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Abstract
A real-time optical phase sensing scheme based on weak value amplification was proposed to monitor the especially binding process of Pertuzumab combined with Trastuzumab on HER2 positive cells. From the wavelength shift of output spectrum, the phase difference between measuring and referential path related to the concentration of Pertuzumab as well as Trastuzumab could be calculated. With this approach, the limit of detection (LOD) of 5.54 × 10−13 M for Pertuzumab assay was achieved. Besides, the kinetics signal of Pertuzumab in combination with Trastuzumab binding to HER2 was detected in real time. Experimental results demonstrated that both Trastuzumab and Pertuzumab can be captured by HER2, but the former was significantly superior to the latter in terms of the target number. Additionally, the binding speed was analyzed and demonstrated to be closely correlated with the initial concentration of the targeting agents.
© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement
1. Introduction
HER2-targeted treatments were standard adjuvant treatments for patients with HER2-positive (HER2+) breast cancer, which occurs in approximately 15–20% of breast cancer cases and causes the highest rates of metastasis and mortality in human breast cancer [1,2]. Trastuzumab, which could bind at a high affinity to the extracellular domain IV of HER2, became the first and the most successful targeted agent by downregulating the expression of HER2. As reported [3], Trastuzumab exhibits antitumor effects, such as stimulating antibody-dependent cell-mediated cytotoxicity [4,5] and physically inhibiting either homodimerization or heterodimerization [6,7]. Although the use of Trastuzumab for early-stage breast cancer could reduce the recurrence rate and the risk of death by 23%-40% and 24%−37%, respectively [8], there remains resistance and refractoriness with monotherapy of Trastuzumab [9]. Pertuzumab, another monoclonal antibody, is aimed to the extracellular domain of HER2 receptors. By inhibiting the homodimerization of HER2 and disturbing the formation of HER2/HER3 heterodimer, Pertuzumab prevents the activation of phosphatidylinositol 3-kinase (PI3K) signaling pathways that mediate cancer cell proliferation and survival [10–12]. Additionally, it was proved complementary to Trastuzumab in treating HER2-positive cancer [13,14]. Hence, the double-target treatment mode of Pertuzumab + Trastuzumab in the field of neoadjuvant therapy has important status. With the dual blockade of Pertuzumab and Trastuzumab in HER2-targeted therapy, an 8-year overall survival rate of 37% was demonstrated [15].
The detection of HER2-targeting antibody–drug conjunction is an essential method for determining the prognosis and therapy for HER2 + patients [16]. HER2 testing with high accuracy is necessary for the early diagnosis and the process monitoring of cancer therapy, since the error rate as high as 20% exists in immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) [17,18]. Nowadays, diagnostic tools and analytical technologies and biosensors are at the forefront of analytical methods. Biosensors, which transduce the content of the targeted molecules to the physical and chemical signal and provide fast and accurate detection for biomolecules, show the ability to determine the effectiveness of anticancer chemotherapy agents [19]. As for the monitoring of the binding between anti-HER2 monoclonal antibody to the HER2 receptor, despite of the conventional measuring methods such as IHC and FISH [20], different kinds of biosensors including electrochemical, piezoelectric, mass-based, calorimetric and optical sensors according to the principle of their transducers were raised [19,21]. Specifically, optical biosensors that realize the signal transducing via the refractive index, fluorescence, Rama scattering and optical absorption in an optical system, stand out among numerous sensing technologies with the merits of quick response, high sensitivity, stability, low noise, and immunity to external disturbance [22,23].
Optical phase, an essential element in high precision detection, plays a critical role in the investigation of interdisciplinary with the ability of combining optical technology and biological detection, subsequently spawning varied optical biosensors. Typically, Surface Plasmon Resonance (SPR) biosensor, which takes the phase difference between p-polarization and s-polarization as the transducer, was popular with the merits of being label-free in biomedical detection [24–26]. Recently, SPR biosensors have shown an important role in the detection of HER2-antibodies [27–29]. Similarly sensitive to the phase delay corresponding to the refractive index of sample, the interferometry technology, in which the measuring sample decided the interference effects between two beams from the same light source, performs better in most cases compared with SPR [30]. In recent years, a new precision detection technique based on weak value amplification has been proposed based on the interferometry structure. It was reported to be superior to traditional interferometers in the precision [31], and shows great potential in numerous biomolecular detection [32]. Moreover, compared with SPR sensors or Photonic and Plasmonic Metasensors [33], the technology based on weak measurement shows distinct merit that there is no need to preprocess the detector, and it is beneficial for large-scale production and application.
