Purpose: Poorly water-soluble drugs compose approximately 40% of drugs on the market and 90% of drugs in the development pipeline, making this issue a crucial point in pharmaceutical research. One method to improve this solubility issue is to deliver these potent drugs within nanoparticles. The technology developed here are polymeric nanoemulsion carriers that can be loaded with various therapeutic and diagnostic agents. This work aims to provide a tunable, nanoemulsion platform that increases the delivery of hydrophobic compounds needed for a range of disease and imaging treatments.
Methods: Polymeric nanoemulsions are colloidal nanoparticles prepared from two immiscible liquids and a stabilizing surfactant. Nanoemulsions are especially advantageous delivery systems due to their relatively large oil droplet core, perfect for the solubilization of hydrophobic drugs, and their kinetic stability over time. The Mecozzi group has developed a new triphilic semifluorinated polymer to serve as the stabilizing surfactant for oil-in-water nanoemulsions. This polymer is composed of hydrophilic, fluorophilic, and lipophilic blocks and forms super-stable nanoemulsions with a variety of payloads. The introduction of the key fluorocarbon moiety provides enhanced colloidal stability and molecular organization due to the presence of the fluorous phase in solution. The fluorous phase forms due to solvophobic effects that lead to dual hydrophobicity and lipophobicity of fluorocarbons in solution (Figure 1). The nanoemulsions described here will be formulated with a variety of payloads, thoroughly characterized, and evaluated for potential translation to the clinic.
Results: This nanoemulsion technology can be tuned to fulfill a variety of treatment needs. The triphilic Mecozzi polymer focused on here uniquely demonstrates that hydrophobic drugs, more specifically chemotherapeutics, can be encapsulated with high loading and retention within a lipophilic oil droplet core. Sustained, slow drug release makes this platform an excellent candidate for therapeutic delivery (Figure 2). Alternatively, this technology can be formulated with a fluorophilic oil droplet core with preserved particle stability. The fluorous excipient selected is an effective 19F-MRI contrast agent which converts these nanoparticles into a diagnostic system. Magnetic resonance imaging (MRI) is an increasingly common imaging technique due to its noninvasive nature, high sensitivity, and deep tissue penetration. Clinical MRI scanners typically focus on 1H nuclei, but these scanners can easily be tuned to monitor 19F instead. Not only is the sensitivity of 19F similar to 1H but the natural abundance is higher and there is a near-zero background due to the lack of endogenous 19F making this diagnostic platform desirable. Finally, this nanoemulsion technology can be formulated to include both the therapeutic benefits as well as the diagnostic benefits in a resulting theranostic system. The ability to track the delivery and effect of drug via highly sensitive MRI is a valuable tool for many treatment applications, cancer therapy being one especially relevant example. This work covers the tunability of this technology including the use of these nanoemulsions as therapeutic, diagnostic, and theranostic delivery systems. Emphasis will be placed on nanoparticle formulation and characterization, in vitro drug release, in vitro cancer cell inhibition, in vitro and in vivo 19F-MRI diagnostics, and rationale for the unique oil droplet core interactions leading to these results.
Conclusion: A highly stable nanoemulsion delivery platform has been developed with the use of novel Mecozzi semifluorinated polymers. These nanoemulsions can be tuned to deliver high concentrations of drug with sustained release or unprecedented amounts of fluorous contrast agent for potent 19F-MRI or a theranostic combination of drug and imaging agent. This technology shows great promise for practical translation and impact.
Sandro Mecozzi– Professor of Pharmaceutical Sciences and Chemistry, University of Wisconsin, Madison, Madison, Wisconsin