Abstract
Self-assembly of ionically charged small molecule drugs with water-soluble biodegradable polyelectrolytes into nano-scale complexes can potentially offer a novel and attractive approach to improving drug solubility and prolonging its half-life. Nanoassemblies of quisinostat with water-soluble PEGylated anionic polyphosphazene were prepared by gradient-driven escape of solvent resulting in the reduction of solvent quality for a small molecule drug. A study of binding, analysis of composition, stability, and release profiles was conducted using asymmetric flow field flow fractionation (AF4) and dynamic light scattering (DLS) spectroscopy. Potency assays were performed with WM115 human melanoma and A549 human lung cancer cell lines. The resulting nano-complexes contained up to 100 drug molecules per macromolecular chain and displayed excellent water-solubility and improved hemocompatibility when compared to co-solvent-based drug formulations. Quisinostat release time (complex dissociation) at near physiological conditions in vitro varied from 5 to 14 days depending on initial drug loading. Multimeric complexes displayed dose-dependent potency in cell-based assays and the results were analyzed as a function of complex concentration, as well as total content of drug in the system. The proposed self-assembly process may present a simple alternative to more sophisticated delivery modalities, namely chemically conjugated prodrug systems and nanoencapsulation-based formulations.
Highlights
Histone deacetylase inhibitors (HDACis) represent a class of promising chemotherapeutic agents [1] with a number of these compounds, such as belinostat, chidamide, panobinostat, romidepsin, and vorinostat, already approved for clinical use under different jurisdictions [2]
We recently introduced anionic polyphosphazenes with biodegradable backbone containing graft poly(ethylene glycol) PEG chains (PPEGs), which were characterized by improved water-solubility and stability to aggregation [21]
Anionic PEGylated polyphosphazene—PPEG (“polyelectrolyte”) was driven by a gradual removal of DMSO—a cosolvent needed for maintaining solubility of the drug [15,27,28,29]
Summary
Histone deacetylase inhibitors (HDACis) represent a class of promising chemotherapeutic agents [1] with a number of these compounds, such as belinostat, chidamide, panobinostat, romidepsin, and vorinostat, already approved for clinical use under different jurisdictions [2]. Clinical results with HDACis as monotherapies have been either modest or disappointing and these drugs are currently used in combination with other therapies [2,3,4]. These limitations are reportedly imposed by low bioavailability and short half-life of drugs [5,6], as well as a number of class- and agent-specific serious or severe adverse effects, notably myelosuppression and cardiac effects, associated with their clinical use [2]. The search for formulation and delivery approaches that can further prolong drug exposure, minimize drug toxicity to normal tissues, and improve therapeutic index continues [2,6,13,14]
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