A new animal study from the Israeli research team explored the accumulation of nanoparticles in the reproductive system of female mice. The results showed that accumulation of nanoparticles in the female reproductive organs seems to impair the development of oocytes and can compromise fertility. In addition, cancer treatment with nanomedicine seems to be affected by the specific distribution of nanoparticles in the female reproductive system.
In European legislation, a nanomaterial is defined as “an insoluble or bio-persistent and intentionally manufactured material with one or more external dimensions, or an internal structure, on the scale from 1 to ≤100 nm”. Nanoparticles can exert their harmful toxic effects on cells by increasing the production of reactive oxygen species, damaging DNA and mitochondria and inducing cell death, and these properties of nanomaterials represent significant concerns in the field of nanomedicine.
About the study
The research team investigated the effect of nanoparticles on the female menstrual cycle and female fertility. They also explored whether the stages of the menstrual cycle affect the accumulation and effectiveness of nanoparticles.
The menstrual cycle of the female mouse has four phases: proestrus, estrus (period of ovulation), metestrus and diestrus. The accumulation of nanoparticles in follicles before, during, and after ovulation was investigated with intravenously administered liposomes (80±10 nm) loaded with gadolinium (Gd-lipo). The results showed that the content of ovarian and uterine nanoparticles increased twice during ovulation compared to the non-ovulatory phase. The smallest accumulation of nanoparticles was seen during the diestrus phase.
It appears that physiological changes during the menstrual cycle affect the biodistribution and accumulation of nanoparticles in the reproductive system of female mice.
To explore whether the ovaries have a nanoscale size limitation, PEGylated gold nanoparticles of various sizes: 20, 50, 100, and 100 200 nm were administered intravenously in the estrus phase. The results showed that 80 nm liposomes were found around the follicle, specifically at the outer thecal layer 24 hours after intravenous injection. These findings indicate that 80 nm liposomes did not cross the blood-follicle barrier that protects the developing oocyte from toxic and foreign molecules.
The potential toxic effect of liposomal doxorubicin on the ovaries has also been investigated. Free doxorubicin (free-DOX) or doxorubicin-loaded liposomes (DOX-lipo) were administered intravenously to healthy female mice during the estrus and diestrus phases. The results showed an increase in the percentage of apoptotic follicles in the free-DOX treated group compared with the DOX-lipo treated group after 24 hours. After 48 hours, the percentage of apoptotic follicles did not increase in the free-DOX group. However, in the DOX-lipo treated mice, the percentage of apoptotic follicles increased significantly after 48 hours. According to the authors, initial accumulation of DOX-lipo in the ovaries resulted in delayed toxic effect.
To explore the impact of nanoparticles on fertility, the healthy female mice were divided into 3 groups: free-DOX treated, DOX-lipo treated, and untreated control. The results showed that only 70% of the mice in the DOX-lipo group became pregnant. Pup viability was 100% in the control group and only 60%±14% in the DOX-lipo group. The period before the first litter was 59±24 days for the free-DOX treated group and 62±10 days for the DOX-lipo group.
Finally, the authors investigated biodistribution of 80 nm liposome during the estrus and diestrus in mice with breast or ovarian cancer. In the breast cancer model, the reproductive system has accumulated 2.6-times more liposomes than at the site of the tumor during the estrus phase. However, if the reproductive system was the target of nanomedicine treatment, as in ovarian cancer, the result was different. Ovarian cancer treatment with doxorubicin-loaded liposomes resulted in increased accumulation of nanoparticles in the ovaries during ovulation compared to the diestrus phase. Treatment with nanomedicines during ovulation in both cases has resulted in a higher accumulation of drugs in the reproductive system.
The authors concluded that accumulation of nanoparticles in the female reproductive organs seems to impair the development of oocytes and can compromise fertility. In addition, the biodistribution of therapeutic nanoparticles in the female reproductive system is affected by phase of the menstrual cycle. Therefore, the menstrual cycle phase and possible ovarian toxicity caused by the accumulation of nanoparticles should be considered when implementing nanotherapies in female patients of reproductive age. Additionally, cancer treatment with nanomedicines seems to be affected by the specific distribution of nanoparticles in the female reproductive system.
This article was published in the scientific journal ACS Nano. Poley M. Nanoparticles Accumulate in the Female Reproductive System during Ovulation Affecting Cancer Treatment and Fertility. ACS Nano 2022, 16, 4, 5246–5257 https://pubs.acs.org/doi/10.1021/acsnano.1c07237
The article is also available on the pre-print server (Open Access). https://www.biorxiv.org/content/10.1101/2020.07.22.216168v1.full
It should be noted here that previous data have shown that nanoparticles, due to their unique physicochemical properties, can directly cross the placenta and cause damage to the fetus, resulting in various fetal abnormalities. Nanotoxicity at the maternal–fetal interface involves various underlying molecular mechanisms such as oxidative stress, DNA damage, apoptosis, and autophagy. https://discovermednews.com/nanoparticles-can-cross-the-placental-barrier-and-cause-fetal-damage/