Drug Delivery Research of Cancer Cell Membrane-Coated Nanoparticles
In recent years, malignant tumors have posed a serious threat to human health. Chemotherapy, as the main anti-tumor treatment, is often limited in efficacy due to the lack of targeted drug release, which in turn produces high toxicity to normal tissues. At present, most clinical drug molecules are non-targeted, have low bioavailability, require large doses to reach the effective concentration, and are easily excreted quickly, resulting in non-specific toxic and side effects. Cell membranes coated nanoparticles (CNPs) are widely used in cancer treatment due to their high biocompatibility. CNPs can disguise themselves as autologous cells to evade the recognition and clearance of the immune system, prolong blood circulation time and improve tumor targeting, which is crucial for tumor drug delivery therapy. At present, red blood cell membranes, white blood cell membranes, etc. are used to construct nano drug delivery systems. Red blood cell membranes can prolong the circulation time of drugs in the body; white blood cell membranes can aggregate to inflammatory areas. However, no significant results have been seen in tumor targeting. Tumor cells use specific membrane proteins on their surface to avoid immune surveillance and strengthen cell-to-cell adhesion. The abundant Ca2+-dependent proteins on their surface are not only conducive to cell-to-cell adhesion, but also help tumor cells resist apoptosis and maintain clustering. Based on these characteristics, nano-drug carriers wrapped with cancer cell membranes (CCM) can avoid immune clearance and non-specific binding, thereby significantly improving the targeted treatment effect of tumors.
Biological Barriers
Blood Barrier
Nanoparticles (NPs) can be coated with opsonins in the blood, which can bind to the surface of NPs, making them easily recognized by phagocytes. Phagocytes can bind to NPs through mechanisms such as opsonin conformational changes, adsorption, and complement system activation, thereby capturing and eliminating them. After ingesting nanoparticles, phagocytes release enzymes and reactive oxygen species to decompose these nanoparticles. These non-degradable NPs accumulate in immune organs such as the spleen and liver for a long time, and fail to be effectively decomposed, which may cause toxic side effects in these organs.
Tumor Microenvironment
The abnormal structure of tumor blood vessels and the rapid growth of tumor cells increase the accumulation of interstitial fluid in the tumor. Under the environment of high interstitial pressure, NPs have difficulty penetrating the blood vessel wall and entering the deep layer of tumor tissue, resulting in uneven distribution in the tumor, which reduces the efficiency of drug delivery. The abnormal deposition and reorganization of extracellular matrix (ECM) components form a dense and irregular network, which sets up a physical barrier for the nanoparticle drug delivery system. Therefore, the interaction of factors such as insufficient blood supply inside the tumor, limited vascular permeability, diversity of the extracellular matrix, high pressure in the tumor stroma, and excessive cell density together leads to the uneven distribution of NPs inside the tumor, which directly affects the efficacy of NPs as drug delivery carriers.
Cell Barrier
NPs can cross the cell membrane by binding to receptors on the cell membrane, nonspecific adsorption, or endocytosis. Once inside the cell, the endocytic vesicles encapsulating the NPs may be transported to the lysosome for degradation, or return to the cell surface by releasing ligands. When nanoparticles enter the cell, the overexpression of P-glycoprotein by the activated cell’s internal transport mechanism may pump NPs out of the cell, thereby preventing it from acting inside the cell.
Mechanisms of Cancer Cell Membranes Overcoming Biological Barriers
Immune Escape
NPs can be quickly cleared by the immune system in the body, reducing their utilization and efficacy, and may produce toxic side effects. The content of CD47 protein on the surface of cancer cells is often high. CD47 is a type of transmembrane glycoprotein that can bind to SIRPα protein on the surface of immune cells and send a “do not engulf” signal to immune cells. This effect can effectively prevent macrophages from engulfing nanoparticles wrapped in cancer cell membranes, preventing these drug delivery nanocarriers from being recognized and cleared by the immune system.
Homologous Tumor Targeting
Due to the uneven blood supply inside the tumor and the diversity of matrix composition, the distribution of NPs inside the tumor is usually uneven. In order to improve the uniformity of NPs distribution in tumor tissues and achieve targeted drug delivery, an active targeting strategy can be adopted. Highly expressed cell adhesion molecules unique to the surface of cancer cells, such as focal adhesion proteins, integrins, focal adhesion kinases, and RHO family proteins, are involved in self-recognition and mutual adhesion between cells. Using these molecular characteristics, nanoparticles covered with cell membranes can be developed to achieve active targeting of cancer cells.
Research on CCM in Tumor Drug Delivery
Drug Delivery to the Tumor Microenvironment
Drug Delivery in Tumor Blood Vessels
Tumor progression is often accompanied by the formation of new blood vessels, which are usually imperfect in structure and prone to leakage, providing sufficient nutrients and oxygen to the tumor to support its rapid proliferation. At the same time, these blood vessels also facilitate tumor cells to enter the blood circulation and promote distant metastasis. Therefore, tumor spread can be limited by intervening in key targets such as vascular endothelial growth factor receptors (VEGFRs).
Drug Delivery in Tumor Extracellular Matrix
The extracellular matrix is mainly produced by cancer-associated fibroblasts (CAFs) and contains proteoglycans, fibrogenic proteins, and glycoproteins. During tumor progression, enhanced CAFs activity leads to ECM hardening and reduced blood perfusion, which in turn causes reduced tissue oxygen content, upregulation of cell glycolysis, ECM acidification, and the formation of immunosuppressive TME. Treatment targeting ECM can prevent tumor metastasis and growth, and can be combined with chemotherapeutic drugs to avoid drug resistance and improve efficacy.
Drug Delivery to the Cell Membrane
On the surface of cancer cells, the overexpression of multiple receptors provides opportunities for targeted drug delivery. Among them, transferrin and folate receptors are widely used as selective ligands on the surface of nanoparticles due to their high expression levels on various cancer cells to promote the entry of drugs into cancer cells through the cell membrane. Folate receptors are one of the targets for cancer treatment. After binding to their ligands, they can be internalized by cancer cells or released into the cytoplasm. Compared with normal cells, tumor cells efficiently transport folate complexes through folate receptors.
The expression of transferrin in cancer cells, especially metastatic cancer cells, is much higher than that in normal cells, making transferrin an important target in cancer treatment. After transferrin binds to the transferrin receptor on the cell surface, it enters the cell through endocytosis and plays a role in targeting the cell membrane.
Drug Delivery into Cells
NPs usually enter cancer cells through energy-dependent endocytosis, but this process easily leads to the decomposition of NPs in lysosomes, thereby reducing the drug concentration in cancer cells. Various strategies to improve cancer cell penetration have been studied to overcome this obstacle. Since cell-penetrating peptides (CPPs) are mainly composed of positively charged alkaline amino acids, they can bind to the negatively charged surface of cancer cell membranes and are more likely to target cancer cells than normal cells. After CPPs bind to cancer cell membranes, they promote the formation of holes or channels in the cell membranes through their amphiphilic properties, allowing the peptides and the nanoparticles they carry to enter the cells.
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