Light-Cross-linked Enediyne Small-Molecule Micelle-Based Drug-Delivery System

Abstract

Light-cross-linked small-molecule micelles with enediyne units are designed for developing efficient drug-delivery systems. Gemcitabine (GEM) is chosen as a model hydrophilic drug and tethered with a maleimide-based enediyne (EDY) as a hydrophobic tail in the preparation of amphiphilic EDY–GEM. The stable micellar particles are obtained by cross-linking the enediyne moieties via photoinduced Bergman cyclization polymerization in aqueous media. The light-cross-linked spherical micelles with a size of 80 nm are characterized with dynamic light scattering and electron microscopy, showing robust micellar stability, bright fluorescent emission due to their intrinsic conjugated structure, and potential passive tumor-targeting ability through the enhanced permeability and retention effect. The drug-loaded micelles, as an example of light-cross-linked small-molecule micelle-based drug-delivery system, exhibit high drug-loading contents (50%) and greatly improved cytotoxicity toward A549 cells (decreasing the IC50 value of Gemcitabine by 10 times), thanks to the greatly increased cellular uptake of the drug-loaded micelles as confirmed by confocal laser scanning microscopy. The light-cross-linked enediyne-based small-molecule micelles system therefore provides a simple yet efficient drug-delivery platform for cancer chemotherapy.

Strategies to Obtain Encapsulation and Controlled Release of Small Hydrophilic Molecules

“…While the hydrophobicity decreases their interactions with the hydrophilic drugs, leading to low loading capacity. The high and stable hydrophilic drug loading in micelles could be achieved by covalently linking the drug with polymer backbone (Liao et al, 2016;Danafar et al, 2017).…”

Reduced Thiol Compounds – Induced Biosensing, Bioimaging Analysis and Targeted Delivery

“…In addition to the nano drug delivery carriers, some small molecular carriers for drug delivery or prodrugs have also received widespread attention. The most widely used small molecular drug carriers include light‐cross‐linked enediyne micelle, [79‐80] natural active ursolic acid [81] and so on. Furthermore, one of the advantages of small‐molecule prodrugs is the potential for a high drug content, especially for amphiphilic drug−drug conjugates, in which one drug acts as the promoiety of the other [82‐84] .…”

Controllable Release Mode Based on ATP Hydrolysis-Fueled Supra-Amphiphile Assembly

“…The loading and release of molecular cargos play a major role in the design of efficient transport vehicles. − At present, the transport vehicles mainly release cargo through slow or controlled release modes. − Slow release modes refer to the fact that, after the cargo is loaded into the assembled or synthetic nanoscale containers, a sustained release can be achieved by the free diffusion of the cargo molecules. If the containers can be broken by the external stimuli, the loaded cargo will be controllably released. − Based on the two release modes, a huge amount of vehicles have been fabricated, such as doxorubicin liposomal, , stimulus-responsive drug delivery system, − gene carriers, and others. , The slow or controlled release are both operated in thermodynamically equilibrium states. However, in living systems, the loading and release of cargos are always operated away from equilibrium. − That is to say, a persistent energy is required to sustain their continuous loading or release.…”