Biomedical Engineering Reference
In-Depth Information
6.3.4.5 Albumin Nanoparticles
Albumin, a major serum protein component, possesses several amino and carboxylic groups, which
are available for covalent modifi cation and drug or protein attachment. Albumin nanoparticles can be
prepared by a desolvation-crosslinking method, where albumin dissolved in water is desolvated by
dropwise addition of ethanol and glutaraldehyde to induce the crosslinking of albumin nanoparticles
[23]. Albumin nanoparticles are investigated for DNA delivery because DNA-albumin can avoid
opsonization and uptake by the macrophage system encountered by positively charged complexes
in vivo
[68,69]. In January 2005, the FDA approved the use of paclitaxel albumin nanoparticles
(~30 nm) (ABI-007 or Abraxane, American Pharmaceutical Partners, Schaumburg, IL) for the clinical
treatment of metastatic breast cancer [70]. The overall response rate for Abraxane was 33%, compared
with 19% for Taxol [71]. Several methotrexate immunoconjugates and 5-fl uoro-2'-deoxyuridine have
been prepared with human serum albumin as an intermediate carrier. The conjugates were more cyto-
toxic
in vitro
(IC
50
1.1 ng/mL methotrexate) against osteogenic sarcoma cells than free methotrexate
(IC
50
2.8 ng/mL) [23].
6.4
IN VIVO
BIODISTRIBUTION
6.4.1 B
IODISTRIBUTION
OF
P
ARTICULATE
D
RUG
C
ARRIERS
The fate of a drug carrier after administration
in vivo
is determined by a combination of several
processes: distribution and elimination when given intravenously; absorption, distribution, and elimi-
nation when an extravascular route is used. Regardless of the mechanisms involved, each of these
processes depends mainly on the physiochemical properties of the drug carrier [49].
Phagocytosis is the defense mechanism of the body that clears invading pathogens, unwanted
cells, and small particles. Phagocytic cells primarily consist of circulating polymorphonuclear
leukocytes and mononuclear phagocytes. These phagocytes originate from the bone marrow but
become fi xed in certain tissue sites, primarily the liver, spleen, and bone marrow, to form the
mononuclear phagocytic system (MPS) or RES [49]. In the biological environment following
intravenous administration, particulate drug carriers will rapidly interact with plasma proteins.
The adsorption of these plasma proteins is known as opsonization. Classical examples of opsonic
molecules include various subclasses of immunoglobulins, complement proteins like C1q and
generated C3 fragments (C3b, iC3b), apolipoproteins, von Willebrand factors, thrombospondins,
fi bronectins, and mannose-binding proteins [72].
Opsonized particles are recognized by the RES or MPS, which is comprised of macrophages
related to liver (Kuffer cells), spleen, lymph nodes (perivascular macrophage), nervous system
(microglia), and bones (osteoclasts) [2]. These macrophages internalize the opsonized nanoparticles
through phagocytosis and deliver them to the liver, spleen, kidney, lymph nodes, and bone marrow.
This clearance can occur within 0.5-5 min, thus removing the active nanoparticles from the
circulation and prevent their access to the tumor tissue [2].
Particulate uptake or ingestion proceeds by endocytosis following adhesion to the phagocytes
or, alternatively, in the apparent absence of an adhesion step by pinocytosis, whereby small particles
are internalized by endocytosis. Once internalized, the endosome or phagosome so formed will fuse
with lysosomes, which will expose the carrier to highly active enzyme systems [49]. Such propen-
sity of MPS macrophages for endocytosis or phagocytosis provides an opportunity to effi ciently
deliver therapeutic agents to these cells using conventional nanoparticles. This biodistribution can
be of benefi t for the chemotherapeutic treatment of MPS-localized tumors (e.g., hepatocarcinoma or
hepatic metastasis arising from digestive tract, gynecological cancers, or bronchopulmonary tumors
[primitive tumors or metastasis] including nonsmall cells tumors and small cells tumors, myeloma,
and leukemia) [28]. In addition, the modifi cation of surface properties of the nanoparticles and
reducing their size to less than 100 nm can mask them so that they are no longer recognized by the
MPS and remain in circulation for longer periods of time [2].
