In Vivo Characteristics of Antitumor Drug Liposomes
Anti-tumor drug liposomes need to be studied in vivo during the development process, which includes examination of liposome pharmacokinetics, clinical efficacy and in vivo safety.
- Pharmacokinetics
Liposomes have a greater influence on the pharmacokinetic parameters of drug-loaded drugs, which are characterized by increased AUC(area under the curve, it shows drug’s bioavailabilit), extended half-life period, decreased clearance, decreased volume of distribution, and changes in tissue distribution. The pharmacological changes can be explained and proven from the anatomical characteristics of tumor sites, structural characteristics of liposomes, non-clinical studies and clinical studies.
The targeting of liposomes is divided into passive targeting, physicochemical targeting and active targeting. These targeting effects make the pharmacokinetic behavior of liposome drugs significantly different from ordinary preparations. Taking doxorubicin liposomes (Doxil) as an example, after intravenous injection of Doxil, the AUC of rats increased by 40 times compared with ordinary doxorubicin, the volume of distribution decreased, and the distribution half-life and elimination half-life increased 2 times and 4 times, respectively.
The tissue distribution of liposome drugs also changed significantly. Liposome drugs generally have higher drug concentrations in tumor tissues, that is to say, they show a certain degree of targeting. Non-clinical studies have shown that Doxil’s drug concentration in tumor tissue of nude mice increased significantly. Clinical studies have also demonstrated the targeting of liposome drugs. The distribution characteristics of liposome drugs are also manifested in that the drugs are mainly taken up by the mononuclear macrophage system, and the drugs are accumulated in organs rich in mononuclear macrophages, such as liver, spleen and bone marrow. In clinical studies, l-DTPA-labeled Doxil was operated to gamma-ray imaging. Except for tumor tissues, drugs in the liver, spleen, and bone marrow were intensive. In addition, due to some uncertain factors, liposome drugs may also be enriched in other parts of the blood, tumor sites, and mononuclear giant cell systems. For example, Doxil has a higher concentration in dog skin, but ordinary doxorubicin does not show this characteristic.
- Clinical Efficacy
As the pharmacokinetics of liposomes change, the drug concentration at the tumor site increases and remains for a longer period of time, so the drug efficacy may increase. Non-clinical studies have confirmed that Doxil’s efficacy is significantly increased in rodent and human transplanted tumor immunodeficiency mouse models. In clinical studies, the advantages of liposomal drugs have been shown in malignant tumors such as ovarian cancer, breast cancer and Kaposi’s sarcoma.
- In vivo Safety
Changes in liposome pharmacokinetics not only increase the efficacy, but also bring changes in safety. Due to changes in the distribution of drug tissues, liposomes may have new toxicity or increased original toxicity. The advantage is that it reduces the toxicity. The general adriamycin preparation is changed to liposome with reduced cardiotoxicity. The maximum tolerated dose of ordinary adriamycin preparations is 400mg/m2, and patients are basically unable to tolerate higher doses, but with Doxil, the tolerated dose is increased, and the incidence of cardiotoxicity is only 12%. The disadvantage is that liposomes accumulate in mononuclear macrophage systems, such as the liver, spleen, and bone marrow, and the toxicity to these sites may increase.
The purpose of the research and development of liposome dosage form is to improve the curative effect and reduce the toxic and side effects. Whether an anti-tumor drug is suitable for development as a liposome preparation should be combined with drug characteristics, clinical needs, pharmacokinetic changes, and toxicity changes. Compared with ordinary preparations, liposome preparations have a higher investment risk and less experience in large-scale industrial production. The research cycle is long, so the selection of topics must be cautious. Therefore, the study of new liposome formulations needs to be comprehensively evaluated.