Özet
Human serum albumin (HSA) is the most abundant protein in the blood.
Enlargement of the pores in the glomeruli and remarkable amount of plasma
proteins’ leakage into urine is caused by the kidney damages. A certain amount of
leaked HSA (in spot urine 0-20 mg/L) is defined as microalbumin. Since the
increase in the amount of microalbumin is a sign of some important diseases,
early identification is very important for the diagnosis.
Devices which convert biological response to electrical signals are defined as
‘’Biosensors’’. Biosensors are analytical devices that contain biological recognition
elements and physicochemical transducers in their bodies. Molecular imprinted
polymers was unified with the transducers through major developments in the field
of biosensors and interactions between analyte and MIP can be converted into a
processable signals. In this sense, surface plasmon resonance (SPR) based
optical devices have a great potential.
In this study, it was aimed to prepare SPR based nanosensor using molecular
imprinting technique for microalbumin detection in urine. In the first step, NMethacryloyl-(L)-Leucine
Methyl Ester (MALM) monomer having capability of
interaction with HSA to create cavities was synthesized by reacting of L-Leucine
methyl ester with methacrloyl Chloride. To define optimum ratio between template
HSA molecule and MALM monomer, HSA was mixed with different ratios of MALM
monomer and optimum ratio was determined by using UV-visible
spectrophotometer instrument.
Nanosensor preparation studies were realized according to the optimized ratio
conditions. Nanosensors are prepared in two ways by micro-contact method with
HSA imprinted [PEDMALM-HSA] (MIP) and non imprinted [PEDMALM] (NIP)
nanosensor preparation and by attaching HSA imprinted [PEDMALM-HSA] (MIP)
and non imprinted [PEDMALM] (NIP) nanoparticles to the chip gold surface
respectively.
For this specified purpose, HSA imprinted poly(N-Methacryloyl-(L)-Leucine Methyl
Ester-Human Serum Albumin) [PEDMALM-HSA] (MIP) nanofilm was synthesized
onto the allyl mercaptan modified gold chip surface by micro-contact method.
Mixture prepared from specific proportions of MALM monomer, crosslinker
ethylene dimethacrylate (EDMA) and initiator 2,2'-azobis (isobutyronitrile) (AIBN)
was poured (20 μL) onto the SPR gold sensor surface and after then HSA
immobilized glass slides was inserted onto the poured mixture by pressing to form
stamped structure. Special cavities for the target HSA protein was formed when
the mixture put under the UV light for 4 hours. For control experiments nonimprinted
nanofilm preparation was performed in the same conditions without
adding target HSA protein.
SPR biosensors prepared by HSA imprinted [PEDMALM-HSA] (MIP) and non
imprinted [PEDMALM-HSA] (NIP) nanofilms were characterized by FTIR-ATR,
Atomic force microscope (AFM), Contact angle (CA), Ellipsometer measurements.
Surface rougness measurements were obtained by Atomic force microscopy
(AFM) method and images showed that roughness of HSA imprinted [PEDMALMHSA]
(MIP) and non imprinted [PEDMALM] (NIP) nanofilms was estimated as 3.64
and 2.47 nm respectively. Rougness difference between HSA imprinted
[PEDMALM-HSA] and non imprinted [PEDMALM-HSA] (MIP) nanofilms show that
imprinting process of HSA molecules was performed successfully. Film thickness
of HSA imprinted [PEDMALM-HSA] (MIP) and non imprinted [PEDMALM] (NIP)
nanofilms was estimated by ellipsometry measurements and recorded as 95±4.9
and 89.9±4.9 nm for imprinted and non imprinted nanofilms respectively.
Wettability studies was performed by contact angle measurements. Increasing
contact angle values for unmodified gold chip surface (80°±0.73), HSA imprinted
[PEDMALM-HSA] (MIP) (55.2°±2.24) and HSA non imprinted [PEDMALM] (NIP)
(61.5±4.63°) nanofilms show that imprinting process enabled hydrophilicity
increment.
In the second part of the study to work in a a targeted concentration range
[PEDMALM-HSA] (MIP) nanoparticles were synthesized by a two-phase miniemulsion
polymerization method. The first aqueous phase PHASE I was prepared
by dissolving of PVA (95 mg), SDS (15 mg) and NaHCO3 (12 mg) in 5.0 mL
deionized water. The second phase PHASE II was prepared by dissolving of PVA
(50 mg) and SDS (50 mg) in 100 mL of deionized water. Prepared MALM:HSA
pre-complex (0.15; 0.015 mmol) was dissolved in a crosslinker, ethylene glycol
dimethacrylate (EDMA; 4.8 mmol) to form oil phase. The oil phase was slowly
added to the first aqueous phase. In order to obtain mini-emulsion, the mixture
was homogenized at 25 000 rpm by a homogenizer. After homogenization, mixture
was added to the PHASE II. Then, initiators, sodium bisulfite (125 mg) and
ammonium persulfate (125 mg), were added into the solution. Polymerization was
continued for 24 h at 40°C. Besides this, for control experiment, the non-imprinted
[PEDMALM] (NIP) nanoparticles were synthesized by applying same procedure
with imprinted nanoparticles except addition of template HSA molecules.
Size distrubution of the prepared nanoparticles was characterized by zeta size and
scanning electron microscopy measurements. Averaged size distrubution value of
the HSA imprinted [PEDMALM-HSA] (MIP) and nonimprinted [PEDMALM] (NIP)
nanoparticles was estimated as 63 and 55 nm respectively. Because of low
polydispersity index values for imprinted and nonimprinted nanoparticles
(PDI:0.138; PDI:0.113) homogeneous average nanoparticle size distrubition was
attained. Average size of HSA imprinted [PEDMALM-HSA] (MIP) nanoparticles
was determined as 60-65 nm by Scanning electron microscopy measurements.
