ABSTRACT
Selectins are optimal biological molecules for targeted delivery of therapeutic agents because of their localized and carefully regulated expression in several human diseases, and their highly specific interactions with their counter receptors. In this study, we describe a targeted delivery system that can potentially deliver anti-inflammatory drug to sites of chronic inflammation using Poly(lactic-co-glycolic acid) (PLGA) and selectin-ligand chemistry. Biotinylated-sialyl Lewis(x) (sLe(x)), a carbohydrate that serves as a ligand to selectins, was attached to the surface of avidin-linked PLGA microspheres. These carbohydrate-coated microspheres mimic the adhesive behavior of leukocytes on selectins in flow chambers, displaying slow rolling under flow. The rolling velocity of these artificial leukocytes is similar to that displayed by leukocytes rolling on P- or E-selectin coated surfaces. We can tune rolling velocity, and hence residence time of capsules on surfaces, by changing the density of sialyl Lewis(x) on the microsphere surfaces. Therefore, we have made a targeted drug delivery vehicle that mimics the adhesive properties of leukocytes and is biodegradable.
Subject(s)
Drug Delivery Systems/methods , Lactic Acid/administration & dosage , Polyglycolic Acid/administration & dosage , Polymers/administration & dosage , Selectins/administration & dosage , Lactic Acid/chemistry , Leukocytes/chemistry , Leukocytes/drug effects , Microspheres , Polyglycolic Acid/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Polymers/chemistry , Selectins/chemistryABSTRACT
The overexpression of lectins by malignant cells compared with normal ones can be used for the targeting of drug-loaded liposomes to tumours with the help of specific carbohydrate ligands (vectors). Recently we have shown that liposomes bearing specific lipid-anchored glycoconjugates on a polymeric matrix bind in vitro to human malignant cells more effectively and, being loaded with a lipophilic prodrug of merphalan, reveal higher cytotoxic activity compared with unvectored liposomes. In this study, carbohydrate-equipped cytotoxic liposomes were tested in vivo in a mouse breast cancer model, BLRB-Rb (8.17)1Iem strain with a high incidence of spontaneous mammary adenocarcinoma (SMA). Firstly, a cell line of the SMA was established which was then used to determine the specificity of the tumour cell lectins. After screening of the lectin specificity of a number of fluorescent carbohydrate probes, SiaLe(X) was shown to be the ligand with the most affinity, and a lipophilic vector bearing this saccharide was synthesised. Then different liposomal formulations of the synthetic merphalan lipid derivative and SiaLe(X) vector were prepared and applied in the treatment of mice with grafted adenocarcinomas. The results of the tumorigenesis data show that the therapeutic efficacy of merphalan increases sharply after its insertion as a lipophilic prodrug into the membrane of SiaLe(X)-vectored liposomes.
