New Discover: Alendronate-composed Iron Nanochelator Can Effectively Treat Peritoneal Cancer

Professor Pan Yihang’s team from Sun Yat-sen University, found that alendronate iron nano chelating agent can effectively treat peritoneal cancer, published a paper entitled “Engineering Alendronate-Composed Iron Nanochelator for Efficient Peritoneal Carcinomatosis Treatment” in ADVANCED SCIENCE(IF=17.521, Q1). In this experiment, BLT Biotechnology’s Anivew 100 was used in observing the distribution of CaALN nanoparticles and the efficacy of CaALN in anti-tumor in animal models. 

Research Background

Iron is a necessary element for various cellular metabolism. Cancer cells have a strong demand for iron during their proliferation, invasion, and metastasis processes. Alendronate (ALN) is an FDA-approved bisphosphonate with metal chelating ability. In both theoretical and experimental studies, it was initially demonstrated to selectively bind to intracellular Fe3+.

Therefore, a CaALN iron nano chelator was reasonably designed in the study to kill cancer cells through the synergistic effect of iron consumption and calcium accumulation. In vitro experiments and RNA sequencing analysis showed that CaALN nanomedicine inhibited the proliferation of cancer cells by consuming Fe, interfering with DNA replication, and triggering intracellular reactive oxygen species (ROS). At the same time, the released Ca2+ and ROS promote each other and induce cell macromolecular damage, leading to mitochondrial apoptosis in cancer cells.

In a mouse model of intraperitoneal dissemination containing human ovarian cancer cell SKOV3, CaALN nanoparticles selectively accumulate in tumor tissue and cause significant delays in tumor growth and ascites formation. The average survival time of mice carrying SKOV3 in the treatment group was extended from 33 days to 90 days. These results indicate that iron chelators derived from alendronate can serve as effective strategies for the treatment of peritoneal cancer.

Research Method

To evaluate the in vivo distribution of CaLAN, intraperitoneal injection of 5×106 SKOV3 cells was transplanted into NOD/SCID mice to establish a xenograft model of intraperitoneal disseminated tumors.

To achieve real-time monitoring in vivo, CaALN nanoparticles were labeled with DiR fluorescence. As shown in the first row of Figure 3A, luciferase signals can be detected in the abdominal cavity, indicating the successful establishment of a mouse model for intraperitoneal xenotransplantation. After 14 days of tumor establishment, the distribution of CaALN nanoparticles in mice was evaluated by intraperitoneal injection of CaALN/DiR or free DiR.

The imaging and quantitative fluorescence intensity of tumors and organs confirmed that intraperitoneal injection of CaALN nanoparticles can target tumor tissue after 4 hours of injection (Figure 3A, B). In the free DiR group, fluorescence was not only distributed at the tumor site but also in the liver and spleen (Figure 3C, D). The tumor-targeting advantage of CaALN may be attributed to the presence of a peritoneal plasma barrier, which maintains a high concentration of CaALN nanoparticles in the peritoneal cavity and is ultimately absorbed by cancer cells (Figure 3E). In contrast, small molecules can enter the subperitoneal capillaries through the peritoneal plasma barrier and metabolize through the liver and spleen (Figure 3F).

△ Figure 3. In vivo biodistribution of CaALN. In vivo time-dependent bioluminescence and fluorescence images of SKOV3 tumor-bearing mice after i.p. injection of A) CaALN/DiR and C) free DiR i.p. treatment. B,D) In vitro bioluminescence and fluorescence images of tumors (Tu), livers (Li), hearts (He), spleens (Sp), lungs (Lu), and kidneys (Ki) dissected from SKOV3 tumor-bearing mice post 72 h i.p. injection. E) Illustration of in vivo distribution of CaALN nanoparticles and small molecules. F) Fluorescence intensity of in vitro tissues from mice treated with CaALN/DiR and DiR (mean ± SD, n = 3, ***P < 0.001, **P <0 .01)

Affected by its in vitro anti-tumor activity and in vivo tumor targeting ability, the author further evaluated the in vivo tumor inhibitory activity of CaALN nanoparticles. After 5 days of tumor cell transplantation, mice carrying SKOV3 were treated with PBS and two different doses of CaALN (10 and 25mg/kg, n=8), respectively. Perform regular imaging on 5 of the mice and monitor them by collecting weight, abdominal circumference, and survival data. (Figure 4A).

As shown in Figure 4 B and C, the Bioluminescence of the two CaALN treatment groups was maintained for 15 days, which means that the tumor growth was completely inhibited.

△ Figure 3: In vivo antitumor effect of CaALN on SKOV3 bearing mice. A) Scheme illustration of the in vivo antitumor experiment using SKOV3 intraperitoneal xenograft model. B) Bioluminescence images, C) bioluminescence intensity, D) body weight, E) abdominal girth, and F) survival curves of SKOV3 tumor-bearing mice in each treatment group. G) H&E staining images and tunnel histochemical images of representative tumor sections at day 31. H) H&E staining images of organs from experimental mice.

Summary

In a mouse model of intraperitoneal dissemination of human ovarian cancer cell SKOV3, it has been demonstrated that CaALN nanoparticles mainly accumulate in tumor tissue after intraperitoneal injection. In addition, CaALN nanoparticles not only reduce tumor burden but also inhibit the formation of ascites, which has significant clinical application value in the treatment of ovarian cancer. This study has demonstrated a unique strategy of using iron nano chelators formed by alendronate sodium to improve therapeutic efficacy and reduce small molecule side effects, effectively treating peritoneal cancer.

Reference

https://doi.org/10.1002/advs.202203031