Facile Fabrication of Dual-Activatable Gastrointestinal-Based Nanocarriers for Safe Delivery and Controlled Release of Methotrexate.

Colon cancer is emerging as one of the most common cancers worldwide, ranking in the top three in morbidity and mortality. Oral methotrexate (MTX) has been employed as a first-line treatment for various cancers, such as colon, breast, and lung cancer. However, the complexity and particularity of the gastrointestinal microenvironment and the limitations of MTX itself, including severe adverse effects and instability, are the main obstacles to the safe delivery of MTX to colon tumor sites. Herein, an innovative oral administrated anticancer therapeutic MTX@Am7CD/SDS NPs equipped with both pH and temperature sensitivity, which could effectively prevent MTX@Am7CD/SDS NPs from being degraded in the acidic environment mimicking the stomach and small intestine, thus harboring the potential to accumulate at the site of colon lesions and further release intestinal drug under mild conditions. In cellular assays, compared with free MTX, MTX@Am7CD/SDS NPs showed a favorable tumor inhibition effect on three tumor cell lines, as well as excellent cell uptake and apoptosis-inducing effect on SW480 cells. Therefore, this work provides a feasible solution for the safe use of MTX in the treatment of colon cancer and even other intestinal diseases.

pH-Activatable Charge-Reversal Polymer-Based Nanocarriers for Targeted Delivery of Antihepatoma Compound.

Chemotherapy is one of the available cancer treatments which has been successfully employed to prolong the survival of cancer patients. However, it remains a major challenge to develop effective chemotherapeutic agents by reducing off-target toxicity, improving bioavailability, and effectively prolonging blood circulation. The pH profile of tumor cells is abnormal to that of normal cells, making it a potential breakthrough for designing effective chemotherapeutic drug agents. Here, the pH-activatable charge-reversal supramolecular nanocarriers, named MI7-ß-CD/SA NPs, were prepared through a simple and "green" constructive process. MI7-ß-CD/SA NPs possess both pH-induced charge-reversal and disassembly properties that were exploited to investigate the loading, delivery, and pH-responsive controlled release of the antitumor compound celastrol (CSL). CSL@MI7-ß-CD/SA NPs displayed low hemolysis, good biocompatibility, and targeted uptake. Furthermore, CSL@MI7-ß-CD/SA NPs exhibited superior apoptosis rates against SMMC-7721 cell lines compared with CSL, when CSL@MI7-ß-CD/SA NPs and CSL were administered at a mass concentration of 5.0 µg/mL, i.e., the CSL content in CSL@MI7-ß-CD/SA NPs was relatively lower than that of intact CSL. We expected that MI7-ß-CD/SA NPs featuring pH-triggered charge reversal could offer a promising controlled release strategy that would then facilitate the clinical conversion of antitumor drugs.

A Supramolecular Nanovehicle Featuring a pH/Enzyme Co-Response for Targeted Delivery of the Antitumor Compound.

Triptolide (TPL) has gained much attention as an antitumor compound with potential applications. However, TPL suffers from low bioavailability, severe toxic side effects, and limited targeted uptake by tumor cells, thus restricting the conversion of its clinical application. Here, a supramolecular nanovehicle, named TSCD/MCC NPs, featuring pH/AChE co-response was designed and prepared for loading, delivery, and targeted release of TPL. The cumulative release rate of TPL from TPL@TSCD/MCC NPs reached ∼90 % within 60 h at pH 5.0 and AChE co-stimulation. Bhaskar model is used to study TPL release procedure. In cell experiments, TPL@TSCD/MCC NPs showed high toxicity to the four tumor cells lines A549, HL-60, MCF-7, and SW480, and favorable biosafety to normal cells BEAS-2B. Furthermore, TPL@TSCD/MCC NPs containing relatively small amounts of TPL presented similar apoptosis rates to those of intrinsic TPL. We anticipate that TPL@TSCD/MCC NPs may facilitate the conversion of TPL into clinical applications through further studies.

Inclusion complex of 20(S)-protopanaxatriol with modified ß-cyclodextrin: Characterization, solubility, and interaction with bovine serum albumin.

20(S)-protopanaxatriol (PPT) is one of the ginsenosides isolated from Panax ginseng which have many pharmaceutical activities. However, the poor water solubility of PPT restrict its applications. Herein, a novel bridged-bis-[6-(3,3'-(ethylenedioxy) bis (propylamine))-6-deoxy-ß-cyclodextrin] (EDBA-bis-ß-CD) was designed and synthesized, and the inclusion complex (IC) of EDBA-bis-ß-CD with PPT was successfully prepared in the solid state, and characterized by UV, 1H NMR, 2D ROESY, FT-IR, XRD and SEM and molecular modelling methods. The continuous variation method analysis indicated that the stoichiometry of the IC was 1:1. UV-vis spectral analysis demonstrated the binding constant Ks was 995.94 M-1, and the solubility study showed that the solubility of PPT improved 290 times. The interaction of the IC with bovine serum albumin (BSA) was investigated via fluorescence spectroscopy. The results indicated that fluorescence quenching of BSA by IC was static quenching. Thermodynamic studies showed that van der Waals forces and hydrogen bonding play significant roles in interaction. The esterase-like activity of BSA in the presence of IC showed that it reduce the esterase activity of BSA in a competitive manner. Furthermore, molecular docking and molecular dynamics simulations for EDBA-bis-ß-CD/PPT and BSA/IC systems were generated to provide information on the stability and the forces in the binding.

Experimental and molecular docking investigation of the inclusion complexes between 20(S)-protopanaxatriol and four modified ß-cyclodextrins.

20(S)-Protopanaxatriol (PPT) is a type of ginsenoside isolated from panax notoginseng or ginseng, which is an essential ingredient in functional food, healthcare products and traditional medicine. However, the research and development of PPT are restricted due to its poor solubility. To circumvent the associated problems, a novel bridged-bis [6-(2,2'-(ethylenedioxy) bis (ethylamine))-6-deoxy-ß-CD] (H4) was successfully synthesized. The four inclusion complexes of the mono-[6-(1,4-butanediamine)-6-deoxy-ß-CD] (H1), mono-[6-(2,2'-(ethylenedioxy) bis (ethylamine)-6-deoxy-ß-CD] (H2) and their corresponding bridged bis(ß-CD)s (H3, H4) with PPT were prepared and studied by UV, 1H NMR, 2D ROESY, FT-IR, XRD and SEM technology. The UV-spectrometric titration showed that H1-4 and PPT formed 1:1 inclusion complexes and the binding constants were 297.61, 322.25, 937.88 and 1742 M-1, respectively. It was further revealed that the size/shape-matching relationship, hydrophobic interactions and hydrogen bond interactions play the crucial role in determining the stability of H1-4/PPT inclusion complexes. The solubility of PPT was evidently enhanced by193, 265, 453 and 593 times after the formation of inclusion complexes with H1-4, respectively. Furthermore, molecular docking was used to verify the inclusion mode of H4/PPT inclusion complex and also to investigate the stability of H4/PPT in water phase. The molecular simulation results agreed well with the experimental results. This research provides an effective way to obtain novel PPT-based functional food and healthcare products.