Phototherapeutics

Chemotherapeutics are an essential component of the therapeutic arsenal employed to treat solid and liquid tumors. However, chemotherapeutic potential is most often limited by systemic toxicity caused by off target side effects. Consequently, drug platforms that locally deliver efficacious therapeutic agents to diseased sites, while sparing healthy tissue, are highly sought after.

In work published in the journal Small, Christina Marvin and collaborators from the David Lawrence Group describe the use of red blood cells, RBCs, as carriers of cytoplasmically interned phototherapeutic agents. Photolysis promotes drug release from the RBC carrier thereby providing the means to target specific diseased sites.

This strategy is realized with a vitamin B12‐taxane conjugate, B12‐TAX, in which the drug is linked to the vitamin via a photolabile Co—C bond. The conjugate is introduced into mouse RBCs, mRBCs, via a pore‐forming/pore‐resealing procedure and is cytoplasmically retained due to the membrane impermeability of B12.

Photolysis separates the taxane from the B12 cytoplasmic anchor, enabling the drug to exit the RBC carrier. A covalently appended Cy5 antenna sensitizes the conjugate, Cy5‐B12‐TAX, to far red light, thereby circumventing the intense light absorbing properties of hemoglobin, 350–600 nm. Microscopy and imaging flow cytometry reveal that Cy5‐B12‐TAX‐loaded mRBCs act as drug carriers.

Furthermore, intravital imaging of mice furnish a real time assessment of circulating phototherapeutic‐loaded mRBCs as well as evidence of the targeted photorelease of the taxane upon photolysis. Histopathology confirms that drug release occurs in a well resolved spatiotemporal fashion. Finally, acoustic angiography is employed to assess the consequences of taxane release at the tumor site in Nu/Nu‐tumor‐bearing mice.

This system extends phototherapeutics into the optical window of tissue, where light enjoys the greatest depth of tissue penetration. In addition, phototherapeutics in combination with RBCs offer a number of potential advantages relative to synthetic drug carriers, including enhanced circulatory lifetime, biocompatibility, and a large drug payload per carrier. As natural carriers, RBCs serve as a barrier, protecting the phototherapeutic from clearance mechanisms while protecting healthy tissue from the undesired assault of the cytotoxic agent. These advantages suggest that the amalgamation of B12‐based phototherapeutics and RBCs carriers have the potential to serve as a synergistic combination for the precision delivery of therapeutic agents.