Light-Controlled Release of Therapeutic Proteins from Red Blood Cells

Abstract

Protein therapeutics are a powerful class of drugs known for their selectivity and potency. However, the potential efficacy of these therapeutics is commonly offset by short circulatory half-lives and undesired action at otherwise healthy tissue. We describe herein a targeted protein delivery system that employs engineered red blood cells (RBCs) as carriers and light as the external trigger that promotes hemolysis and drug release. RBCs internally loaded with therapeutic proteins are readily surface modified with a dormant hemolytic peptide. The latter is activated via easily assigned wavelengths that extend into the optical window of tissue. We have demonstrated that photorelease transpires with spatiotemporal control and that the liberated proteins display the anticipated biological effects in vitro. Furthermore, we have confirmed targeted delivery of a clot-inducing enzyme in a mouse model. Finally, we anticipate that this strategy is not limited to RBC carriers but also should be applicable to nano-and microtransporters comprised of bilayer lipid membranes.

Taking phototherapeutics from concept to clinical launch

“…Protein therapeutics is another class of drugs that could benefit from targeted delivery mechanisms 83 , 84 . The RBC-conveyed drug delivery strategy has been expanded to include protein therapeutics using a photohaemolytic trigger comprised of melittin (Mel), an active component of bee venom 85 (Fig. 4f ).…”

“…4f ). Proteins loaded and photoreleased include the vascular endothelial growth factor (VEGF), which has received significant attention for therapeutic angiogenesis 86 , and thrombin (see the section entitled The phototherapeutic effect), which is representative of clotting proteins 85 .…”

“…Only 44 with illumination compromised tumour blood vessel integrity. A Cbl scaffold has also been used to trigger the photohaemolysis of RBCs and, thereby, release protein therapeutics 85 (Fig. 4f ).…”

The Issue of Tissue: Approaches and Challenges to the Light Control of Drug Activity

“…A significant strength of this approach is that the activation wavelength is as high as 660 nm. [29] A significant advantage of the photodegradation approach is the potential, at least in theory, to have more than one drug molecule released for each photo-stimulated event. In photocleavage or photoconformational control, each photostimulated event is associated with a single drug being released or activated.…”

“…Melittin can then induce hemolysis of the RBC, releasing the therapeutic contents of the cell. A significant strength of this approach is that the activation wavelength is as high as 660 nm [29] …”