Biomedical Engineering Reference
In-Depth Information
expression, with immense silencing efficiency and relatively low toxicity.
siRNAs degrade extremely rapidly in physiological environments and are
eliminated almost immediately from circulation upon injection. Liposomes
prove ideal carriers for biological agents such as siRNA because of their
stable aqueous core. Moreover, it is possible to combine RNA-interfering
strategies with traditional chemotherapeutics. One example is the Raf/
MEK/extracellular signal-related kinase (ERK) pathway, which is essential
for cellular proliferation, and found to be aberrant in several cancers [121].
As a result, several inhibitors of key proteins in the cascade have been de-
veloped as potential chemotherapeutics. Recently, it has been demonstrated
that liposomes encapsulating a Mcl1-specific siRNA (siMcl1) and a chemi-
cal MEK inhibitor (PD0325901) showed a valid antitumor efficacy in vitro
and in vivo. Following encapsulation and complexation of PD0325901 and
siMcl1 respectively, the liposomal formulation was administered to KB cells.
Western blot results showed that co-delivery of both agents significantly re-
duced expression of Mcl1 and pERK1/2 proteins [122]. Antisense therapy
represents a gene silencing strategy that stands to make a profound impact
on cancer therapy. In a phase I study, a liposomal formulation, LErafAON,
that encapsulates the raf antisense oligonucleotide, was administered with
the purpose of acting on c-raf, a protein that bestows cancer cells with resis-
tance to radiation or chemotherapy. In patients with advanced solid tumors
undergoing radiation therapy, the c-raf-1 mRNA was inhibited in three, four
exhibited partial response, four had stable disease, and four showed progres-
sive disease [123]. Recently, the use of bisphosphonates, such as zoledronic
acid, was explored as a treatment strategy, given its ability to inhibit the re-
lease of growth factors essential for cancer cell growth and differentiation in
bone. Emerging data from several clinical trials serves to highlight a poten-
tial anticancer effect of zoledronic acid, as well as chemotherapeutic synergy
with established drugs [124]. However, zoledronic acid has an extremely
rapid blood clearance and preferential accumulation in bone, necessitat-
ing encapsulation in nanoparticles. Lipo-ZOL is a liposomal formulation
of zoledronic acid that increases circulation times, reduces accumulation in
bone, and increases targeting to tumors [125].
5.4 Gold and silver nanoparticles
Gold nanoparticles (GNPs) (Figure 2-2) exhibit unique physicochemical
properties, including the ability to bind amine and thiol groups, allowing
surface modification and use in biomedical applications. GNPs are used to
prepare nanoshells composed of gold and copper, or gold and silver to func-
tion as contrast agents in MRI, and gold-silica for photothermal ablation of
tumor-cells. Classically GNPs enter into cells with a non-specific receptor
mediated endocytosis mechanism [126]. In vivo GNPs passively accumulate
at tumor sites that have leaky immature vasculature with wider fenestrations
than normal mature blood vessels. Difficulties in utilizing the EPR effect for
