An ideal therapy for venous thrombi would induce local thrombolysis while leaving the systemic fibrinolytic system undisturbed. Such a therapy does not currently exist. It is hypothesized in this proposal that magnetically guided albumin microspheres containing activators or potentiators of the fibrinolytic system can approach these ideal requirements. Magnetite containing microspheres (MaguSphs) were prepared with the activator, low molecular weight urokinase (UK) and with the potentiator, flufenamate (FLU). Three properties were studied in this proposal: physical, magnetic, and fibrinolytic. Physical variations in the release of UK and FLU were accomplished by altering the degree of chemical crosslinking. Chromogenic assays of UK and HPLC assays of FLU were carried out in a serum albumin release media. Alternative formulations were investigated to optimized the release of the larger UK molecule. Magnetic properties of interest are capture and transport. Capture is the removal of MaguSphs from a flowing fluid by an external magnet. This is to simulate the need to treat a non- occluding thrombus. Transport is the ability of a magnetic field to move MaguSphs through a static fluid. This is to simulate the therapeutic needs of an occluding venous thrombus. Both of these magnetic guidance properties were quantitated using 125-I- labelled MaguSphs. Finally, fibrinolytic properties of MaguSphs were studied using a 125-I-fibrin clot attached to a magnetic glass rod. The synergistic interactions of Lysplasminogen, the UK potentiator dicloxacillin, and MaguSphs of UK and FLU were studied with respect to their fibrinolytic end point. Thirteen experiments were designed to study these interactions. Replicates of these experiments were analyzed using a one-way Duncan multiple range test.
| Bhargava, K; Ando, H Y (1992) Immobilization of active urokinase on albumin microspheres: use of a chemical dehydrant and process monitoring. Pharm Res 9:776-81 |
