Drug conjugates that self-assemble into their own delivery vehicles

This post is part of a series highlighting the research of those invited to speak at NanoDDS’13.

Most drug-carrying nanoparticles are created by mixing drugs with lipids or polymers in complex mixtures of organic and aqueous solutions to create nanostructures (vesicles or polymer networks) surrounding a small amount of drug. But what if the drug and the nanocarrier material were the same molecule? Chemically attaching the two components not only simplifies the formulation process, but ensures that the drug molecules will remain inside the structure until it’s induced to disassemble and allows precise control over the ratio of drug to surrounding material in each nanostructure. 

A young professor at Johns Hopkins, Honggang Cui, has recently introduced just such a technology. His background developing peptides and polymers that self-assemble into nanostructures led him to recognize the power of this approach to overcome the limitations of other nanoformulations. For example, attaching several drug molecules to each macromolecule composing the surrounding structure enables each nanocarrier to incorporate high proportions of drug. Increasing the amount of drug incorporated into each nanoparticle would increase effectiveness, as it would require fewer nanoparticles to reach the target tissue to have the same therapeutic effect. The control over drug loading provided by the drug self-assembly approach is also a major advantage over delivery in liposomes or polymeric nanoparticles, in which loading varies significantly from batch to batch, which could affect the reliability of dosing.

The first demonstration of this concept, recently published in JACS, yielded an impressively high 38% loading of the anticancer drug camptothecin when each assembling molecule contains four camptothecin units (1). This study attached the drug molecules to a peptide derived from Tau protein that was already known to aggregate into filaments; future studies could employ other peptides that assemble similarly (into β sheets).

Self-assembling drug amphiphiles. Left, schematic; right, transmission electron micrograph. Blue ribbons represent the Tau peptide; red ovals, drug; green, degradable linkers. Image from Cheetham et al., JACS 2013.
Self-assembling drug amphiphiles. Left, schematic; right, transmission electron micrograph. Blue ribbons represent the Tau peptide; red ovals, drug; green, degradable linkers. Image from Cheetham et al., JACS 2013.

Considerable research remains to develop this concept towards clinical applicability. At this preliminary stage, these drug assemblies’ efficacy at killing cancer cells is actually lower than that of free drug, which likely results from their nanofiber shape; long, thin particles are not readily taken up by most cells. Altering the molecular design to promote the formation of spherical assemblies would increase cellular uptake. Because the linker between the drug and the rest of the molecule is towards the interior of the nanofiber and degrades upon exposure to reducing conditions, the assemblies must dissociate and diffuse into the cytosol to release active drug. Therefore, another potential route to increasing the amount of active drug within cells would be to engineer the assemblies to be less stable at low pH so that assemblies would dissociate within the cellular recycling vesicle. 

1.  Cheetham AG, Zhang P, Lin Y-a, Lock LL, & Cui H (2013) Supramolecular Nanostructures Formed by Anticancer Drug Assembly. J Am Chem Soc 135(8):2907-2910.