Heuristics of self-assembly, thermoresponsivity and drug release with extracellular matrix inspired peptide nanovesicles

Abstract

The field of nanomedicine is currently blossoming as is evidenced by the creation of the COVID-19 nanovaccines which have now inoculated millions of people in the United States (and world-wide) for protection from the SARS-CoV-2 virus. Additionally, the number of nanomedicines being studied in clinical trials continues to rise as pharmaceutical companies invest more into their research and development. Yet many nanomedicines that carry drug or gene therapeutic molecules (nanocarriers) still employ technologies and strategies that have been utilized for several decades. While this enables a more facile translation of nanocarriers to the clinic, it restricts nanocarriers to a relatively small functional landscape despite there being enormous potential for more advanced nanocarrier systems to better aid the treatment of diseases. ☐ One type of advanced next generation nanomedicines that are of particular interest are stimuli-responsive nanocarriers that can respond either to endogenous cues that are found within the body (e.g., pH and redox stimuli) or exogenous cues (e.g., temperature, light, or magnetism) that can be applied to a living system externally. Such stimuli-responsive systems are advantageous as they can either directly respond to a diseased tissue microenvironment or can be used as a means to spatially and temporally control therapeutic delivery by applying the external stimulus wherever and whenever it is needed by the clinician. Although stimuli-responsive systems have been reported in the literature before, their application and benefits remain unclear. ☐ To address this apparent lacuna, herein is described a novel extracellular matrix inspired peptide nanovesicle system that possesses dual temperature stimuli-responsivity that is thought to be potentially applicable to many different diseases. Specifically, this dissertation describes the design of elastin-like-block-collagen-like peptide (ELP-CLP) amphiphilic conjugates that are capable of thermoresponsive self-assembly and disassembly. A heuristic, but rationale approach is utilized to determine how sequence specific effects of both the collagen-like peptide domain and the elastin-like peptide domain modulate the thermal stability of ELP-CLP nanovesicles. These effects are also studied in the presence of a model therapeutic drug compound and how the thermal properties of these nanovesicles can modify the rate of drug release to an external environment. We additionally explore the potential functionality of these ELP-CLP nanovesicles as future nanocarriers through in vivo retention and characterization work. The total sum of this work shows some of the first preliminary evidence that these ELP-CLP nanovesicles can serve as functional and applicable next generation nanomedicines for the benefit of improved therapeutic outcomes.