Biomedical Engineering Reference
In-Depth Information
interstitial hypertension, in turn, hinders drug delivery by abolishing the fluid
pressure gradients that lead to rapid convective transport across the vessel wall
and into interstitial space, while the complex extracellular matrix hinders
diffusion. Typically, poor tumor penetration presents as a major barrier for
effective delivery of nanomedicines into solid tumors.
The nanoparticle size, shape, and surface property all have significant
impact on the tumor penetration of nanoparticles. Rational design of
nanoparticle properties can improve tumor penetration by overcoming these
barriers. Chilkoti and colleagues demonstrated the molecular weight (particle
size) dependence on tumor penetration using macromolecular dextran as a
model carrier system in a dorsal skin fold window chamber.
34
They found that
increasing the molecular weight of dextran significantly reduced its vascular
permeability, and dextrans of 3.3-10 kDa penetrated deeply (.35 mm) and
were distributed homogeneously in the tumor tissues; however, dextrans of
higher molecular weight (40-70 kDa) were observed only 15 mm from the
vessel wall. Kataoka et al. demonstrated that only the 30 nm micelles could
penetrate poorly permeable pancreatic tumors to achieve an antitumor effect,
whereas 50-100 nm micelles showed much less tumor response.
35
In addition,
they also demonstrated that the penetration and efficacy of larger micelles
could be enhanced by using a transforming growth factor-b inhibitor to
increase the permeability of the tumors.
To increase nanoparticle penetration into tumor tissue, Dai et al. developed
a multistage nanoparticle delivery system in which 100-nm nanoparticles
''shrink'' to 10-nm nanoparticles after they extravasate from leaky regions of
the tumor vasculature and are exposed to the tumor microenvironment.
36
The
''shrunken'' nanoparticles can more easily diffuse throughout the tumor
interstitial space with a dense collagen matrix. Jain et al. recently reported that
normalization of tumor vasculature improves the delivery of nanomedicines in
a size-dependent manner.
37
They found that repairing the abnormal vessels in
mammary tumors, by blocking vascular endothelial growth factor receptor-2,
improves the delivery and anticancer efficacy of smaller nanoparticles (12 nm)
while hindering the delivery of larger nanoparticles (125 nm).
Besides particle size, nanoparticle shape can also significantly influence the
tumor penetration of nanoparticles. Jain et al. reported a shape-dependent
tumor penetration of nanoparticles.
38
They found that nanorods penetrate
tumors more rapidly than nanospheres due to improved transport through
pores. More fundamental studies are warranted to systematically investigate
the synergy in simultaneous control of nanoparticle size, shape, and surface
properties, and their influence on systemic and local tumor pharmacokinetics.
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2.3 Active Targeting by Surface-Functionalized
Nanomedicines
Compared with normal cells, tumor cells undergo rapid proliferation and
uncontrolled cell growth. Many cell surface receptors that respond to growth
