Targeted delivery of therapeutic agents to the heart

Abstract

For therapeutic materials to be successfully delivered to the heart, several barriers need to be overcome, including the anatomical challenges of access, the mechanical force of the blood flow, the endothelial barrier, the cellular barrier and the immune response. Various vectors and delivery methods have been proposed to improve the cardiac-specific uptake of materials to modify gene expression. Viral and non-viral vectors are widely used to deliver genetic materials, but each has its respective advantages and shortcomings. Adeno-associated viruses have emerged as one of the best tools for heart-targeted gene delivery. In addition, extracellular vesicles, including exosomes, which are secreted by most cell types, have gained popularity for drug delivery to several organs, including the heart. Accumulating evidence suggests that extracellular vesicles can carry and transfer functional proteins and genetic materials into target cells and might be an attractive option for heart-targeted delivery. Extracellular vesicles or artificial carriers of non-viral and viral vectors can be bioengineered with immune-evasive and cardiotropic properties. In this Review, we discuss the latest strategies for targeting and delivering therapeutic materials to the heart and how the knowledge of different vectors and delivery methods could successfully translate cardiac gene therapy into the clinical setting.

Fig. 1 |. Exosomes can envelope AAV vectors to shield them from neutralizing antibodies.

a | Neutralizing antibodies bind to adeno-associated viruses (AAVs) and prevent the uptake by cardiomyocytes of AAVs containing therapeutic genetic material. b | Exosome-associated AAVs (exo-AAVs) are more resistant to AAV-neutralizing antibodies because the exosome encapsulates the AAVs and shields them from neutralizing antibody-mediated detection and degradation. Exo-AAVs have a longer half-life in the circulation than AAVs and can penetrate deep tissues. Bioengineered surface and/or content modifications of exosomes could further improve the transduction efficacy of exo-AAVs.

Fig. 2 |. Delivery methods targeting the heart.

The therapeutic agent is depicted in green. a | Surgical approaches. (1) A cell sheet, tissue strip or biomaterial patch is about to be applied to a diseased area of the myocardium, such as an infarcted region (purple). (2) An epicardial injection is applied to the border zone of the diseased area. (3) Painting is applied on the right atrium. (4) Using cardiopulmonary bypass, retrograde recirculation via the coronary sinus allows cardiac-targeted delivery. b | Catheter-based approaches. (5) The coronary arteries are accessed using a guidewire and a guiding catheter (light blue), and coronary balloon occlusion is incorporated to facilitate transduction of the therapeutic agent. (6) The coronary sinus is selected using a guidewire and a balloon catheter (light blue), and the therapeutic agent is injected retrogradely in a coronary vein. (7) Transvalvular endocardial injection from the left ventricle. (8) Pericardial injection is administered using a percutaneous access sheath and an injection catheter (light blue).

Fig. 3 |. Factors that influence cardiac uptake of therapeutic agents.

Several factors influence the cardiac uptake of therapeutic agents including the type, dose and modification of the vector. Modifications include conjugation, coating and encapsulation (BOX 1). The delivery route should be selected on the basis of the therapeutic agent (epicardial intramyocardial injection, endocardial intramyocardial injection, antegrade intracoronary administration and pericardial administration are shown). For intracoronary administration, delivery pressure, delivery flow, capillary permeability and venous drainage influence the transduction efficacy. Venous drainage also influences direct injections. Neutralizing antibodies can reduce the effective titre of some classes of vector.