This document summarizes a method for preparing polymer-coated magnetic nanoparticles for targeted delivery of drugs to treat brain tumors. Magnetite nanoparticles are first synthesized and then coated with oleic acid. The oleic acid-coated nanoparticles are then encapsulated in poly(DL-lactic-co-glycolic acid) (PLGA) using an oil-in-water emulsion method. This PLGA coating makes the nanoparticles biocompatible and able to pass through the blood-brain barrier to accumulate in tumor tissues via the enhanced permeability and retention effect. The polymer-coated magnetic nanoparticles allow for targeted delivery of drugs to brain tumors while avoiding effects on other tissues.

1. Role of polymer coated magnetic nanoparticles as targeted delivery for managing brain tumors
Abstract
preparation of poly (DL-Lactic-co-glycolic acid) (PLGA)-coated magnetic nanoparticles (MNPs)
is a method of targeted delivery through the advantage of being negatively charged and the
phenomenon of "enhanced permeability and retention" (EPR) to increase their accumulation and
passage through BBB, and decreasing their toxicity via coating with a biocompatible polymer. For
this purpose, magnetite (Fe3O4) iron oxide nanoparticles is synthesized as a core material and then
coated with oleic acid. oleic acid coated nanoparticles (OA-MNPs) was encapsulated into PLGA.
Role of polymer-coated magnetic nanoparticles as targeted delivery for
managing brain tumors
By: ph. Abeer abd elrahman
B.sc of pharmacy

2. Introduction
Brain tumor :
Brain tumor is one of the most severe medical conditions. A brain tumor is a space occupying
lesion in the brain, and it is one of the leading cause of death, disability and hospitalization. It is an
abnormal tumor growth within the brain with the tendency to change in size and shape. Depending
on which cells involve, the brain tumors can be classified into many classes according to type of
cells affected. The nerve cells can be glial , astrocytes, oligodendrocytes, and ependymal cells.
More importantly the symptoms of brain tumor are mostly non-specific depending on the area or
the centers affecting which hinders early diagnosis of disease.
And because of the nature of BBB which is a highly selective permeability barrier that separates
the circulating blood from the brain extracellular fluid in the central nervous system (CNS). The
blood–brain barrier is formed by brain endothelial cells, which are connected by tight junctions.
The blood–brain barrier allows the passage of water, some gases, and lipid-soluble molecules by
passive diffusion, as well as the selective transport of molecules such as glucose and amino acids
that are crucial to neural function. Representing a major obstacle against passage of many drugs .
however, these difficulties can be overcome by carefully modulating the size and surface
characteristics of nanovehicles. The use of MNPs with a particle size of around 1-100 nm allows
their transport via "enhanced permeability and retention" process which allows small molecules to
accumulate in tumor tissue much more than they do in normal tissues due to leaky blood vessels
that is formed by tumor tissue . Furthermore, tumor tissues usually lack effective lymphatic
drainage. All of these factors lead to abnormal molecular and fluid transport dynamics.
The EPR effect helps to carry the nanoparticles and spread inside the cancer tissue.

3. Magnetic nanoparticles:
Magnetic nanoparticles (MNPs) have been actively investigated as the next generation of targeted
drug delivery for more than thirty years. The importance of targeted drug delivery is to transport
drug directly to the centre of disease under various conditions with no effects on other body tissues.
The major disadvantage of current chemotherapeutic agents is that they are non-specific. for
example, drugs are administered intravenously leading to general systemic distribution causing the
well known side effects of chemotherapy as the cytotoxic agents attack normal healthy cells as well
as tumor cells.
Using MNPs for targeted delivery depends largely on preparation process to select optimal
conditions and elect agents to modify their surface.
MNPs can be used in MRI as a diagnostic tool, as drug delivery system and also as a cytotoxic
agent via "hyperthermia phenomenon" in which MNPs are injected into body and accumulated in
tumor via previously mentioned (EPR) effect while normal tissue remain unaffected , then an
external magnetic field is applied causing resonance of the injected MNPs generating heat which is
sufficient to cause lysis of the containing tumor cell.