In our previous work, the biosensing method of weak value amplification was applied for HER2 evaluation through the conjunction of Trastuzumab to HER2 receptors [34]. With appropriate pre- and post-selected polarizations, the concentration of biomolecule was evaluated through a spectrum analysis, real-time monitoring of the binding of Trastuzumab to HER2 on the SK-BR-3 cells was realized. In this work, given the different domains of HER2, the conjunction of Trastuzumab and Pertuzumab to HER2 was investigated based on the weak value amplification. With our method, the kinetics signal of the specific binding between the two targeted agents and HER2 + cells was detected and analyzed in real time.
2. Methods and materials
2.1 Optical biosensors based on weak measurement
In the scheme of weak measurement that depends on orthogonal polarizations as the eigenvectors, the optical phase was a degree of freedom for the weak reaction. As reported [35], the wave-based interferometer was suitable for the scheme of weak value amplification. In Mach-Zehnder interferometer, by preselecting the state of the incident light with linear polarization, the eigenvectors of the system could be realized with a polarization beam splitter, which splitting two orthogonal polarizations in different paths. The polarized light of the two components were re-coupled into a new beam after passing through another polarization beam splitter. Finally, by conducting a postselection of the appropriate polarization for the projection measurement, the phase difference between the two paths caused by the sample was determined through the output spectra. With this method, the concentration of biomolecule could be estimated.
Hence, in this work, a weak measurement system based on Mach-Zehnder interferometer was built, as shown in Fig. 1. Two polarizers were utilized for the polarization selection, and two cuvettes located in the two paths of this system worked as the sample cells. The solution in the cuvettes provides an additional phase variation for the light passing through deriving because of the higher refractive index than the air. According to previous work on the weak value amplification method [34], the phase difference between the two paths can be determined by the wavelength shift $\mathrm{\delta \lambda }$ with the following equation.
Here, ${A_w}$ was the weak value defined by ${A_w} = \phi |A |\psi /\phi |\psi $, in which the $|\psi \rangle $ and $\left\langle {\phi |} \right.$ were the pre- and post-selected polarizations that were controlled by the two polarizers, respectively. With an appreciative polarization adjustment, the direction angles of the two polarizers were represented with $\mathrm{\alpha }$ and $\mathrm{\beta }$, and with the y axis and x axis as the references, and $\mathrm{\gamma } = \mathrm{cos\alpha } \cdot \textrm{sin}({\mathrm{\alpha } + \mathrm{\beta }} )/\mathrm{sin\alpha } \cdot \textrm{cos}({\mathrm{\alpha } + \mathrm{\beta }} )$. Hence, the phase difference $\mathrm{\varphi }$ between the two paths, corresponding to the refractive index change caused by sample concentration can be calculated with the central wavelength shift. One of the mirrors was fixed on a precision translation stage to adjust the initial phase difference of x for an appropriate working point. By moving the mirror slightly, a phase delay was produced by the varied optical path.
Fig. 1. the sketch of weak-measurement-based biosensor with a structure of Mach-Zehnder interferometer. SLD, Superluminescent diode (Thorlabs Inc., SLD830S-A20) centered at 830 nm with a band width of 20 nm. Filter aimed to shape the spectrum with a Gaussian appearance. P1 and P2 are two same polarizers. M1 and M2 are two same mirrors.
2.2 Combination of Pertuzumab and Trastuzumab to HER2
As Fig. 2 shows, the HER2 receptors on cells, which were fixed on a slide, contain the targets both aimed to Trastuzumab and Pertuzumab. In the circumstance of HER2-targeted drug, the activated HER2 receptors captured relevant antibody molecules specifically.
