UC Berkeley

3-Helix Micelles as Drug Nanocarriers

Control over particle size, cargo loading, encapsulation stability, and drug release is critical to optimize the safety and efficacy of drug formulations. This dissertation is focused on evaluation, optimization, and validation of 3-helix micelles as drug nanocarriers. The fundamental understanding of molecular parameters than can be used to tune loading content, drug retention stability, and release of drug from 3-helix micelles is important for their clinical translation as a viable platform for drug formulation and delivery. It is equally critical to characterize the structure and stability of drug loaded 3-helix micelles in biological conditions relevant to different applications, which in turn would dictate the pharmacokinetics, biodistribution, efficacy and clearance of drug formulations based on 3-helix micelles. The knowledge gained from these studies serves as guideline to identify the suitable design features to facilitate the development of 3-helix micelle based therapeutic nanocarriers.

3-helix micelles are formed by the self-assembly of a new family of amphiphilic peptide-polymer conjugates. Studies aimed at understanding intermolecular interactions that dictate the structure of the amphiphilic conjugates allowed to identify the building block that can be used to generate 3-helix micelles with requisite structure and stability. 3-helix micelles assembled from different amphiphiles were investigated for their biological stability and blood circulation time, and this set of studies resulted in a set of guidelines that could be used to tailor the stability of 3-helix micelles for different biological applications.

Systematic studies on encapsulation of drugs with different molecular structure underscored the significance of molecular geometry of drugs on their loading content in 3-helix micelles. These studies were critical in understanding the parameters that could be used to tune cargo loading content in 3-helix micelles. Drugs loadings of 7-8 wt% could be achieved depending on the cargo and micelle composition. This loading content is close to the theoretical limit imposed by the small core size of 15 nm 3-helix micelles, and carriers with similar loadings have shown enhanced therapeutic effect.

Doxorubicin (DOX) loaded 3-helix micelles exhibited efficient cellular internalization, elicited cytotoxicity for a range of cancer cell lines, and were sensitive to proteolytic degradation to facilitate drug release. Intravenous administration of DOX loaded 3-helix micelles showed selective accumulation in tumor tissue for an extended period with reduced off-target toxicity, relative to free drug.

Lastly, in vivo studies with 3-helix micelles demonstrated that they could be administered to brain by two different techniques that have been developed for anatomical targeting of severely restricted brain tissue. The results demonstrated that 3-helix micelles could penetrate into deep regions in the brain, not commonly accessible to conventional nanocarriers, which is very encouraging for their potential as nanocarriers for drug delivery to brain.