HYALURONIC ACID-MODIFIED BIOADHESIVE LIPOSOMES AS LOCAL-DRUG DEPOTS -EFFECTS OF CELLULAR AND FLUID-DYNAMICS ON LIPOSOME RETENTION AT TARGET SITES

Bioadhesive liposomes, in which hyaluronic acid is the surface-anchore d bioadhesive ligand, are being tested in vitro in order to evaluate t heir bioadhesivity. The first part of the test, binding to monolayers of cells modeling the in vivo designated sites under static conditions , was reported in a previous communication. This communication reports the results of the second and third parts of the test, which consist of evaluating the retention of bound liposomes in the face of tissue-r elated events such as cell migration, proliferation, and death, and un der fluid flow. The in vivo-designated binding sites for the bioadhesi ve liposomes were modeled, as before, by monolayers of the A431 cell. line served. A setup for perfusing a culture flask containing a monola yer of cells was devised for measuring the retention under fluid flow. The major findings are: (1) Over a selected tested period of 28 h, th e cell cultures mimicked the tissue-related events described above, wh ether they did or did not receive a dose of liposomes. Over the same p eriod and throughout these events, the bioadhesive liposomes remained bound at equilibrium-like levels, in the range of 0.03 ng lipid/10(5) cells. (2) Fluid flowed over a cell monolayer dosed with bioadhesive l iposomes swept away part of the dose. This loss was due mostly to that fraction of the dose which was in excess of the binding capacity of t he monolayer, and occurred over the first 15 min of flow. Thereafter, the cell monolayer retained the bound liposomes, at equilibrium-like l evels and with no further loss, even for the longest dow period tested (45 min of continuous flow) and under a flow rate of 0.64 ml/min. Thi s study, together with previous results, shows that the hyaluronic aci d-modified liposomes meet all parts of the bioadhesivity test. We ther efore find merit in their further investigation. (C) 1998 Academic Pre ss.