Experimentally, two slides with SK-BR-3 cells were prepared for comparison. One slide was soaked in the Pertuzumab solution with concentration of $6.42 \times {10^{ - 10}}$ M for 24 hours, and then be washed with PBS (phosphatic buffer solution). As a reference, another slide with SK-BR-3 cells was prepared without any binding reaction. Both slides were photographed by Scanning Electron Microscope (SEM), as shown in Fig. 3(a) and (b) respectively. It’s clearly indicated that the Pertuzumab were combined with the cells, as identified in Fig. 3(a).
Fig. 3. SEM images of SK-BR-3 cells surface. (a) Pertuzumab bind at the interface of SK-BR-3 cell. (b) SK-BR-3 cell surface without Pertuzumab.
In this work, experimental anti-HER2 agents including Trastuzumab and Pertuzumab at different concentrations were prepared in two independent cuvettes, with the PBS as the solvent. The slide covered with HER2-positive SK-BR-3 cells was immersed into the Trastuzumab-cuvette. Captured by the special domain of HER2, the number of the dissociative Trastuzumab molecules decreased sequentially. Then, the slide was taken out, and immersed into the Pertuzumab-cuvette after being cleaned by PBS, which was aimed to wash the Trastuzumab molecules attached through nonspecific adsorption away from the cells. Similarly, the special combination of the extracellular domain of HER2 reduced the dissociative Pertuzumab molecules in the solution. Thus, the Trastuzumab/Pertuzumab/HER2 ternary complex was produced on the cells.
2.3 Materials
In our study, the cuvettes were purchased from Wuxi Shufu Instrument Co., Inc, the phosphate buffer saline (PBS) was purchased from Beyotime Co., Inc, the Trastuzumab was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd, the Pertuzumab was purchased from Selleckchem Co., Inc. The SK-BR-3 cells were cultured by the affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine.
3. Experiment and results
3.1 Concentration detection of Pertuzumab
In the experiment, the cuvettes with the size of 10*10*30 mm were setup with the light in the condition of a normal incidence. After a manually clean with deionized water, each cuvette was injected into 2.5ml of PBS. The position of cuvettes was adjusted to ensure the light in measuring and referential paths entirely pass through the PBS. For an appreciated working point, which could be assessed by the output spectrum that was collected by the Labview program with an integral time of 200 $\mathrm{\mu s}$, which revealed the sample to result time. The phase difference between the two paths was fine-tuned through the mirror on the precision translation stage. $1.70 \times {10^{ - 11}}$M of Pertuzumab was prepared for the concentration response test. The Pertuzumab of 100 $\mathrm{\mu L}$ was added to the cuvette of the measuring path. The central wavelength of output spectra was monitored in real time. Every two minutes, the operation of Pertuzumab addition was performed. With an increasing concentration of the solution in the cuvette due to the mix of Pertuzumab in the PBS, the phase difference between the two paths was enhanced subsequently. Hence, the central wavelength shifted with a reshaped spectrum. When the solution was mixed evenly, the value of the central wavelength was extracted. Compared with the initial central wavelength, the wavelength shift could be obtained. The spectra of the output light were collected as shown in Fig. 4(a). Pertuzumab in the measuring cuvette with different concentrations, $6.52 \times {10^{ - 13}}$ M, 1.2 $6 \times {10^{ - 12}}$ M, 1.$82 \times {10^{ - 12}}$ M, were prepared, while the cuvette in the referential arm was filled with PBS. Hence, the phase difference generated and reshaped the output spectrum for a $\mathrm{\delta \lambda }$ as Eq. (1) presents. With a higher concentration corresponding to the phase difference, the center of the spectrum shifted to the left versus the initial state, result in an increasing wavelength shift.
Fig. 4. (a) the spectra of output light in distinct measuring concentration of Pertuzumab. (b) the concentration response of Pertuzumab depend on the results of (a).
The wavelength shift in distinct concentrations was calculated and displayed in Fig. 4(b). With an increasing concentration, the central wavelength shifted with a monotonic tendency. The function of concentration is obtained by linear fitting, which is $\textrm{y} ={-} 1.19\textrm{x} + 0.07.{\; }$In the linear interval, a sensitivity $\textrm{S} = 1.19 \times {10^{12}}$ nm/M, which could be calculated by the slope of the concentration calibration curve according to Fig. 4(b). According to 5 measurements in the same condition, the error bars were achieved, and they revealed the repeatability for this proposed optical biosensor. The replication experiments at the lowest experimental concentration of $6.52 \times {10^{ - 13}}$ M were carried out for the calculation of LOD. Through 10 times of repeated measurements, a standard deviation of 0.22 nm could be assessed as the noise of the system in the concentration detection. According to the equation $\textrm{LOD} = 3\mathrm{\delta }/\textrm{S}$, the LOD could be evaluated to be 5.54 × 10−13 M.
