In recent years, cell drug conjugates (CDCs) have gradually become a hot topic in medical research as an emerging drug delivery system. On July 1, 2024, Professor Gu Zhen and others from Zhejiang University published a review paper titled "Cell Drug Conjugates" in the Nature Journal of Biomedical Engineering. The article deeply explores the principles, preparation methods, and applications of this technology in cancer and immune diseases. This article will explain the content of the literature in detail, taking you to understand the core and prospects of this innovative technology.

01

What are cell drug conjugates (CDCs)?

Cell drug conjugates are a complex that combines live cells and therapeutic drugs, capable of simultaneously exerting the functions of both, particularly suitable for the treatment of complex diseases such as cancer and autoimmune disorders. Unlike traditional drug delivery systems such as liposomes, nanoparticles, etc., CDCs utilize the physiological characteristics of cells, such as migration ability, barrier penetration, etc., to deliver drugs more accurately and sustainably in disease specific microenvironments.

The main functions of CDCs are:

1. Long term circulation of drugs: By utilizing the characteristics of long-lived cells such as red blood cells and platelets, CDCs can significantly prolong the circulation time of drugs in the body, thereby improving treatment efficacy.

2. Penetrating physiological barriers: CDCs can cross physiological barriers such as the blood-brain barrier (BBB) to achieve precise drug delivery, especially showing potential in brain cancer and central nervous system diseases.

3. Targeted delivery: By utilizing the chemotaxis of cells, CDCs can accurately deliver drugs to diseased tissues or organs, reducing the side effects of drugs.

Figure 1: Schematic diagram of the definition, preparation, and therapeutic application of CDC

02

Preparation method of CDCs

The article points out that there are three main ways to prepare CDCs: covalent modification, non covalent binding, and genetic engineering.
1. Covalent modification: covalently binding drugs to proteins, sugars, and other substances on the cell membrane through chemical reactions. Although this method has strong stability, it may affect the integrity of the cell membrane.
Example: Targeted drug delivery in cancer treatment can be achieved by binding drugs to T cells through the thiol maleimide reaction.
2. Non covalent binding: Using electrostatic interactions, receptor ligand binding, and other methods to attach drugs to the surface of cells. This method is mild, but the drug stability is poor.
Example: Positively charged nanoparticles are used to adhere to the surface of red blood cells through electrostatic adsorption, in order to prolong the in vivo circulation time of drugs.
3. Genetic engineering: By using gene editing technology, drugs or drug anchoring proteins are directly expressed on the surface of cells. This method can maintain the integrity of the cell membrane, but the preparation cycle is longer and the cost is higher.

Figure 2: Method for preparing CDCs by covalent modification

03

Application areas of CDCs

The article mentions that CDCs have shown broad application prospects in various fields such as cancer and immune diseases
1. Cancer treatment:
T cells: By coupling immune modulators (such as IL-15SA) with T cells, their anti-cancer activity can be enhanced. For example, lipid nanoparticles conjugated with IL-15SA and IL-21 can stimulate T cell proliferation and enhance their anti-tumor ability in animal models.
Macrophages: By loading interferon gamma (IFN gamma) onto the surface of macrophages, tumor associated macrophages can be transformed from immunosuppressive (M2) to pro-inflammatory (M1), thereby inhibiting tumor growth.

Figure 3: CDCs used for cancer treatment

2. Immune disease treatment:
Red blood cells: PD-L1 can induce depletion of T cells by coupling to the surface of red blood cells, and is used to treat autoimmune diseases such as type 1 diabetes.

Figure 4: CDCs used for the treatment of autoimmune diseases

3. Brain diseases: By utilizing the barrier penetrating properties of CDCs, drugs can more effectively cross the blood-brain barrier and be applied in the treatment of neurological diseases such as brain cancer and Alzheimer's disease.

04

Future challenges and development opportunities

Although CDCs have shown broad application prospects, they still face some challenges in clinical translation. The article points out that the development of CDCs still needs to overcome the following difficulties:
1. Immune response: Allogeneic cells may trigger host immune rejection, and in the future, it is necessary to reduce this risk through improved genetic engineering techniques or the development of novel immunosuppressive strategies.
2. Drug loading: How to increase drug loading while maintaining cellular biological function is a key issue in the development of CDCs.
3. Preparation process: The existing preparation process takes a long time, and how to improve preparation efficiency and reduce costs is also an urgent issue to be solved.
However, with the continuous advancement of biotechnology and materials science, CDCs are expected to become an important therapeutic approach in the future, especially in personalized treatment of cancer and chronic diseases.

05

epilogue

Cell drug conjugates expand the boundaries of traditional drug delivery by binding drugs to living cells, providing a new direction for future precision medicine. With the deepening of research, CDCs are expected to become a safe and efficient treatment method, benefiting more patients.