Surfactant Free Delivery of Docetaxel by Poly[(R)‐3‐hydroxybutyrate‐(R)‐3‐hydroxyhexanoate]‐Based Polymeric Micelles for Effective Melanoma Treatments

Abstract

Docetaxel (DTX) is a new semisynthetic chemical in the taxoid family and serves a wide spectrum of chemotherapeutics. Current commercial formulation of DTX is based on the addition of the nonionic surfactants (i.e., ethanol and Tween 80), which are reported to cause severe hemolysis, hypersensitivity reactions, or neurotoxic toxicity and greatly hinders patient tolerance or compliance. In this report, a novel low‐toxic, biodegradable, and amphiphilic poly[(R)‐3‐hydroxybutyrate‐(R)‐3‐hydroxyhexanoate] (PHBHx)‐based polyurethane (a copolymer made of hydrophobic PHBHx with biocompatible D‐3‐hydroxybutyric acid as degradation product, thermosensitive polypropylene glycol (PPG), and hydrophilic polyethylene glycol (PEG) segments) with nanosized micelle formation ability to encapsulate DTX, as a surfactant free formulation, is reported. Interestingly, this DTX‐loaded poly(PHBHx/PEG/PPG urethane) micelle formulation with >90% drug loading efficiency shows significantly improved DTX solubility in aqueous medium, reduced hemolysis for better blood compatibility, and increased drug uptake in A375 melanoma cells, which provides the possibility of systematic delivery of DTX. As a proof‐of‐concept, an A375 melanoma xenograft mouse model is established to verify the therapeutic effect of this DTX‐loaded poly(PHBHx/PEG/PPG urethane) micelle formulation, indicating the promising application of PHBHx‐based polymeric nanosized micelle as a surfactant free formulation of chemotherapeutics which might greatly be beneficial for controllable delivery of pharmaceutics and cancer therapy.

ROS‐Sensitive Degradable PEG–PCL–PEG Micellar Thermogel

“…The triple bands at 338, 356, and 377 nm of the dye appeared after increasing polymer concentrations at a fixed dye concentration (4.0 × 10 ‐6 m ) ( Figure a). The dye exhibits the triple bands in a hydrophobic solvent, or a hydrophobic domain of a micelle core . The CMC of the aqueous PEG–PCL–PEG triblock copolymer solution was 0.001−0.005 wt% as determined by extrapolating the two lines of absorbance at 377 nm (Figure b).…”

“…A UV–vis spectrophotometer (S‐3100; SCINCO, Korea) was used to measure the absorbance of the solution at 20 °C. Critical micelle concentration was determined by extrapolating two lines at high and low concentration regions …”

“…Here, we report thermogelling PEG–PCL–PEG triblock copolymers that can be degraded by ROS. Thermogelling systems have been investigated for drug delivery, 3D cell culture, and prevention of postoperative tissue adhesion . The degradation of a middle oxalate functional group leads to PEG–PCL diblock copolymers that are expected to show different phase behavior and a corresponding reduction in gel duration.…”

Recent Progress in Polyhydroxyalkanoates‐Based Copolymers for Biomedical Applications

“…By further using dibutyltin dilaurate as catalyst (95%) and a coupling agent HDI, PHBHx‐diol was conjugated with PEG or PPG fragments to obtain the target copolymer. This copolymer is not only amphiphilic and biodegradable, but also has good blood compatibility and temperature sensitivity, which is a good candidate for drug delivery …”

“…Wu and collaborators designed and synthesized an amphiphilic PHBHHx‐based polyurethane, which can significantly improve the solubility of the hydrophobic drug docetaxel in water. More interestingly, this DDS is effective in reducing hemolysis reactions and greatly improving the blood compatibility of the drug compared to commercial docetaxel formulations . In DDSs, developing intelligent and accurate DDSs has been highly desirable.…”