SELF-ASSEMBLING MULTIDOMAIN PROTEIN MICELLES FOR MOLECULAR IMAGING AND DRUG DELIVERY

Proteins are versatile biomacromolecules with strong self-assembly properties that play a vital role in virtually all forms of life. By taking advantage of these properties, it is possible to design biocompatible, biologically active materials that can be used for a range of biomedical purposes, such as molecular imaging as well as targeted drug delivery. Unlike many other material systems, proteins can be recombinantly expressed and purified with multiple functional domains encoded in a single gene, often eliminating the need for additional chemical conjugation steps. Here we describe the design and engineering of multidomain proteins containing at least one coiled-coil domain and one disordered elastin-like polypeptide domain per chain. These proteins spontaneously assemble into micelles in aqueous solution. By incorporating targeting peptides into the genetic sequence, we can additionally alter the pharmacokinetics and organ tropism of the resulting micelles. Chapter 1 provides a brief overview of the field of protein biomaterials, while Chapters 2-4 delve in the design and characterization of protein micelles with multiple functional domains. First, in Chapter 2, we devise a collagen-binding molecular imaging probe for the monitoring of metabolic associated steatohepatitis (MASH) disease progression. This probe, collagen type I-binding thermoresponsive assembled protein (Col1-TRAP), was first characterized in vitro before being used to study a mouse model of MASH. It was found to preferentially accumulate in the livers of mice with MASH compared to normal mice. Next, in Chapter 3, we investigate the effect of increasing the multiplicity of the coiled-coil domain on improving hydrophobic drug loading capacity and delivery efficiency. Increasing the number of repeats of the coiled-coil domain from 1 to 2 was found to increase the drug loading capacity by 1.7-fold while reducing micelle packing by 25%. This construct, targeted multidomain protein assembly (TMPA), was found to preferentially accumulate in tumor sites in mice implanted with glioblastoma xenografts. Finally, Chapter 4 focuses on the targeting of TMPA for specific drug delivery to HER2+ breast cancer by using the peptide P51. Targeted micelles loaded with doxorubicin displayed improved uptake into and cytotoxicity against breast cancer cells overexpressing the HER2 receptor, while showing no selectivity in triple-negative breast cancer cells. All micelle-drug formulations were found to be more effective than free drug alone, showing the utility of these protein materials.

Citation

Wang, A. (2025). SELF-ASSEMBLING MULTIDOMAIN PROTEIN MICELLES FOR MOLECULAR IMAGING AND DRUG DELIVERY [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/16991

SELF-ASSEMBLING MULTIDOMAIN PROTEIN MICELLES FOR MOLECULAR IMAGING AND DRUG DELIVERY

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