Comparative analysis of the approaches for optimization of ATA pharmacokinetics
| Carrier . | ATA loading method . | Advantages . | Disadvantages . | ∼T1/2 in blood . |
|---|---|---|---|---|
| PEG coating | Covalent chemical conjugation | Biocompatible; extensively studied in vitro and in animals; FDA approved, clinically used for other drugs | Reduction of ATA activity; product heterogeneity | Minutes to hours |
| Liposomes | Encapsulation | Same as PEG conjugates | Low encapsulation efficiency; limited stability and stealth features | Minutes to hours |
| Polymeric nanoparticles | Encapsulation or surface coating | Biodegradable; tunable properties (size, shape, release kinetics); stability | Harsh preparation procedures aggravate loss of activity; delayed drug release; potential toxicity; mostly in vitro studies | Minutes to hours |
| Dendrimers | Conjugation | Precise control of size and structure | Same as polymeric nanoparticles; low drug loading; laborious synthesis | Minutes to hours |
| ELIPs | Encapsulation | Biocompatible; imaging capacity; | Same as liposomes, ultrasound-induced enzyme inactivation | Minutes to hours |
| ultrasound-enhanced drug release | ||||
| SA-NTs | Conjugation | Biodegradable; shear-based local drug release in stenotic vessels | Early development stage; low conjugation efficiency; product heterogeneity; unknown whether fully occlusive clots can be attacked | Not reported |
| Filomicelles, RBC/platelet mimetics | ATA not yet loaded | May significantly prolong circulation of ATA | Untested for ATA delivery; limited data in animals; potential toxicity; complex production and use | Hours to days |
| RBCs | Conjugation | Significantly prolongs ATA circulation; no diffusion into tissues; no lysis of fresh preformed hemostatic clots; markedly reduced adverse effects of ATA in the CNS; efficacy and safety proven in diverse types of vascular thrombosis in several animal species | Need for ex vivo conjugation of ATA to isolated RBCs and transfusion; cannot be used to dissolve existing occluding clots | Hours to days |
| Carrier . | ATA loading method . | Advantages . | Disadvantages . | ∼T1/2 in blood . |
|---|---|---|---|---|
| PEG coating | Covalent chemical conjugation | Biocompatible; extensively studied in vitro and in animals; FDA approved, clinically used for other drugs | Reduction of ATA activity; product heterogeneity | Minutes to hours |
| Liposomes | Encapsulation | Same as PEG conjugates | Low encapsulation efficiency; limited stability and stealth features | Minutes to hours |
| Polymeric nanoparticles | Encapsulation or surface coating | Biodegradable; tunable properties (size, shape, release kinetics); stability | Harsh preparation procedures aggravate loss of activity; delayed drug release; potential toxicity; mostly in vitro studies | Minutes to hours |
| Dendrimers | Conjugation | Precise control of size and structure | Same as polymeric nanoparticles; low drug loading; laborious synthesis | Minutes to hours |
| ELIPs | Encapsulation | Biocompatible; imaging capacity; | Same as liposomes, ultrasound-induced enzyme inactivation | Minutes to hours |
| ultrasound-enhanced drug release | ||||
| SA-NTs | Conjugation | Biodegradable; shear-based local drug release in stenotic vessels | Early development stage; low conjugation efficiency; product heterogeneity; unknown whether fully occlusive clots can be attacked | Not reported |
| Filomicelles, RBC/platelet mimetics | ATA not yet loaded | May significantly prolong circulation of ATA | Untested for ATA delivery; limited data in animals; potential toxicity; complex production and use | Hours to days |
| RBCs | Conjugation | Significantly prolongs ATA circulation; no diffusion into tissues; no lysis of fresh preformed hemostatic clots; markedly reduced adverse effects of ATA in the CNS; efficacy and safety proven in diverse types of vascular thrombosis in several animal species | Need for ex vivo conjugation of ATA to isolated RBCs and transfusion; cannot be used to dissolve existing occluding clots | Hours to days |
Each ADDS has distinct advantages and disadvantages. However, in general, all suffer from impeded permeation into clots. Newer “smart” systems (SA-NTs, ELIPs) with mechanisms for achieving concentrated local drug delivery may have some success in overcoming this limitation. Alternatively, the use of “natural” delivery systems, such as RBCs, and their mimetics may provide sufficiently prolonged circulation to allow for prophylactic use.