Target protein HSA imprinted [PEDMALM-HSA] (MIP) and non imprinted
[PEDMALM] (NIP) nanoparticles were attached to the chip surface by dropping 5
µl of the prepared particles diluted 100 times with distilled water onto the chip
surface which was already cleaned with ethyl alcohol and dried in a vacuum oven
and put under the UV light for 2 hours.
Prepared HSA imprinted [PEDMALM-HSA] (MIP) and non imprinted [PEDMALM]
(NIP) nanoparticles attached SPR nanosensors were characterized by FTIR-ATR,
atomic force microscope (AFM) method, contact angle (CA), ellipsometer
measurements. Surface rougness measurements were obtained by Atomic force
microscopy (AFM) and images showed that roughness values of HSA imprinted
[PEDMALM-HSA] (MIP) and non imprinted [PEDMALM] (NIP) nanoparticles were
estimated as 1.61 and 1.28 nm respectively. Rougness difference between HSA
imprinted [PEDMALM-HSA] (MIP) and non imprinted [PEDMALM] (NIP)
nanoparticles attached nanoparticles show that imprinting process of HSA
molecules was performed successfully. Thickness of HSA imprinted [PEDMALMHSA]
(MIP) and non imprinted [PEDMALM] (NIP) nanoparticles attached
biosensor chips was estimated by ellipsometry measurements and recorded as
118.4 ±0.3 and 116 ± 0.3 nm for imprinted and non imprinted nanofilms
respectively. Wettability studies was performed by contact angle measurements.
Increasing contact angle values for unmodified gold chip surface (80°±0,73), HSA
imprinted [PEDMALM-HSA] (MIP) (67.3°±2.24) and HSA non imprinted
[PEDMALM] (NIP) (84.5°±4.63) biosensors show that imprinting process enabled
hydrophilicity increment.
Detection of HSA by micro-contact method was performed in the 1,5-300 nM
concentration range and by nanoparticles in the 0,15-500 nM concentration range
for HSA solutions prepared with 50 mM pH= 7.4 phosphate buffer solution.
Desorption studies were carried out by using 0.05 M NaCI solution. Adsorption
analyses for the HSA spiked artificial urine and plasma samples which was
prepared in pH=7.4 phosphate buffer were examined. Selectivity studies of
[PEDMALM-HSA] (MIP) and [PEDMALM] (NIP) SPR biosensors for HSA
determination were investigated by using different protein samples such as
hemoglobine and transferrine. Higher selectivity factor was estimated for the
[PEDMALM-HSA] (MIP) nanosensor which was prepared by micro-contact method
than nanoparticles attached [PEDMALM-HSA] (MIP) nanosensor as k’=5.02,
k’=4.25 for Hb and HTR respectively. Limit of detection value for the nanoparticles
was estimated lower (LOD: 0.7 pM) than the nanofilms prepared by micro-contact
method (LOD: 8.8 pM). As a result nanoparticles attached biosensors more
sensitive than the nanofilm attached ones. Repeatability experiments of
[PEDMALM-HSA] nanosensor prepared by microcontact method and
nanoparticles attached nanosensor was performed five times (5 times) by using
HSA solutions (300 nM and 500 nM respectively) and reflectance values were
measured. Stability studies were performed for the 3 times in the three months
periods with four repeatibity.
To determine the kinetic and adsorption models of interactions between
[PEDMALM-HSA] (MIP) nanofilm attached SPR nanosensor and HSA solution,
four different adsorption models named Scatchard, Langmuir, Freundlich and
Langmuir-Freundlich (LF) were employed. Langmuir adsorption model was found
most applicable model for this affinity system and results showed that affinity
regions on the surface of [PEDMALM-HSA] (MIP) SPR nanosensor for the HSA
template were homogeneously distributed and have monolayer structure.
To determine the kinetic and adsorption models of interactions between
[PEDMALM-HSA] (MIP) nanoparticles attached SPR nanosensor and HSA
solution, four different adsorption models named Scatchard, Langmuir, Freundlich
and Langmuir-Freundlich (LF) were employed. Langmuir adsorption model was
found most applicable model for the low concentratins of HSA while Freundlich
adsorption model fits for the high HSA concentrations in this affinity system and
results showed that affinity regions on the surface of [PEDMALM-HSA] (MIP) SPR
nanoensor for the HSA template were homogeneously distributed and have
monolayer structure for the low concentrations.
As a result, albumin level are used as a Biomarker for the 0-20 mg/L (0-300 nM)
concentration range. Nanosensor prepared by the micro-contact method was
estimated more selective for the HSA determination than the nanosensor prepared
by the nanoparticle attached method. Although the nanosensor prepared by the
micro-contact method can be used successfully for the estimation of HSA in the
1.5-300 nM concentration level, it can not detect precisely 0-300 nM HSA
concentration level. So it has been required to use nanoparticles to detect HSA
with lower concentration limits.
Selective and sensitive nanosensor prepared by micro-contact method can be
used for HSA detection by real time measurement, no need labeling, low cost and
ease of miniaturization when compared with the other methods and nanoparticles
can be used for the detection of lower HSA concentrations. This study will
contribute to the literatüre by comparing the advantages of the nanofilm attached
nanosensor prepared by micro-contact method and nanoparticles attached
nanosensor.
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