Reversible Cross-linked Thermoresponsive Polycaprolactone Micelles for Enhanced Stability and Controlled Release

Abstract

Thermoresponsive amphiphilic poly­(ε-caprolactone)­s (PCL)­s are excellent candidates for drug delivery due to their biodegradability, biocompatibility, and controlled release. However, the thermoresponsivity of modified PCL can often lead to premature drug release because their lower critical solution temperature (LCST) is close to physiological temperature conditions. To address this issue, we developed a novel approach that involves functionalizing redox-responsive lipoic acid to the hydrophobic block of PCL. Lipoic acid has disulfide bonds that undergo reversible cross-linking after encapsulating the drug. Herein, we synthesized an ether-linked propargyl-substituted PCL as the hydrophobic block of an amphiphilic copolymer along with unsubstituted PCL. The propargyl group was used to attach lipoic acid through a postpolymerization modification reaction. The hydrophilic block is composed of an ether-linked, thermoresponsive tri­(ethylene glycol)-substituted PCL. Anticancer drug doxorubicin (DOX) was encapsulated within the core of the micelles and induced cross-linking in the presence of a reducing agent, dithiothreitol. The developed micelles are thermodynamically stable and demonstrated thermoresponsivity with an LCST value of 37.5 °C but shifted to 40.5 °C after cross-linking. The stability and release of both uncross-linked (LA-PCL) and cross-linked (CLA-PCL) micelles were studied at physiological temperatures. The results indicated that CLA-PCL was stable, and only 35% release was observed after 46 h at 37 °C while LA-PCL released more than 70% drug at the same condition. Furthermore, CLA-PCL was able to release a higher amount of DOX in the presence of glutathione and above the LCST condition (42 °C). Cytotoxicity experiments revealed that CLA-PCL micelles are more toxic toward MDA-MB-231 breast cancer cells at 42 °C than at 37 °C, which supported the thermoresponsive release of the drug. These results indicate that the use of reversible cross-linking is a great approach toward synthesizing stable thermoresponsive micelles with reduced premature drug leakage.

Maleimide functionalized polycaprolactone micelles for glutathione quenching and doxorubicin delivery

“…In an oven-dried 10 mL Schlenk flask, dried monomer (200 mg, 0.385 mmol), benzyl alcohol (0.83 mg, 0.008 mmol), and Sn(Oct) 2 (3.12 mg, 0.008 mmol) in dry toluene (0.2 mL) were added inside a nitrogen-filled glove box according to our previous reports. 3,4,76 The flask was tightly sealed and then placed in a preheated thermostat-controlled oil bath at 110 °C. The consumption of monomer was monitored using 1 H NMR spectroscopy and the monomer was consumed fully after 6 h. The polymerization mixture was then brought to room temperature and precipitated in cold methanol.…”

“…Empty micelles were prepared by solvent evaporation method. 3,4,6,61,76,82 Polymer weighing 5.0 mg was dissolved in 1.5 mL THF and was added dropwise to 5.0 mL deionized (DI) water while homogenizing for 30 min. The polymer solution was then kept on a vortex with gentle agitation to slowly remove the organic solvent to obtain a final polymer concentration of 1 mg mL −1 .…”

“…The DOX-loaded micelles were also prepared following this method with slide modification. 3,76 To prepare the DOX solution, 1.0 mg of DOX HCl was dissolved in 1.0 mL of THF, and 3.0 equivalents of triethylamine were added to neutralize the DOX HCl. A solution of polymer to DOX of a 10 : 1 weight ratio was prepared.…”

“…The synthesis of small organic molecules with anticancer activity is on the rise, as is the use of nanocarriers for drug delivery. 1–9 Bridging these two fast-growing fields to design novel materials to accelerate cancer therapy is worth pursuing. Among many reported small organic molecules with anticancer properties, molecules that promote the build-up of inherent suicidal chemical species such as reactive oxygen species (ROS) within the microenvironment of the cancer cells are interesting yet under-reported.…”

Effect of aromatic substituents on thermoresponsive functional polycaprolactone micellar carriers for doxorubicin delivery

“…Polymeric micelles formed from polycaprolactone (PCL)-based amphiphilic diblock copolymers can be employed in drug delivery applications due to their biocompatibility and (bio)degradability. ( Shah and Vasava, 2019 ; Ahmad Shariff et al, 2022 ; Kuperkar et al, 2022 ; Bhadran et al, 2023a ; Patha et al, 2023 ). The micelles can physically pack poorly water-soluble drugs in their hydrophobic core and stabilize them in aqueous solutions with the help of their hydrophilic shell.…”