3.2 Real-time monitoring of Pertuzumab-HER2 binding
HER2-positive SK-BR-3 cells were cultured and fixed on round slides of 14 mm in diameter, and were immersed into PBS in reserve. In order to avoid any unreliable readouts due to non-specific recognition, the SK-BR-3 cells were blocked with bovine serum albumin (BSA) in advance. Replaced the cuvettes with bigger ones with the size of 20*20*20 mm, we conducted the experiment for the real-time monitoring of Pertuzumab-HER2 binding. To block the targets of Trastuzumab on the HER2 positive cells thoroughly, the slides with SK-BR-3 cells covered was soaked in $1.44{\; } \times {\; }{10^{ - 7}}$ M of Trastuzumab solution for 12 h. Then, after being cleaned with PBS, the slides were stored in 24-well plates and refrigerated for spare. The $5.45{\; } \times {\; }{10^{ - 11}}$ M of Pertuzumab solution was prepared and added in the cuvettes both on the measuring path and referential path in the system. The central wavelength was collected in real time, and presented a relatively stationary state as shown in Fig. 5. At this moment, a prepared slide was added in the cuvette of the measuring path. A bracket was used to suspend the slide in the solution to realize a maximum interaction between the cell and solution.
Pertuzumab was captured from the solution by binding on the special epitope of the HER2 ectodomain. Hence, the concentration of the solution in measuring cuvette decreased and led to an increasing phase difference between the two paths. Then, a clear binding kinetics signal could be observed, as the red line shows in Fig. 5.
3.3 Binding kinetics of Pertuzumab and Trastuzumab to HER2
Hence, with the wavelength shift, the concentration of the sample in the measuring cuvette could be calculated. Either path could be taken as the measuring path for the concentration detection, since the central wavelength is sensitive to the phase difference either positively or negatively, which induces opposite directions of the wavelength shift. As a consequence, the two cuvettes could be exploited for a multi-channel application, such as the detection of dual target drugs.
The Pertuzumab and Trastuzumab with concentrations at 1.11 × 10−11 M and 1.18 × 10−10 M were prepared in the referential and measuring cuvettes, respectively. As Fig. 6(a) shows, a stable state revealed by the central wavelength was in an almost constant level. A slide with HER2 positive SK-BR-3 cells on was immersed in the Pertuzumab solution. As the binding of Pertuzumab on HER2 going on, the central wavelength shift presented a negative growth since the Pertuzumab decreased. The central wavelength shift tended to saturate until the conjunction was almost completed. Then, this cell slide was taken out and rinsed with PBS, and it was immersed in the measuring cuvette with Trastuzumab in. Subsequently, the central wavelength appeared significantly increased due to a positive phase difference. Thus, the dual target binding response was observed visually in Fig. 6(a). The assay of dual target binding response by reserving the adding order of cell slide in Pertuzumab and Trastuzumab was carried out, and exhibited in Fig. 6(b). Here, the concentration of Trastuzumab was raised to 4.64 × 10−10 M while that of Pertuzumab remained to be the same. In this case, the decreasing concentration of Trastuzumab and Pertuzumab induced a positive and negative wavelength shift, respectively, which agreed with the result shown in Fig. 6(a). Obviously, after the completed conjunction of Pertuzumab/Trastuzumab, the cells could still react with Trastuzumab/Pertuzumab. It demonstrated the selectivity of antibodies and cells. Notably, the slides with SK-BR-3 cells were much smaller than the cuvette, so it was difficult to ensure that the slides located in the same position in different tests, and it would lead a difference on the response time of the signal, such as the oscillations presented in Fig. 6. Additionally, the magnitude of the wavelength shift in the two Trastuzumab-HER2 binding process revealed an apparent discrepancy because of the different concentrations. Besides, nether Fig. 6(a) and (b) denoted an important conclusion that the number of targets aimed to Trastuzumab was much more than that to Pertuzumab on HER2 ectodomain. It was in accord with the fact that Trastuzumab was the drug of first choice for the treatment of HER2-positive breast cancer patients. Furthermore, such a result also demonstrated that Pertuzumab in combination with trastuzumab provides more effective antitumor activity than either single agent for HER2-positive breast cancer.
