Nanoparticles to Cross Biological Barriers - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 104

nanoparticles and lipid membranes resulting from changes in size and surface
charge. Changes in surface pressure were used to identify interaction between
particles and the membrane. It was found that positively charged, 60-nm
polystyrene nanoparticles increased the surface pressure, indicating that the
phospholipid layer had condensed. The positive charges may have created
electrostatic interactions with the phosphate head groups. Negative charges
had no effect, and neutral charged particles reduced the surface pressure. A
reduction in surface pressure suggests a dispersion of the lipid layer. Likewise,
size was shown to influence surface pressure: 20-nm particles always increased
the surface pressure when compared to larger, 60-nm particles, regardless of
surface charge. The authors stressed that this model is applicable only to endo-
thelial cells, and interactions may be different based on the different chemical
composition of the membranes of interest, especially the influence of mem-
brane proteins, lipids, and carbohydrates. Moreover, they emphasize that this
model is merely a lipid monolayer and might not be representative of the inter-
action of nanoparticles with a full plasma membrane lipid bilayer, complete
with transmembrane proteins and extracellular matrix components.
Intracellular vs. Extracellular Drug Delivery
Finally, the nanocarriers will have to release the payload extracellularly or
intracellularly. In general, intracellular delivery is a more efficient strategy for
increasing cytotoxicity and in some cases reducing drug resistance [196, 197].
Impaired drug delivery, mutations in cellular genetics, and non-genetic envi-
ronmental factors can result in multidrug resistance (MDR), a phenomenon
of cancerous cells being resistant to structurally unrelated drugs that have
discrete and separate modes of action [198-200]. There are several methods by
which tumor cells can be resistant to drugs, namely activation of ATP-driven
efflux pumps, inhibition of the influx of drugs to the cytoplasm, activation of
DNA repair mechanisms, and activation of detoxifying agents [199]. Much of
the research has focused on the efflux of hydrophobic drugs by ATP-binding
cassette (ABC) transporters. These ATP-dependent transmembrane proteins
are known to confer MDR to cancer cells, and cancer cell line cultures have
been shown to overexpress certain ABC transporters [199, 201]. P-glycoprotein
(Pgp), a twelve-pass transmembrane ABC transporter, is known to export
drugs such as docetaxel, paclitaxel, doxorubicin, daunorubicin, etoposide,
actinomycin D, methotrexate, mitoxantrone, and others [201-204]. It is hypoth-
esized that loading nanoparticles with drugs will decrease drug recognition
by efflux pumps, leading to higher intracellular concentrations and thus
more efficient treatment [199, 205]. Moreover, the flexibility of nanocarrier
engineering may be employed to circumvent MDR through coadministration
of chemotherapeutic agents with drug efflux protein inhibitors [196, 199, 200,