Nanoparticles to Cross Biological Barriers - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 98

barrier [132]. Micellar formulations and core-shell nanoparticles have also
been investigated for transdermal delivery [108, 136, 137]. Nanoparticle
formulations can be combined with other delivery mechanisms such as
microneedles [138], chemical enhancers [121], or mechanical stimuli [139] in
order to optimize skin permeation. It is believed that the controlling factors
in transcutaneous transport of nanoparticles are size, surface charge, and
lipophilicity.
The transdermal route is a promising avenue for drug delivery. Along with
current advances in transdermal delivery methods, nanoparticles may serve
as an excellent vehicle for carrying drugs. In this regard, nanoparticles will
need to be either localized in the skin for cutaneous delivery, or be delivered
transdermally into systemic circulation. Transdermal delivery is effective
owing to its ability to deliver doses over long periods of time, avoid first-pass
clearance in the liver, and avoid metabolic degradation in the GI tract.
Long-Circulating NPs
The inherent material properties of nanoparticles can be used for specific
applications as a non-ligand-mediated targeted systems. Anderson et al. [43]
developed new materials defined as “lipidoid” for siRNA delivery using
high-throughput in vitro screening. Their work determined the best formu-
lation to deliver siRNA in the liver at single nanomolar concentrations based
on serum stability and toxicity using macrophages, HeLa, and HepG2 cells.
In vivo non-human primate results showed significant knockdown at a very
low, 2.5 mg/kg dose. In contrast, long-circulating NPs will require reduced
mononuclear phagocyte system (MPS) uptake to increase their circulation
time and accumulation in the site to be treated. Nanocarriers can be engi-
neered to reduce their clearance from systemic circulation [140-142]. Surface
functionalization can be tuned to increase residence time in the blood,
reduce nonspecific body distribution, and, in some cases, target specific tis-
sues or cell surface antigens with targeting ligands such as peptides, apat-
mers, antibodies, and small molecules. For instance, it is well established
that hydrophilic polymers, most notably poly(ethylene glycol) (PEG), can be
grafted, conjugated, or adsorbed to the surface of nanoparticles to form a
corona, which provides steric stabilization and confers “stealth” properties
that reduce rapid clearance, such as the prevention of protein adsorption.
Thus, over the past 20 years, numerous approaches to improve nanoparticle
blood residence and accumulation in specific tissues for therapy and diagno-
sis have been developed [140, 143, 144]. The resultant rapid clearance is due to
interaction with blood cells and proteins, phagocytosis by the mononuclear
phagocyte system (MPS) in the liver, and filtration by the spleen [142, 145].
Non-PEGylated liposome drug-encapsulated formulations accumulated