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Cerna et al. Nanodrugs in brain tumors

been investigated in vitro with HER2+ breast cancer The authors have studied antibody targeted apoferritin
cells. [33] mediated transport of doxorubicin, in which the surface
of apoferritin can be modified with antibodies to
Folic acid (FA) is essential for DNA synthesis, DNA enhance its targeting ability. These studies compared
repair, and methylation of DNA and is therefore the cytotoxic effect of doxorubicin-loaded apoferritin,
necessary for cell survival and proliferation. The human with and without surface targeting antibody anti-GCPII
folate receptor (FR), a glycosylphosphatidylinositol- (PSMA), with that of free doxorubicin in vitro on prostatic
anchored membrane protein of 38 kDa, has high cancer cell line (LNCaP) expressing PSMA as well as
affinity for FA, and is currently considered an essential human umbilical vein endothelial cells (HUVEC) as a
component in the cellular accumulation of FA required model of nonmalignant cells. The effect of doxorubicin-
in chemotherapy. FR expression is very low or loaded apoferritin nanocarriers on cancer and healthy
undetectable in most normal cells and tissues, but it is cells was similar to that of free doxorubicin. However,
upregulated in ovarian, breast, brain, lung, colorectal the real-time impedance-based platform demonstrated
cancers as well as brain tumors. [34,35] Through the lower toxicity to HUVEC with doxorubicin loaded
process of endocytosis, ligand-bound receptor is apoferritin than with free doxorubicin [Figure 2]. Entry
internalized and released from the receptor through of doxorubicin-loaded apoferritin nanocarriers with and
intravesicular reduction in pH. Ligand-free receptor without targeting antibody was higher into LNCaP than
[36]
is then recycled to the cell surface. Interestingly, into HUVEC (Cerna et al., unpublished results).
covalent conjugation of small molecules, proteins and
even liposomes to the gamma-carboxyl moiety of FA Oligopeptides are also molecules used for targeting.
does not alter FA ability to bind to the FR and undergo The RGD (Arg-Gly-Asp) oligopeptide is a component
endocytosis by receptor bearing cells. FR-mediated of the extracellular matrix protein fibronectin and
liposomal delivery has been shown to enhance the promotes cell adhesion and regulates migration, growth,
antitumor efficacy of doxorubicin both in vitro and in and proliferation. [25,40] RGD is known to serve as a
vivo, and to overcome P-glycoprotein-mediated multi- recognition motif in multiple ligands for several different
drug resistance. [37] integrins. RGD-containing peptide can be internalized
into cells by integrin-mediated endocytosis. Recently,
Transferrin (Tf) is a single-chain iron-transporting integrin-mediated carriers have been investigated as
glycoprotein that supplies iron into cells via receptor- gene vehicles to enhance gene transfection and as
mediated endocytosis. The TfR is expressed at low vehicles to deliver anticancer agents. The upregulation
levels in most normal tissues but is overexpressed of integrins is known to be promoted by angiogenic
in many tumor types. The crucial aspect of Tf for factors in several cancer types.
molecular targeting applications, the binding of Tf to
TfR on the external surface of tumor cells, is 10 times to NANOPARTICLES IN THERAPY OF BRAIN
100 times more effective in tumor cells than in normal TUMORS
[38]
cells. Drug delivery systems can take advantage
of this feature, most often by labeling the surface of Nanoparticles represent one of the possibilities of
the drug carrier with Tf, which is recognized by, and overcoming the BBB and delivering anticancer drugs
actively transported into, tumor cells. Therefore, Tf- to the brain. Therapy for brain tumors, particularly

modified liposomes, nanoparticles and dendrimers glioblastoma, using nanoparticles has been the subject
have been widely investigated in recent years. Despite of several preclinical experiments and clinical studies,
the perceived potential of anti-TfR antibody-drug but no nanodrug is as yet approved for brain tumor
conjugates, a BBB-permeable drug using this approach therapy.
has not yet been introduced for clinical use. [16]
Preclinical studies in brain tumors
Ferritin protein also self-assembles naturally into Lipid nanoparticles loaded with doxorubicin have been
a hollow nanocage called apoferritin, useful for investigated as a potential drug carrier to the brain,
encapsulation of any molecule of interest. Apoferritin although doxorubicin cannot cross the BBB. The
[39]
can be modified with recognition ligands to achieve pharmacokinetics and tissue distribution of doxorubicin
tumor-specific targeting. These extra surface were studied in healthy rats, using i.v. administration of
modifications can avoid renal clearance and ensure either free doxorubicin or doxorubicin incorporated into
EPR effect; however, they also eliminate the intrinsic solid lipid nanoparticles (NANO DOX) in equivalent
tumor-specific binding of natural ferritin and disturb its doses. Several blood samples and tissue samples
[42]
in vivo performance and biocompatibility due to altered of liver, spleen, heart, lung, kidney, and brain were
surface physicochemical properties of ferritin. collected. The mean peak plasma concentrations of
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ October 31, 2016 411