Controlled Drug Release from Cyclodextrin-Gated Mesoporous Silica Nanoparticles Based on Switchable Host-Guest Interactions.

With the development of materials science and pharmaceutics, the application of mesoporous silica nanoparticles with a gated switch in the field of drug delivery has attracted much attention in the past decades. Cyclodextrins (CD) as promising gated materials have become a new area of interest in recent years due to their properties of self-assembly and function of host-guest interaction. CD is one kind of extensively studied host molecules and the host-guest interactions with different guest molecules can respond to different signals, and thus can be applied as intelligent gated switches for smart drug carriers. Switchable gatekeepers based on CD hosts with different guest molecules (such as benzimidazole, azobenzene, and ferrocene) respond to different stimuli modes (such as pH, light, and redox) that change the host-guest interactions and trigger drug release. The different structural features, mechanisms of action, and potent applications of these switchable gatekeepers are discussed. In addition, some personal perspectives and challenge on this field are presented.

Host-guest inclusion system of rhein with polyamine-modified ß-cyclodextrins: characterization and cytotoxicity.

We report the preparation of inclusion complexes between rhein and four polyamine-modified ß-cyclodextrins, namely amino-ß-cyclodextrins (NH2-ßCD), ethylenediamine-ß-cyclodextrins (EN-ßCD), diethylenetriamine-ß-cyclodextrins (DETA-ßCD) and triethylenetetramine-ß-cyclodextrins (TETA-ßCD) using suspension method. The solution and solid state forms of the inclusion complexes of rhein with polyamine-ß-cyclodextrins were characterized by multiple techniques. Additionally, saturated solution and MTT methods were implemented to assess the water solubilization and in vitro cytotoxicity of the inclusion complexes, respectively. The results suggested that rhein was encapsulated within the CD cavity to form a 1:1 host-guest inclusion complex. Notably, a significant enhancement of the water solubility and in vitro cytotoxicity of rhein was found in the form of inclusion complex with polyamine-ß-cyclodextrin.

Folic-Acid-Targeted Self-Assembling Supramolecular Carrier for Gene Delivery.

A targeting gene carrier for cancer-specific delivery was successfully developed through a "multilayer bricks-mortar" strategy. The gene carrier was composed of adamantane-functionalized folic acid (FA-AD), an adamantane-functionalized poly(ethylene glycol) derivative (PEG-AD), and ß-cyclodextrin-grafted low-molecular-weight branched polyethylenimine (PEI-CD). Carriers produced by two different self-assembly schemes, involving either precomplexation of the PEI-CD with the FA-AD and PEG-AD before pDNA condensation (Method A) or pDNA condensation with the PEI-CD prior to addition of the FA-AD and PEG-AD to engage host-guest complexation (Method B) were investigated for their ability to compact pDNA into nanoparticles. Cell viability studies show that the material produced by the Method A assembly scheme has lower cytotoxicity than branched PEI 25 kDa (PEI-25KD) and that the transfection efficiency is maintained. These findings suggest that the gene carrier, based on multivalent host-guest interactions, could be an effective, targeted, and low-toxicity carrier for delivering nucleic acid to target cells.

Scutellarin-loaded pH/H2O2 dual-responsive polymer cyclodextrin mesoporous silicon framework nanocarriers for enhanced cancer therapy.

Stimulus-responsive nanomaterials, particularly with targeting capabilities, have garnered significant attention in the cancer therapy. However, the biological safety of these innovative materials in vivo remains unknown, posing a hurdle to their clinical application. Here, a pH/H2O2 dual-responsive and targeting nano carrier system (NCS) was developed using core shell structure of Fe3O4 mesoporous silicon (MSN@Fe3O4) as main body, scutellarin (SCU) as antitumor drug and polymer cyclodextrin (PCD) as molecular switch (denoted as PCD@SCU@MSN@Fe3O4, abbreviated as NCS). The NCS, with an average particle size of 100 nm, displayed exceptional SCU loading capacity, a result of its uniform radial channel structure. The in vitro investigation under condition of pH and H2O2 indicated that NCS performed excellent pH/H2O2-triggered SCU release behavior. The NCS displayed a higher cytotoxicity against tumor cells (Huh7 and HCT116) due to its pH/H2O2 dual-triggered responsiveness, while the PCD@MSN@Fe3O4 demonstrated lower cytotoxicity for both Huh7 and HCT116 cells. In vivo therapeutic evaluation of NCS indicates significant inhibition of tumor growth in mouse subcutaneous tumor models, with no apparent side-effects detected. The NCS not only enhances the bioavailability of SCU, but also utilizes magnetic targeting technology to deliver SCU accurately to tumor sites. These findings underscore the substantial clinical application potential of NCS.

