Effectiveness of an ocular adhesive polyhedral oligomeric silsesquioxane hybrid thermo-responsive FK506 hydrogel in a murine model of dry eye.

Dry eye is a common ocular disease that results in discomfort and impaired vision, impacting an individual's quality of life. A great number of drugs administered in eye drops to treat dry eye are poorly soluble in water and are rapidly eliminated from the ocular surface, which limits their therapeutic effects. Therefore, it is imperative to design a novel drug delivery system that not only improves the water solubility of the drug but also prolongs its retention time on the ocular surface. Herein, we develop a copolymer from mono-functional POSS, PEG, and PPG (MPOSS-PEG-PPG, MPEP) that exhibits temperature-sensitive sol-gel transition behavior. This thermo-responsive hydrogel improves the water solubility of FK506 and simultaneously provides a mucoadhesive, long-acting ocular delivery system. In addition, the FK506-loaded POSS hydrogel possesses good biocompatibility and significantly improves adhesion to the ocular surface. In comparison with other FK506 formulations and the PEG-PPG-FK506 (F127-FK506) hydrogel, this novel MPOSS-PEG-PPG-FK506 (MPEP-FK506) hydrogel is a more effective treatment of dry eye in the murine dry eye model. Therefore, delivery of FK506 in this POSS hydrogel has the potential to prolong drug retention time on the ocular surface, which will improve its therapeutic efficacy in the management of dry eye.

Preparation of mixed micelles carrying folates and stable radicals through PLA stereocomplexation for drug delivery.

Multifunctional mixed micelles possessing targeting folates on the periphery and stable radicals in the core were prepared from the mixture of folate-poly(ethylene glycol)-block-poly(d-lactide) (FA-PEG-b-PDLA) and poly(ethylene glycol) methyl ether-block-poly(l-lactide)- 2,2,6,6-tetramethylpiperidine-1-oxyl (mPEG-b-PLLA-TEMPO). FA-PEG-b-PDLA and mPEG-b-PLLA-TEMPO were prepared by combining ring-opening polymerization (ROP) of lactide with a series of conversion of the end functional groups. The synthesized block copolymers and their intermediates were well characterized by gel permeation chromatography (GPC) and 1H nuclear magnetic resonance (1H NMR) spectroscopy. The mixture of FA-PEG-b-PDLA and mPEG-b-PLLA-TEMPO self-assembled into spherical micelles with the average diameter about 200 nm through PLA stereocomplexation, which were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and differential scanning calorimetry (DSC). The formed micelles were confirmed to emit electron paramagnetic resonance (EPR) signals by EPR spectroscopy. Additionally, the formed micelles exhibited high loading capacity of hydrophobic anticancer drug, controlled in vitro drug release, satisfied biocompatibility and a significantly higher cellular uptake, indicating promising applications in smart drug delivery.

Cyclodextrin based unimolecular micelles with targeting and biocleavable abilities as chemotherapeutic carrier to overcome drug resistance.

An amphiphilic star-shaped copolymer ß-CD-g-PCL-SS-PEG-FA, consisting of a ß-cyclodextrin (ß-CD) core as well as grafted with bioreducible disulfide linkage in PCL-SS-PEG multiarms and targeting folic acid (FA) as end moiety, is designed with unimolecular micelles formation ability for targeted transport of chemotherapeutics to drug resistant tumor cells. Firstly, ß-CD was utilized as core to growth PCL arms by ring-opening polymerization (ROP) of ε-CL, before disulfide terminal group transformation to render ß-CD-g-PCL-SS-COOH. Secondly, α-hydroxy-ω-amine protected PEG (HO-PEG-NHBoc) was connected to ß-CD-g-PCL-SS-COOH to obtain amphiphilic ß-CD-g-PCL-SS-PEG, where PCL and PEG were connected via bioreducible disulfide bond. After deprotection of -Boc group, FA was introduced onto the distal end of block arms to obtain the desired ß-CD-g-PCL-SS-PEG-FA copolymer. Because of highly branched core-shell amphiphilic structures, ß-CD-g-PCL-SS-PEG-FA could act as unimolecular micelles. Interestingly, this unimolecular micelle could release the encapsulated drug in a glutathione (GSH) dependent manner due to disulfide linkage. More importantly, this unimolecular micelle could load doxorubicin (DOX) to promote its cellular uptake in multidrug resistance (MDR) protein overexpression tumor cells, by taking the advantage of FA targeting group and intracellular high GSH level in cancer cells. Together with satisfactory biocompatibility, this novel star-like ß-CD-g-PCL-SS-PEG-FA unimolecular micelle could potentially be utilized as targeting nanocarriers in drug resistant cancer therapy.