Targeted Delivery of Plasminogen Activators for Thrombolytic Therapy: An Integrative Evaluation

Yunn-Hwa Ma, Chih-Hsin Liu, Yueh Liang, Jyh-Ping Chen, Tony Wu, Yunn-Hwa Ma, Chih-Hsin Liu, Yueh Liang, Jyh-Ping Chen, Tony Wu

Abstract

In thrombolytic therapy, plasminogen activators (PAs) are still the only group of drug approved to induce thrombolysis, and therefore, critical for treatment of arterial thromboembolism, such as stroke, in the acute phase. Functionalized nanocomposites have attracted great attention in achieving target thrombolysis due to favorable characteristics associated with the size, surface properties and targeting effects. Many PA-conjugated nanocomposites have been prepared and characterized, and some of them has been demonstrated with therapeutic efficacy in animal models. To facilitate future translation, this paper reviews recent progress of this area, especially focus on how to achieve reproducible thrombolysis efficacy in vivo.

Keywords: drug delivery; nanoparticles; plasminogen activators; thrombolysis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic diagram of proposed steps in development of therapeutic nanocomposites for target thrombolysis. Arrows indicate sequences or feedback consideration in the development. This review focuses on the pharmacological evaluation of the nanocomposites, as included in the red area.
Figure 2
Figure 2
Illustration of thrombolytic nanocomposites demonstrating pharmacological efficacy in a disease model in vivo. Both immobilized and protected plasminogen activator in the polymeric (upper panel) and liposomal (lower panel) nanocomposites can be used.
Figure 3
Figure 3
Schematic diagram of the rat iliac thromboembolic model and the magnetic guiding strategy. A preformed clot may be introduced from the right iliac cannula and lodged in the left iliac artery; FeCl3-induced thrombosis can be triggered in the left iliac artery. A mobile magnetic guiding strategy has been demonstrated crucial to achieve thrombolytic efficacy of rtPA nanocomposites administered from the right iliac artery (modified from [24]).
Figure 4
Figure 4
Target thrombolysis induced by immobilized rtPA plus heparin under magnetic guiding in a FeCl3 thrombosis model of the rat. (A) illustrates representative effects of MNP-rtPA plus heparin on the mean iliac artery blood flow (MIBF). FeCl3-induced thrombosis (arrow head) reduced left iliac blood flow to below 1 mL/min; MNP-rtPA (0.2 mg/kg) with heparin (500 mg/kg plus 500 IU/kg.hr for one hr) was administered from the right iliac artery, as indicated by the arrow. (B) Tissue perfusion of hind limb (HLP) and cremaster muscle (CP) was measured by laser speckle contrast imaging; the signals acquired in the areas are denoted as in the squares. Mean arterial pressure (MAP; C), mean iliac blood flow (MIBF; D), HLP (E) and CP (F) were measured with time. FeCl3 (20%) filter paper was placed on the left iliac artery at time 0. MNP-rtPA with heparin (H; 500 mg/kg plus 500 IU/kg.h for one hour; n = 5) or equivalent MNP with heparin was administered from the right iliac artery 5 min after complete occlusion. Values were presented as mean ± SE. *, p < 0.05 compared with the corresponding control group. †, p < 0.05 compared with the corresponding MNP-rtPA group.

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