Vasir and Labhasetwar
2007
). Current
research on targeting small peptides and peptide-conjugating molecules which
are specific to the targeting site and of therapeutic potential, are being conducted
(Mendoza et al.
2005
).
The following sections summarize various mechanisms used to traffic peptides,
proteins, and drugs within vesicles to four significant organelles: lysosomes (and
late-endosomes), endoplasmic reticulum (ER), mitochondria, and nucleus.
4.3
Endosomes, Lysosomes and Cytoplasmic Targeting
The treatment for a variety of genetic, metabolic, and oncologic diseases are
focused on targets located within the cytoplasm. Thus, mechanisms to release nano-
particles into the cytoplasm (either through extra lysosomal trafficking or through
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