Liposomes as Carriers of Antitumor Drug

In recent years, the incidence of tumors has become higher and the tumor patients seem to be younger, which has seriously affected people’s health and quality of life. According to statistics, the number of newly diagnosed cancer patients in the world in 2007 has reached 12 million, and as many as 7 million people die from cancer worldwide each year. The current effective method is chemotherapy.

Compared with normal tissues, tumor tissue has increased vascular endothelial cell space, thin blood vessel walls, and increased vascular permeability, and it also lacks of lymphatic vessels in tumor tissue, which reduces the discharge of metabolites. Normal tissues have small capillary endothelial membrane pores. For example, the capillary endothelial membrane pores of pancreatic, intestinal, and renal are about 50-60 nm, and that of liver, spleen, and bone marrow are about 100 nm. Tumor tissue capillary endothelial cell gap is larger than normal tissue, being about 500nm. These characteristics of tumor tissue result in the phenomenon that nanoparticles with a particle size of about 200 nm are able to accumulate in the tumor tissue by the enhanced permeability and retention effect (EPR effect).

Many chemotherapeutic drugs such as 5-fluorouracil (5-FU), doxorubicin, cisplatin, vincristine, etc., kill tumor cells through apoptosis, but due to their serious toxic and side effects, anti-tumor chemical drugs are greatly limited in clinical application. It has become a research hotspot to improve the targeting of existing anti-cancer drugs with new formulation technologies to reduce or eliminate their toxic and side effects. As a targeted drug carrier, liposomes can enrich antitumor drugs in tumor tissues, thus reducing the amount of drugs. What’s more, reduced amount of drugs in normal tissues help to ease the injury to human bodies, improving the effectiveness and safety of drugs. For example, anthracycline anticancer drugs have severe cardiotoxicity, but liposome preparations can reduce cardiotoxicity while retaining their antitumor activity.

Figure 1. Basic structure and composition of liposomes.

Novel Antitumor Drug Liposome

Thermosensitive Liposome

When the lipid membrane is at the phase transition temperature changing from the gel state to the liquid crystal structure, the degree of disorder and activity of the lipid chain of the phospholipid increases, and the fluidity of the film also increases. At this time, the release rate of the encapsulated drug increases; while when the temperature is below this phase transition temperature, the membrane remains stable and the drug release is very little. According to this principle, thermosensitive liposomes can be prepared. Dipalmitoylphosphatidylcholine (DPPC), with a phase transition temperature of 41 °C, is the most commonly used thermosensitive liposome material.

pH sensitive Liposome

Because tumor cells are active in metabolization but inactive in removing the metabolites the pH value of their tissues is lower than that of normal tissues. When pH-sensitive liposomes contact material of low pH value, the polar head of the phospholipid is protonated and a hexagonal crystal phase is formed, causing the liposome membrane to fuse and rapidly release the drug. Dioleoylphosphatidylethanolamine (DOPE) is one of the typical phospholipids with pH sensitivity.

Actively Targeted Liposomes

Many cancer cells overexpress folic acid receptors and become one of the design strategies for actively targeting liposomes. Because the folate receptor is selectively expressed on the surface of the epithelial membrane of some epithelial cells, the drugs in the blood cannot be accessed, so the folic acid modified nanocarrier will not release the drug. However, if the epithelial cells are transformed and the cells lose their polarity, the targeted drugs in the blood circulation can reach the folate receptor. The iron ion demand of tumor cells is higher than that of normal cells, and transferrin receptor is highly expressed on tumor cells, so transferrin can be used as a specific ligand to prepare targeted liposomes. Integrins are a group of divalent ion-dependent cell surface glycoproteins that mediate the adhesion reaction between cells and between cells and extracellular matrix (ECM). Integrin molecules mediate adhesion by recognizing the Arg-Gly-Asp (RGD) sequence. RGD modified stealth liposomes carrying anticancer drugs allows the accumulation of anticancer drugs in tumor tissues, increases the transport of anticancer drugs into tumor cells, and improves the targeting of anticancer drug delivery.

Anti-resistant Tumor Liposomes

With the large-scale use of chemotherapy drugs, the problem of drug resistance in cancer treatment is becoming more and more prominent. Multidrug resistance (MDR) refers to a concept that when tumor cells are resistant to a certain anti-cancer drug, they develop cross-resistance to other drugs with different structures and functions. MDR is currently the main obstacle in clinical cancer treatment. The mechanism of MDR formation includes increased expression of multidrug resistance genes and their encoded P-glycoprotein (P-gp), increased glutathione transferase activity, decreased DNA topoisomerase II activity, or enhanced repairing ability of structurally abnormal DNA, changes in protein kinase C, and overexpression of multidrug resistance-related proteins, among which P-gp is the most important cause of MDR. Substrates with high affinity for P-gp are called MDR reversing agents. Encapsulating the MDR revering agents into the liposome can overcome the drug resistance of the tumor with reduced side effects.