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Cerna et al. Nanodrugs in brain tumors

INTRODUCTION unique material characteristics, and manufactured
nanoparticles may find practical applications in a
Brain tumors are divided into two groups: (i) primary, variety of areas, including medicine. The nanoparticle-
originating and residing within the brain and (ii) mediated targeted delivery of drugs might significantly
secondary (metastatic), originating from a primary reduce the dosage required, increase drug specificity
cancer outside the central nervous system and and bioavailability, overcome chemoresistance and
spreading into the brain. Metastatic tumors are more reduce side effects.
frequent than primary tumors in adult patients while
primary ones are the most frequent solid tumors of The history of therapeutic nanoparticles began in the
childhood. The histological spectrum of brain tumors 1950s with a polymer-drug conjugate designed by
in children and adolescents differs from that in adults. [1] Jatzkewitz, followed by Bangham who discovered
the liposomes in mid-1960s. In 1972, Scheffel and
Primary brain tumors represent a heterogeneous colleagues first reported albumin based nanoparticles,
group as classified according to WHO. According to which formed the basis of albumin-bound paclitaxel
the Central Brain Tumor Registry of the United States (Abraxane). [7]
(CBTRUS) 2005-2009 report, the incidence in the US of
CNS tumors was 20.6 cases per 100,000 persons/year, Targeted delivery in cancer therapy is an important
the incidence of malignant tumors was 7.3/100,000 challenge for oncologists. Nanovectors for drug
persons/year and the incidence of low-grade tumors delivery typically contain a core material or matrix, a
was 13.3/100,000 persons/year. [2] therapeutic payload, and surface modifications in some
cases. Possible advantages of nanoparticle delivery
The most frequent brain tumors in all age groups systems over conventional anticancer chemotherapy
are tumors originating from glial cells - gliomas that include: (i) protection of drugs from degradation in the
represent a wide spectrum of tumors ranging from body; (ii) enhanced absorption into tumor cells; and
slow growing to highly aggressive tumors. WHO (iii) decreased interaction of drugs with normal cells.
[8]
classifies gliomas within four grades: grade I (pilocytic Ideal properties of nanoparticles for drug delivery are
astrocytoma), grade II (diffuse astrocytoma), grade III shown in Table 1. Nano-based drug delivery carriers, or
(anaplastic astrocytoma), and grade IV (glioblastoma nanocarriers, can consist of a wide variety of materials,
multiforme). The grade III and IV are considered high- both organic (polymeric, lipid, protein, or viral) and
grade gliomas (malignant gliomas) and are associated inorganic. The largest nanocarriers are liposomes
with very poor prognosis. In particular, 5 year survival (80-200 nm diameter), polymeric nanoparticles (40-
rate of glioblastoma multiforme, which accounts 100 nm) or micelles (20-60 nm); the smallest ones are
for half of primary brain tumors, is less than 10%. dendrimers (< 10 nm diameter). There have been
[3]
[9]
Brain metastases are the most common intracranial several reports describing the delivery of multiple
tumors in adults, with more than 150,000 cases in anticancer agents using nanocarriers, some having
the USA. In adults with cancer, 8-10% develop brain been evaluated in clinical trials. Some nanodrugs have
metastases, although the incidence of metastases been FDA approved. The approved nanodrugs for
[10]
varies considerably among different primary tumor anticancer therapy are given in Table 2.
types. Lung, breast, colorectal, renal cell cancer or
melanoma can metastasize to the brain and 70% of The blood-brain barrier (BBB) protects brain neural
brain metastases are due to lung and breast cancer. [4,5] tissues and works as a diffusion barrier that impedes
High-grade brain tumors, such as glioblastoma, and the influx of toxins and other compounds, including
brain metastases are often lethal because of their
invasiveness and resistance to surgical procedures Table 1: Ideal properties of nanoparticles for drug
[78,79]
[6]
as well as chemo- and radiotherapy. The urgent delivery. Modified from
need for novel therapies has led to great emphasis Ideal properties of nanoparticles for drug delivery
on the development of new anticancer drugs including Non-toxic
nanoparticles as cytostatic drug delivery vehicles. Biocompatible
Biodegradable
Physically stable in blood
Nanoparticles are structures between one and several Prolonged time in circulation
hundred nanometers in diameter. There are three Non-immunogenic/non-activating neutrophils/non-inflammatory
major physical properties of nanoparticles: (i) they Non-trombogenic/non-agregating platelets
are highly mobile in the free state; (ii) they have large Avoidance of reticuloendothelial system
surface areas; and (iii) they may exhibit quantum Amenable to small molecules, peptides, proteins and nucleic acids
effects due to the movement of electrons. They have Inexpensive/easy manufacturing
408 Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ October 31, 2016