Surface Modification of RGD-Liposomes for Selective Drug Delivery to Monocytes/Neutrophils in Brain

Jing Qin, DaWei Chen, HaiYang Hu, Qiao Cui, MingXi Qiao, BaoYu Chen
2007 Chemical and pharmaceutical bulletin  
The blood-brain barrier (BBB) consists of tight intercellular junctions and plays an important role in the maintenance of the brain microenvironment. 1-3) Moreover, because of the highly lipophilic nature of the BBB, the presence of efflux transport processes, endothelial cell metabolism and plasma protein binding, many drugs fail to enter the brain following systemic administration. Hence the management of brain-related diseases with presently available therapeutic strategies is often very
more » ... icult. 4) Evidence is accumulating that inflammation plays an important role in the pathogenesis of neurodegenerative diseases. An inflammatory reaction in the brain is found in conditions as diverse as ischemia, Alzheimer's disease and AIDS-related dementia. 5-7) In fact, in many neurological diseases, leukocytes including monocytes and neutrophils can across an intact BBB. 3, 8) Thus, one of the strategies to deliver drugs to the brain under pathological conditions is to exploit these inflammatory cells as targeted delivery systems. RGD peptide (Arg-Gly-Asp) can combine with integrin receptors which are expressed on the surface of leukocytes (neutrophils and monocytes). [9] [10] [11] The interaction between the RGD domain on the integrin molecule and the integrin receptor on leukocytes stimulates phagocytosis by polymorphonuclear cells (e.g. neutrophils). 12) Phagocytic and exclusive extravasation property of leukocytes makes it possible to exploit these cells as carrier system for targeted delivery. 4) It seemed possible, therefore, that RGD-liposomes could be developed for selective and preferential presentation to blood monocytes/neutrophils. Subsequently, liposomes could be taken up into the brain in response to the inflammation recruitment. 4,13) Brain targeted delivery would be possible in this elegant way. Traditional Chinese medicines (TCMs) are treatments that are commonly advocated for a wide range of conditions in many Eastern countries and they have also become popular in the West. 14) In addition, TCMs are now being studied in great deal with reference to their low incidence of toxic side effects compared with the side effects of a number of synthetic drugs. 15) Ferulic acid (4-hydroxy-3-methoxycinnamic, FA) is one of the most important active components of several TCMs which have been used in the treatment of neurovascular and cardiovascular diseases for many years. It is known to have a wide range of pharmacological effects including antioxidant, radical scavenging, anti-apoptotic, antiinflammatory, anticancer, antiageing, neuroprotective and antidiabetic properties, [16] [17] [18] [19] [20] and its antioxidant activity is particularly important. 21-23) Hence, it can be used as a promising protective agent for the treatment of neurodegenerative disorders such as Parkinson's, Alzheimer's, and Friedreich's diseases, as well as stroke [24] [25] [26] [27] which are characterized by free radical-mediated oxidative stress, apoptosis and brain inflammation. 28-32) However, its poor penetration into brain limits its application to neurodegenerative diseases. 33) Among various approaches to improve the distribution, RGD-liposome appears to be a more promising strategy. In the present study, an RGD-peptide was coupled to liposomes to allow site-specific drug delivery to brain. Subsequently, an evaluation was carried out of the brain targeting ability under inflammatory conditions and the pharmacological effects of FA and its preparations were also investigated.
doi:10.1248/cpb.55.1192 pmid:17666843 fatcat:z7jm6rgrfnc6rn72etz6ithlve