Fig. 6. (a) binding kinetics of Pertuzumab and Trastuzumab to HER2 in turn. (b) binding kinetics of Trastuzumab and Pertuzumab to HER2 in turn.
3.4 Binding reaction of targeted drug to HER2 with another target blocked
Here, we carried out experiments for the monitoring of Pertuzumab-HER2 and Tratuzumab-HER2 combinations. Firstly, the measuring path was ascertained for the experimental operation. After being cleaned with DI water, the cuvettes in both paths contained 6 ml of PBS and a certain concentration of Pertuzumab solution. In a stable situation, a slide that was pre-processed by the Pertuzumab with the procedure described in section 3.2, was immersed into the Trastuzumab solution in the measuring path. The targets on HER2 of the cells captured Trastuzumab molecules specifically. Subsequently, the concentration of the solution decreased, accompanied by a reduced refractive index. Hence, the phase difference between the two paths was developed with the sustained reaction. By recording the central wavelength in real time, the binding reaction process could be visually observed.
With different initial concentrations, the real-time monitoring curves of Pertuzumab-HER2 binding are shown in Fig. 7(a). With the reaction going on, the concentration of the solution decreased sustainably, introducing a continuously increasing phase difference, which was reflected in the wavelength shift. As a reference, the monitoring in the condition without Trastuzumab, i.e., the sample in measuring cuvette was only PBS, was implemented and exhibited in Fig. 7(a) as the black curve, showing few wavelength shifts. Additionally, we noticed that the reaction speed, which could be represented by the slope of the curve, varied greatly in different concentrations. With the concertation of $4.65 \times {10^{ - 10}}$M, the binding reaction was dramatically faster than that in $2.33 \times {10^{ - 10}}$M in 30 minutes. Similarly, with the same operation procedure, the reaction monitoring of the Pertuzumab was implemented with different concentrations, as shown in Fig. 7(b), which demonstrates that the initial concentration of the targeted drug in the solution is closely related to the binding speed.
Fig. 7. (a) the real-time monitoring of the binding reaction between the Trastuzumab and HER2. (b) the real-time monitoring of the binding reaction between the Pertuzumab and HER2.
4. Discussion
An optical biosensor based on phase detection via weak value amplification was presented. The configuration of Mach-Zehnder interferometer provided an essential way to modify the phase difference between two orthogonal polarizations, thus to realize the weak measurement as well as the concentration detection mechanism for biological samples. By reshaping the spectrum, the concentration variation of measuring molecule corresponding to the phase difference was evaluated by the central wavelength shift with spectrum analysis. As the drugs for the treatment of HER2-positive breast cancer, the concentration of Pertuzumab and Trastuzumab was investigated in the special binding to the HER2 on SK-BR-3 cells fixed on the slides. The concentration calibration curve demonstrated that the LOD reached 5.54 × 10−13 M. Additionally, the conjugation between dual Pertuzumab and Trastuzumab to HER2 was observed by monitoring the central wavelength shift in real time. The kinetic curve reported the conclusion that the targets of Trastuzumab were more than Pertuzumab on the slide covered with cells. Besides, the reliability of this sensing approach was furtherly demonstrated by detecting the kinetic curves of the binding process with different reaction concentrations. Thus, this optical biosensor based on phase detection for the concentration detection plays a significant role in HER2 bioassay and anti-HER2 therapy, and it provides strong evidence that Pertuzumab in combination with trastuzumab can enhance the antitumor activity. Expansively, it shows great potential in the exploration of antitumor activity and pharmacokinetics.
Funding
National Natural Science Foundation of China (62005244, U20A20219); Natural Science Foundation of Zhejiang Province (LGF20C050001, LQ19H160040, LQ21F050008).
Disclosures
The authors declare no conflicts of interest.
Data availability
Data underlying the results presented in this paper are not publicly available at this time but maybe obtained from the authors upon reasonable request.
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