Comparative study on the antitumor effects of gemcitabine polybutylcyanoacrylate nanoparticles coupled with anti-human MUC1 and CA199 monoclonal antibodies on pancreatic cancer in vitro and in vivo

Arab Journal of Gastroenterology

Available online 1 August 2022

Arab Journal of GastroenterologyAbstractBackground and Study Aims

This study was designed to compare the antitumor effects of anti-human MUC1 monoclonal antibody with those of anti-human CA199 monoclonal antibody coupled with drug-loaded polybutylcyanoacrylate nanoparticles on human pancreatic cancer cell lines and pancreatic cancer-bearing model animals and to screen more efficient targeting molecules.

Patients and Methods

Gemcitabine-loaded nanospheres were prepared by emulsion polymerization (GEM-PBCA-NP), and then, anti-MUC1 monoclonal antibody was coupled with GEM-PBCA-NP (MUC1-GEM-PBCA-NP), and anti-human CA199 monoclonal antibody was coupled with GEM-PBCA-NP (CA199-GEM-PBCA-NP), using the chemical crosslinking method. The cell-killing rates were detected using MTT assay. The changes in the tumor cell cycle and apoptosis after treatment were detected using flow cytometry. Then, the subcutaneous planting method was adopted to establish an animal model of pancreatic cancer: two nanometer microspheres were injected into the body of nude mice via the tail vein; the tumor suppression effect was detected after treatment; then, the groups were compared.

Results

In vitro, the cell-killing rate of each experimental group was significantly different from that of the control group (P < 05). The MUC1-GEM-PBCA-NP group had a significantly higher cell-killing rate than the other groups (P < 05). The apoptosis rate of the MUC1-GEM-PBCA-NP treatment group was significantly higher than that of other groups (P < 05). In vivo, the tumor inhibition rate of the MUC1-GEM-PBCA-NP treatment group was 72.69% ± 4.29%, which was significantly higher than those of other groups (P < 0.05). The tumor inhibition rate of the CA199-GEM-PBCA-NP treatment group was 56.58% ± 5.11%, which was significantly higher than those of other control groups (P < 0.05). At the end of treatment, the average tumor mass of the MUC1-GEM-PBCA-NP treatment group was 433.55 ± 12.49 mg, which was significantly lower than those of other groups (P < 0.05).

Conclusion

Compared with CA199-GEM-PBCA-NP, MUC1-GEM-PBCA-NP is more effective in vitro and in vivo. MUC1 could be a target molecule in treating pancreatic cancer.

Introduction

Recently, the incidence rate of pancreatic cancer has increased rapidly in China, and the therapeutic response of the disease is extremely poor [1], [2]. The clinical 5-year survival rate is low in all kinds of human malignant tumors. Therefore, treatment should have more curative effects and less toxic side effects. In the 21st century, the use of molecularly targeted therapy (MDT) is rising rapidly. In the past, the effects of some MDTs have subverted human cognition. MDT for pancreatic cancer has also become a new research hotspot. In our previous studies [3], [4], the therapeutic effects of gemcitabine-loaded polybutylcyanoacrylate nanoparticles (PBCA-NPs) coupled with anti-epidermal growth factor receptor (EGFR) monoclonal antibody was used to treat human pancreatic cancer xenografts in nude mice. The results suggested that it has certain targeting and antitumor effects on pancreatic cancer xenografts. To screen targeted molecules for better therapeutic effect, we further explored other possible targeted molecules in pancreatic cancer. Recently, some progress has been made in the study of target molecules of pancreatic cancer. The results suggest that mucin-1 (MUC1) and CA199 have relatively higher expression and stronger tissue specificity in pancreatic cancer than other molecules [5], [6], [7], [8]. Therefore, these two molecules could be target molecules for treating pancreatic cancer. Moreover, some preclinical studies [9], [10] have confirmed that MDT and immunotherapy targeting these two molecules for pancreatic cancer have a good effect. CA199 is currently the best serum tumor marker for pancreatic cancer, which has been widely used in clinical detection and prognosis judgment worldwide, and has been used as a therapeutic target molecule in experiments [11]. CA199 itself is formed by the mutation of some glycoproteins of the MUC1 molecule, some of which fall off into the blood and can be detected in the serum and become tumor marker antigens [12]. In this study, we compared the antitumor effects of gemcitabine-loaded NPs (CA199-GEM-PBCA-NP and MUC1-GEM-PBCA-NP) on pancreatic cancer cells in vitro and xenografts in vivo to evaluate the possibility of using them as target molecules.

Section snippetsLaboratory animals

Sixty-five female BALB/C nude mice (age, 6–8 weeks), weighing 18–22 g, were used. The animal experiment was performed at the animal laboratory of the 8th Medical Center of the General Hospital of the Chinese People’s Liberation Army. The experimental conditions were as follows: laboratory temperature, 22–25℃; relative humidity, 40%–70%; relative air pressure, 10–20 pa; air exchange frequency, 10–15 times/hour. Central air conditioning and air filtration mechanical equipment, animal cages,

Immunohistochemical detection of MUC1 and CA199 in PANC-1 cells

Uniform brown-yellow granules were observed in the cytoplasm and cell membrane of PANC-1 cells in MUC1 staining slides. The proportion of positive staining cells in cell climbing slides was high, and the nucleus was not stained. In CA199 staining slides, brown-yellow positive signals were mainly located in the cytoplasm, and the proportion of positive staining cells in cell climbing slides was also high (Fig. 1).

Preparation of MUC1-GEM-PBCA-NP and CA199-GEM-PBCA-NP

The NPs obtained using the aforementioned method showed a smooth spherical

Discussion

Pancreatic cancer is one of the malignant tumors of gastrointestinal tract with the worst prognosis worldwide [14], [15]. The effectiveness and side effects of treatment for advanced pancreatic cancer are the focus of this study. Recently, a targeted nano-drug delivery system has become a major direction, and some studies have focused on treating pancreatic cancer using a nano-drug delivery system [16], [17]. PBCA-NPs, as a commonly used nano-drug carrier, have many characteristics, such as

Conclusion

Compared with CA199-GEM-PBCA-NPs, MUC1-GEM-PBCA-NPs are more effective in vitro and in vivo. MUC1 could be a more potential target molecule for treating pancreatic cancer.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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© 2022 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.

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