Nanoparticles to Cross Biological Barriers - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 100

In addition to the paracellular route of exit from the circulation, NPs can
be engineered to cross physical barriers in a process known as transcytosis ,
the intracellular transport across a cell [69, 155, 156]. This allows the passage
of macromolecules through the endothelium/epithelium, and is thought to
be size dependent, whereby larger macromolecules pass through less easily
than smaller molecules [157-160]. Schnitzer et al. [159, 160] have developed
an antibody that binds specifically to lung caveola for the delivery of thera-
peutics across the endothelium barrier. The luminal expression of caveola
on the lung endothelium enabled the transport from blood circulation to
reach tissue accumulation of ~90% in less than one hour. Thus, the strategy
to target caveola differentially expressed in specific tissues offers exciting
possibilities for imaging and therapy.
Tissue Diffusion: Effect of Size, Charge, and Shape
Once out of the circulation, nanoparticles will accumulate in the periph-
eral extracellular matrix of the leaky tissues. The tumor microenvironment
imparts special challenges that nanoparticles must overcome to successfully
deliver therapeutic agents. As a result of the fenestrated, abnormal vascu-
lature and reduced lymphatic development, tumors are characterized by
an elevated interstitial fluid pressure, hypoxic solid tumor centers, and an
acidic tumor microenvironment [51, 161-163]. The disorganized, heteroge-
neous, and tortuous tumor vasculature causes reduced blood flow [161], and
the high interstitial fluid pressure creates a hydrostatic barrier opposing the
convective transport of drugs and nanoparticles into solid tumors.
Next, nanocarriers must negotiate the labyrinth of ECM components
to penetrate tumor tissue and reach their intended target. Diffusion of
nanoparticles can be diminished by their interaction with the interstitial
matrix and the tortuosity of the interstitium [161, 164]. In general, shape, size,
and surface properties of the nanocarriers will contribute to their ability to
penetrate tissues. Studies have demonstrated that channels exist within the
extracellular matrix for these particles to diffuse [165], and further evidence
exists for similar channels in the brain [165-167]. Once outside the circula-
tion, there is evidence of how well nanomaterials can diffuse through tis-
sues [163, 165, 168-170]. Previous studies on the diffusion of macromolecules
through tumor interstitium provide insight into the parameters effecting
intratumor diffusion. Studies conducted on the diffusion of inulin, bovine
serum albumin, and dextran through ex vivo murine fibrosarcoma and
polymeric ECM models showed the molecular weight cutoff to be >40,000
Da. Krol et al. [171] investigated the available volume fraction (K AV ), the inter-
stitial space within the ECM that can contain therapeutic agents, by quan-
tifying the diffusion of fluorescently labeled macromolecules in the ECM