Honggang Cui

Abstract Peptide amphiphiles are a class of molecules that combine the structural features of amphiphilic surfactants with the functions of bioactive peptides and are known to assemble into a variety of nanostructures. A specific type of peptide amphiphiles are known to self‐assemble into one‐dimensional nanostructures under physiological conditions, predominantly nanofibers with a cylindrical geometry. The resultant nanostructures could be highly bioactive and are of great interest in many biomedical applications, including tissue engineering, regenerative medicine, and drug delivery. In this context, we highlight our strategies for using molecular self‐assembly as a toolbox to produce peptide amphiphile nanostructures and materials and efforts to translate this technology into applications as therapeutics. We also review our recent progress in using these materials for treating spinal cord injury, inducing angiogenesis, and for hard tissue regeneration and replacement. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 94:1–18, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Block copolymers consist of two or more chemically different polymer segments, or blocks, connected by a covalent linkage. In solution, amphiphilic blocks can self-assemble as a result of energetic repulsion effects between blocks. The degree of repulsion, the lengths of the block segments, and the selectivity of the solvent primarily control the resultant assembled morphology. In an ideal situation, one would like to be able to alter the morphology that forms without having to change the chemistry of the block copolymer. Through the kinetic manipulation of charged, amphiphilic block copolymers in solution, we are able to generate different nanoscale structures with simple block copolymer chemistry. The technique relies on divalent organic counter ions and solvent mixtures to drive the organization of the block copolymers down specific pathways into complex one-dimensional structures. Block copolymers are increasingly used as templating materials; thus, the ability to control the formation of specific patterns and structures is of growing interest and applicability.

A stable phase of toroidal, or ringlike, supramolecular assemblies was formed by combining dilute solution characteristics critical for both bundling of like-charged biopolymers and block copolymer micelle formation. The key to toroid versus classic cylinder micelle formation is the interaction of the negatively charged hydrophilic block of an amphiphilic triblock copolymer with a positively charged divalent organic counterion. This produces a self-attraction of cylindrical micelles that leads to toroid formation, a mechanism akin to the toroidal bundling of semiflexible charged biopolymers such as DNA. The toroids can be kinetically trapped or chemically cross-linked. Insight into the mechanism of toroid formation can be gained by observation of intermediate structures kinetically trapped during film casting.

The specific sizes that determine optimal nanoparticle tumor accumulation, penetration, and treatment remain inconclusive because many studies compared nanoparticles with multiple physicochemical variables (e.g., chemical structures, shapes, and other physical properties) in addition to the size. In this study, we synthesized amphiphilic block copolymers of 7-ethyl-10-hydroxylcamptothecin (SN38) prodrug and fabricated micelles with sizes ranging from 20 to 300 nm from a single copolymer. The as-prepared micelles had exactly the same chemical structures and similar physical properties except for size, which provided an ideal platform for a systematic investigation of the size effects in cancer drug delivery. We found that the micelle's blood circulation time and tumor accumulation increased with the increase in their diameters, with optimal diameter range of 100 to 160 nm. However, the much higher tumor accumulation of the large micelles (100 nm) did not result in significantly improved therapeutic efficacy, because the large micelles had poorer tumor penetration than the small ones (30 nm). An optimal size that balances drug accumulation and penetration in tumors is critical for improving the therapeutic efficacy of nanoparticulate drugs.

We report here a supramolecular strategy to directly assemble the small molecular hydrophobic anticancer drug camptothecin (CPT) into discrete, stable, well-defined nanostructures with a high and quantitative drug loading. Depending on the number of CPTs in the molecular design, the resulting nanostructures can be either nanofibers or nanotubes, and have a fixed CPT loading content ranging from 23% to 38%. We found that formation of nanostructures provides protection for both the CPT drug and the biodegradable linker from the external environment and thus offers a mechanism for controlled release of CPT. Under tumor-relevant conditions, these drug nanostructures can release the bioactive form of CPT and show in vitro efficacy against a number of cancer cell lines. This strategy can be extended to construct nanostructures of other types of anticancer drugs and thus presents new opportunities for the development of self-delivering drugs for cancer therapeutics.