4. Coating magnetic nanoparticles:
Unfortunately there are some problems hindering the application of MNPs as nephrogenic toxicity
caused by the metal used as NP to be able to be excreted it must have a diameter less than the renal
filtration cutoff of approximately 5–6 nm. Also there is a phenomenon called "phagocytosis" which
means that the phagocytes attack the nanosystem by considering it antigenic. All these
physiological problems can be solved by coating the MNPs with biocompatible polymers which
protect against toxicity and promotes stealth effect (escape nanodrug from phagocytes).
There is also a physical problem related to uncoated MNPs, being of a small nanoscale particle size
with high surface area and surface charge is making the particles tend to form large agglomerates
making them lose their nanopropeties and become larger in size. Polymeric coating prevents these
agglomerates formation.
1-synthesis of magnetite nanoparticles:
To synthesize magnetite nanoparticles co-precipitation technique was used with minor changes.
Briefly FeCl2.4H2O and FeCl3.6H2O with a molar ratio of Fe+2/Fe+3 = 1:2 were vigorously
mixed in 150 ml deionized water . after stirring for 1 hour,25ml NH4OH (32% v/v) was added
dropwise to the mixture under continuous stirring at 90 C. N2 gas was bubbled into solution to
avoid oxidation of magnetite to maghemite . the black precipitate of Fe3O4 was washed several
times with deionized water until the medium PH decrease to 9.0.
2-oleic acid coating on magnetite nanoparticles :
After synthesis of MNPs they are coated with oleic acid. Initially 8 ml oleic acid was added to the
precipitated nanoparticles and stirred at room temperature for 1 hr then the OA-MNPs was washed
several times with 20 ml acetone to get rid of excess oleic acid .
3- preparation of magnetic polymeric nanoparticles :
Single oil in water (O/W) emulsion method was used to encapsulate MNPs into PLGA. certain
amount of OA-MNPs was dispersed in 2 ml dichloromethane (DCM) through ultrasonication (90%
amplitude) for 5 minutes in an ice bath. Then the dispersion was mixed in the organic solution of
polymer (100 ml PLGA in 2 ml DCM) by vortex. 4 ml of an aqueous poly vinyl alcohol (PVA)
solution was added to the mixture and then it was emulsified by ultrasonication for 30 sec .
The obtained emulsion was diluted in 50 ml PVA (0.3 %w/v). the organic solvent was evaporated
overnight under mechanical stirring with a rotation rate of 500 rpm.
For determination of optimum polymer concentration the dried OA-MNPs were added to variable

5. iron oxide/polymer ratio of 1:1 , 1:2 , 1:4 and 1:8 w/w .
After solvent removal PLGA-MNPs were obtained by centrifugation at 15000 rpm for 50 min at 4
C . the particles were washed twice with deionized water and redispersed in 50% aqueous solution
of HCL (32% V/V) to remove unloaded Fe3O4 nanoparticles . then the nanoparticles remaining in
the bellet were washed with deionized water. And magnetite free nanoparticles were separated
from magnetic nanoparticles by magnet and stored at 4 C.
4-magnetic content entrapment efficiency determination:
To find out the amount of Fe3O4 content in polymer coated MNPs, the obtained PLGA-MNPs
were dissolved in DMSO . then the particles were washed with deionized water again and treated
with 6 N HCL to dissolve iron content in polymeric nanoparticles . the iron concentration was
determined via AAS measurement .
The amount of loaded magnetite was estimated from amount of iron measured . magnetic content
(%w/w) and entrapment efficiency (%) were calculated
1- Magnetic content (%w/w) = ( amount of OA-MNPs in PLGA-MNPs / amount of PLGA-
MNPs) x 100
2- Entrapment efficiency (%) = (amount of OA-MNPs in PLGA-MNPs / amount of initial OA-
MNPs ) x 100
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