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

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.

High glutathione production is known to be one of the defense mechanisms by which many cancer cells survive elevated oxidative stress. By explicitly targeting glutathione in these cancer cells and diminishing its levels, oxidative stress can be intensified, ultimately triggering apoptosis or programmed cell death. Herein, we developed a novel approach by creating maleimide-functionalized polycaprolactone polymers, specifically using 2,3-diiodomaleimide functionality to reduce the level of glutathione in cancer cells. Polycaprolactone was chosen to conjugate the 2,3-diiodomaleimide functionality due to its biodegradable and biocompatible properties. The amphiphilic block copolymer was synthesized using PEG as a macroinitiator to make corresponding polymeric micelles. The resulting 2,3-diiodomaleimide-conjugated polycaprolactone micelles effectively quenched glutathione, even at low concentrations (0.01 mg mL-1). Furthermore, we loaded these micelles with the anticancer drug doxorubicin (DOX), which exhibited pH-dependent drug release. We obtained a loading capacity (LC) of 3.5% for the micelles, one of the highest LC reported among functional PCL-based micelles. Moreover, the enhanced LC doesn't affect their release profile. Cytotoxicity experiments demonstrated that empty and DOX-loaded micelles inhibited cancer cell growth, with the DOX-loaded micelles displaying the highest cytotoxicity. The ability of the polymer to quench intracellular GSH was also confirmed. This approach of attaching maleimide to polycaprolactone polymers shows promise in depleting elevated glutathione levels in cancer cells, potentially improving cancer treatment efficacy.

Recent Advances in Polycaprolactones for Anticancer Drug Delivery.

Poly(ε-Caprolactone)s are biodegradable and biocompatible polyesters that have gained considerable attention for drug delivery applications due to their slow degradation and ease of functionalization. One of the significant advantages of polycaprolactone is its ability to attach various functionalities to its backbone, which is commonly accomplished through ring-opening polymerization (ROP) of functionalized caprolactone monomer. In this review, we aim to summarize some of the most recent advances in polycaprolactones and their potential application in drug delivery. We will discuss different types of polycaprolactone-based drug delivery systems and their behavior in response to different stimuli, their ability to target specific locations, morphology, as well as their drug loading and release capabilities.

Covalent and Noncovalent Loading of Doxorubicin by Folic Acid-Carbon Dot Nanoparticles for Cancer Theranostics.

With special properties such as excellent fluoresce features, low toxicity, good biocompatibility, permeability, and easy clearance from the body, carbon dot (CD)-based nanoparticles (NPs) have the potential to deliver drugs and use in vivo diagnostics through molecular imaging. In this work, folic acid-CD (FA-CD) NPs were prepared to deliver doxorubicin (Dox) covalently and noncovalently as cancer theranostics. FA was conjugated to the surface of CDs for targeting cancer cells with overexpressing folate receptors. CDs prepared with various amounts of precursors lead to their associated NPs with different photoluminescence properties and drug release profiles. The loading of Dox and its releasing data depends on the linkage of drug Dox to FA-CD and CD composition. All NPs were characterized by UV-vis, Fourier transform infrared spectroscopy, and dynamic light scattering. The noncovalent FA-CD-Dox NPs were preferred with a simple preparation process, excellent photoluminescence, and in vitro drug release properties. The noncovalent FA-CD-Dox showed the best efficacy against MDA-MB-231 compared to the CD-Dox and covalent FA-CD-Dox.