Description

Here, we provide background elements about cancer, chemotherapy and liposomes, as well as a short description of our project.Welcome to project Calipso!

Key figures concerning cancer over the world

Cancer is defined by the World Health Organization as a large group of diseases that can start in almost any organ or tissue of the body when abnormal cells grow uncontrollably, go beyond their usual boundaries to invade adjoining parts of the body, and/or spread to other organs [1].

This disease still represents a major public health and economic issue and its burden is set to spiral with the aging and growth of the world population [2, 3, 4]. We are all affected by this disease, either directly or indirectly, we (very) probably know someone in our circle that has/had to struggle against cancer. It is high time for an inclusive and collaborative worldwide effort to combat cancer.

In 2020, the organization has recorded more than 19 million new cases of cancer all over the world. Cancer diseases, that affect people of all ages, are responsible for one in six deaths, which makes it the second most common cause of death globally (10 million deaths in 2020). The most deadly forms are lung, colon and rectum, liver, stomach, and breast cancer [5].

In France, in 2020, cancers are responsible for 29% of accounted deaths for men and 23% for women making it the leading cause of death for men and the second for women [6].

Figure 1: Cancer was responsible for 1 in 6 deaths in 2020.

Chemotherapy, a heavy treatment for patients

To fight cancer, different treatments exist depending on the type of cancer, its location, and stage of development. The best known are radiotherapy (to destroy cancerous cells using X-rays), surgery (to remove localized cancerous tissues), immunotherapy (to target the immune system surrounding the tumor to activate it), and chemotherapy (to diffuse anticancer drugs into the body that kill cancer cells).

Chemotherapy is one of the most common treatments against cancer. The anticancer drug is directly administered intravenously or intramuscularly in the patient’s body. This makes it easy to reach cancer cells which are often difficult to access surgically. However, the main limitation of this technique is its inability to differentiate healthy cells and cancerous cells. Chemotherapy primarily targets dividing cells such as cancer cells but also hair follicle or digestive tract lining cells, making healthy mucosa particularly fragile. In addition, intravenous administration leads to systemic toxicity, local reactions, and lesions when the drug flows out of the veins.

This technique is therefore a source of numerous side effects due to its lack of specificity. Tissue embrittlement leads to fatigue, hair loss, nausea, pain, and weight issues.

It attacks fertility by reducing sperm count and promotes menopause. In the blood, this leads to neutropenia (decrease in polynuclear neutrophils), anemia and thrombocytopenia (lack of platelets), causing altogether aplasia and making the patient more susceptible to infection. And all the other treatments against cancer also have limitations, such as lack of specificity, or difficulty in accessing the tumor, often leading to side effects.

The challenge for new cancer therapies is, therefore, to improve their specificity in order to limit damage to healthy cells and secondary effects and improve the patient’s living conditions.

Using liposomes to treat cancer

What is a liposome?
A liposome is an artificial vesicle which membrane consists of one or more lipid bilayers. In aqueous solutions, a suspension of phospholipids spontaneously forms vesicles due to their amphiphilic nature: phospholipids have a hydrophilic head and a hydrophobic tail. Therefore, the most stable organization is a bilayer, with the polar heads in contact with water and the apolar tails pointing to the interior of the bilayer.

Advantages in cancer treatment:
Liposomes exhibit many features explaining why they are already used as a drug delivery system. They can encapsulate water-soluble molecules, ions and biological materials inside the aqueous medium of their lumen. They can also be loaded with hydrophobic molecules inside their lipidic membrane. Moreover, the liposome surface can be functionalized with targeting ligands (proteins, antibodies, peptides, carbohydrates, etc) to enhance specific drug delivery to tumor cells [7, 8]. Finally, as liposomes resemble biomembranes they are biocompatible, biodegradable, and present low toxicity [9].

Current applications of liposomes in cancer treatment:
Liposomes represent an emerging platform for targeted cancer treatments. Noteworthily, the work of Jois et al. [10] demonstrated the utilization of a ligand-functionalized HER2-targeted liposome for the delivery of Doxorubicin in cancer therapy. This article describes one of the first strategies to target cancer cells using a liposome, an approach that showed benefits compared to a normal treatment with chemotherapy.

CALIPSO: intelligent liposomes for cancer treatment

We, the Toulouse-INSA-UPS iGEM team, decided to tackle the challenge of side effects in cancer treatment by improving the specificity of cytotoxic drugs. Enhancing cancer therapies not only aims at improving patients' physical well-being but also to enrich their mental health and overall quality of life.

Unlike traditional approaches that directly encapsulate the active drug molecule, we use functionalized liposomes loaded with inactive precursors. The prodrug will be enzymatically converted into the active drug only upon recognition of cancer-specific markers following a signaling cascade within the liposomes. The active drug is produced at the tumor site, offering a more targeted and less invasive approach to cancer treatment.

Figure 5: Simplified scheme of the CALIPSO system

Figure 6: CALIPSO logo.

CALIPSO stands for:

Cell-targeting

Advanced

LIPosomes for

Selective

Oncotherapy.

This name also draws its inspiration from the nymph Calypso, who offered Ulysses immortality, making him immune to death, aging, and illness.

In summary, the CALIPSO project aims to improve cancer treatments by realizing the first integrated liposome platform to enable the targeted production of anticancer agents at the tumor site.