Biomedical Engineering Reference
In-Depth Information
and between different tumors, as well as from patient to patient. 20,21 Second,
some tumor types (e.g., pancreatic tumor) have low vascularity, which may limit
the nanomedicine access to the tumor parenchyma. Finally, clearance by the
reticuloendothelial system (RES) and the nanomedicine stability can also
dramatically affect the delivery efficiency of the nanomedicine to the tumor site.
d n 4 y 3 n g | 0
2.2.1 Nanomedicine Clearance by the Reticuloendothelial System
Opsonization is the process in which opsonin proteins bind to the surface of a
foreign organism or particle so that they are more visible to phagocytic cells.
Depending on their surface properties, such as surface charge and hydro-
phobicity, nanomedicines can be opsonized within minutes upon exposure to
blood. 22 Subsequently, macrophages in the liver, spleen, and bone marrow
rapidly take up opsonized nanomedicines. 23 As a result, the nanomedicines are
removed
bloodstream, 24
from
the
which
will
limit
the
passive
targeting
efficiency to tumors.
To prevent phagocytic clearance by the RES, the most commonly used
strategy is to introduce poly(ethylene glycol) (PEG) or other neutral
hydrophilic polymers (e.g., polyvinylpyrrolidone, PVP) onto the surface of
nanomedicines. 25,26 The resulting stealth nanomedicines contain a hydrated
barrier that hinders the adsorption of opsonin proteins. 27 PEGylation
effectively reduces the rate of RES uptake and increases the circulation half-
life of various types of nanomedicines. 28,29 The most representative example is
the PEGylated Doxil 1 , which prolongs the blood circulation time of
doxorubicin to 45 hours in humans. Our labs pioneered the development of
b-lapachone (b-lap) nanomedicines by loading the drug into poly(ethylene
glycol)-co-poly( D , L -lactic acid) (PEG-PLA, MW 10,000 Da) polymeric
micelles. 9 The pharmacokinetics of b-lap micelles were examined in athymic
mice bearing A549 NSCLC xenografts. The blood concentration of b-lap
micelles was prolonged with an elimination half-life (t 1/2 , b ) of 28 h, much
longer than b-lapNHP-b-CD complexes (t 1/2 , b 5 24 min). As a result, b-lap
micelles
showed
higher
tumor
accumulation
and
significantly
improved
antitumor efficacy than b-lapNHP-b-CD complexes.
2.2.2 Tumor Penetration by Nanomedicines
Systemic delivery of nanomedicines to tumors is a three-step process. Firstly,
nanoparticles transport to different regions of the tumors via blood vessels.
They must then cross the vessel wall and, finally, penetrate through the
interstitial space to reach the cancer cells. 30 Delivery of therapeutic agents
differs between tumor and normal tissues. The abnormal organization and
structure of the tumor vasculature lead to tortuous and leaky vessels and
heterogeneous vascular perfusion throughout the tumor. 31,32 In addition,
hyperpermeability of the abnormal vasculature and lack of functional
lymphatics lead to elevated levels of interstitial fluid pressure (IFP). 33
This
 
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