Multifunctional co-transport carriers based on cyclodextrin assembly for cancer synergistic therapy.

In the past few years, drug delivery systems have been used extensively to improve solubility, stability, and pharmacokinetics of chemotherapeutic drugs. However, traditional delivery systems fail to fulfill the required standard of effectiveness, primarily owing to issues of drug resistance exhibited by cancer cells and inherent differences among the patients. In this regard, combination therapy offers advantages of synergistic mechanism, reduced drug dosage, and enhanced therapeutic effect, which can be effectively utilized for the treatment of cancer. However, different types of therapeutic agents exhibit different pharmacokinetic properties and action targets in vivo, which lead to uncontrollable concentration ratio of therapeutic agents at the lesion site. This in turn causes serious side effects and affects synergistic anticancer effect. Importantly, multifunctional co-delivery systems are characterized by good pharmacokinetic properties, ability to provide targeted delivery, and controlled release in response to tumor microenvironment. Such delivery systems are widely used for co-delivery of therapeutic agents, which further assist in obtaining better synergistic anticancer effect, and can be potentially used for clinical application. Multifunctional co-delivery systems often exhibit complex structures and construction process. Since cyclodextrin is characterized by self-assembly property, it is possible to quickly construct cyclodextrin-based multifunctional co-delivery systems, with convenience and flexibility. The application of cyclodextrin in the construction of multifunctional co-delivery systems for cancer therapy has gained immense attention in the past few years. The present study provided overview of latest progress in the field of cyclodextrin-based multifunctional co-delivery systems for cancer synergistic therapy.

Self-Assembly System Based on Cyclodextrin for Targeted Delivery of Cannabidiol.

Cannabidiol (CBD) is one specific kind of the cannabinoid in Cannabis sativa L with a wide range of pharmacological activities. However, the poor water solubility and specificity of CBD limits its application in pharmaceutical field. For solving these problems, in this work, we successfully prepared a targeted carrier by grafting biotin (BIO) onto ethylenediamine-ß-Cyclodextrin (EN-CD) in a single step to generate a functionalized supramolecule, named BIO-CD. Subsequently, an amantadine-conjugated cannabinoids (AD-CBD) was prepared and self-assembled with the BIO-CD. A series of methods were used to characterize the inclusion behavior and physicochemical properties of AD-CBD and BIO-CD. The results showed that AD-CBD entered the cavity of BIO-CD and formed a 1:1 host-guest inclusion complex. MTT assay and confocal laser scanning microscopy (CLSM) revealed that the targeting effect and anticancer activity of AD-CBD/BIO-CD inclusion complex against three human cancer cell lines were higher than BIO-CD, AD-CBD and free CBD. Moreover, the inclusion complex could release drugs under weakly acidic conditions. These results demonstrated that AD-CBD/BIO-CD inclusion complex possess excellent targeted and anticancer activity, which is hopeful to be applied in clinic as a new therapeutic approach.

Cyclodextrin pendant polymer as an efficient drug carrier for scutellarin.

A novel ß-cyclodextrin pendant polymer (ε-PL-CD), composed of poly(ε-lysine) (ε-PL) main chain and glycine-ß-cyclodextrin (Gly-CD) side chains, was prepared by a simple two-step procedure. The ε-PL-CD was investigated as a drug carrier of hydrophobic drug scutellarin (SCU). The characterization and complexation mode of the SCU:ε-PL-CD were researched in both solution and solid state by means of photoluminescence spectroscopy, 1H and 2D NMR, X-Ray powder diffraction (XRPD), thermal gravimetric analysis, Particle size and Zeta potential. The solubility test indicated that the solubilizing ability of SCU:ε-PL-CD was significantly improved compared with SCU:ß-CD and free SCU. Besides, in vitro cell experiment, it was found that SCU:ε-PL-CD has a strong inhibitory effect on the growth and invasion of tumor cells. The present study provides useful information for ε-PL-CD as a drug carrier material.

Cyclodextrin-based biological stimuli-responsive carriers for smart and precision medicine.

Spurred on by recent progress in nanotechnology and precision medicine, smart drug carriers are entering an entirely new era. Smart drug carriers have been widely studied in recent years as a result of their ability to control drug release under different microenvironments (such as pH, redox, and enzyme) in vivo. Host-guest interactions based on cyclodextrins have proven to be an efficient tool for fabricating smart drug carriers. Because of the application of host-guest interactions, many kinds of biological molecules or supramolecular building blocks can combine into an organic whole at the molecular level. In this review, the features, mechanisms of action, and potent applications of biological stimuli-responsive drug carriers based on cyclodextrins are discussed. In addition, some personal perspectives on this field are presented.