The "Waterloo" of folic acid molecule in targeted Drug Delivery
The active targeted delivery strategy has been proposed as early as the 1980s, aiming at the surface modification specific target molecules of the drug delivery system, by identifying the corresponding target, guide the modified nanomedical drugs to cross the physiological barrier and increase the drug distribution at the focal site. The key to this strategy is to find the right "magic bullet". Among them, folic acid is undoubtedly a star molecule, which is often used as a modification on the surface of various drugs to realize active targeting by recognizing folic acid receptors highly expressed in tumor tissues. There are tens of thousands of publications based on folic acid targeting. Over the past 50 years, several folate-targeting drugs have entered clinical trials. Unfortunately, with the exception of a few folate-probes used to aid surgical navigation, all clinical studies of folate-targeted therapeutics have failed (e.g. Vintafolide, EC150), casting a shadow over the clinical translation of folate-targeted therapeutics. In the field of basic research, folic acid targeting is also controversial, mainly reflected in the inconsistent results in vivo and in vitro. The results of in vitro cell experiments are good, but once in vivo, the targeting effect is greatly reduced. Therefore, clarifying the delivery process of folic acid molecule-mediated targeted delivery system in vivo and revealing the regulatory mechanism related to its delivery are important steps to promote the development and clinical transformation of this type of drug.
In this paper, the team of Professor Zhan Changyou of Fudan University and Associate Professor Wang Huan of Naval Medical University have made a series of work in the field of folate-targeting nanomedicine in recent years.
Origin: Specific adsorption of natural IgM
The delivery process of drug delivery system in the body is extremely complex, and many factors determine its fate in the body. In recent years, the role of plasma proteins in drug delivery systems has received more and more attention. Take liposomes as an example. During blood circulation, liposomes adsorb plasma proteins on their surface to form a protein crown, thus changing the surface properties of liposomes. For example, the fate of liposomes in vivo is negatively regulated by increasing the particle size of liposomes, shielding surface potential, and enhancing the recognition of mononuclear macrophage system through adsorption of opsonins. In particular, active targeting of liposomes can significantly increase the adsorption of plasma protein on the surface of liposomes after modification of target molecules, seriously affecting its targeting, pharmacokinetics, immunogenicity and other properties in vivo.
In the team's previous research, it was found that the natural immunoglobulin M (IgM) in the blood would be widely adsorbed on the surface of various targeted liposomes, resulting in rapid clearance of liposomes. Among them, folic acid liposomes had the highest IgM adsorption, which attracted the attention of the team. There are two main types of natural IgM, the first is free IgM, that is, sIgM, which is usually a pentamer of five IgM monomers connected by disulfide bonds and J chains, with a molecular weight of about 950 kD. It contains 10 Fab segments and 5 Fc segments, and its antigen binding ability and complement activation ability are higher than IgG. sIgM is mainly distributed in the blood and is an important part of the body's innate immune system. The second is the membrane-bound type, mIgM, which is mainly expressed on the surface of B cells in the form of monomer and constitutes the B cell receptor complex, which regulates the humoral immune function of the body.
Based on the specific binding of natu...
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