alpha-cyclodextrin and Neoplasms

Locally administrable drugs with controllable release on external cues hold great promise for antitumor therapy. Here, we report an injectable, supramolecular hydrogel (SHG), where the drug release can be controllably driven by near infrared (NIR) irradiation. The SHGs are formed by electrostatic interactions with LAPONITE® (XLG), in which upconverting nanoparticles (UCNPs) modified with α-cyclodextrin (α-CD) are used as the core, and azobenzene quaternary ammonium salts (E-azo) are further assembled through host-guest interactions. The hydrogel demonstrates reversible phase transition between gel and sol states and photothermal conversion capability. In detailed in vitro and vivo trials, drug-loaded SHGs successfully suppressed invasion by cancer cells. Phase transitions that are regulated by NIR light and promote drug release using photothermal effects, highlighting the considerable potential of supramolecular hydrogels in anticancer therapies, especially for treatments requiring long-term, on-demand drug supply in clinics.

Topics: alpha-Cyclodextrins; Animals; Antineoplastic Agents; Azo Compounds; Doxorubicin; Drug Carriers; Drug Liberation; Female; Humans; Hydrogels; Infrared Rays; Lanthanoid Series Elements; Luminescent Agents; Metal Nanoparticles; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Optical Imaging; Phase Transition; Photothermal Therapy; Quaternary Ammonium Compounds; Silicon Dioxide; Static Electricity

Multidrug resistance (MDR) is one of the major problems responsible for inefficiency of cancer chemotherapy. Currently, there is still unmet demand for innovative strategies as well as effective and safe sensitizers to overcome MDR. In this study, we developed a nanosensitizer based on a pH-responsive nanoparticle (NP) derived from acetalated α-cyclodextrin (Ac-aCD). This pH-responsive NP could be effectively endocytosed by MDR cancer cells, and intracellularly transported by endolysosomal compartments. Ac-aCD NP was able to dramatically potentiate the activity of anticancer drugs including paclitaxel, docetaxel, cis-diamminedichloroplatinum, camptothecin, and doxorubicin. This sensitizing capability of Ac-aCD NP on MDR cells was resulted from the combined effects of decreased Pgp expression, attenuated Pgp ATPase activity, and the reduced intracellular ATP level. Ac-aCD NP exerted these diverse biological functions by intracellularly released α-cyclodextrin molecules, which were produced due to hydrolysis of Ac-aCD in acidic subcellular organelle. On the other hand, treatment with Ac-aCD NP showed no significant effects on the integrity of the plasma membrane, cytoskeleton, cell cycle, mitochondrial membrane potential, and apoptosis. These findings suggest that this pH-responsive NP has great potential for effective therapy of resistant cancers by combining with chemotherapeutic agents. It may also serve as a pharmacologically active nanocarrier for intracellular delivery of a plethora of antitumor drugs.

Topics: Acetylation; Adenosine Triphosphatases; alpha-Cyclodextrins; Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Cycle; Cell Line, Tumor; Cell Membrane; Cytoskeleton; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Endocytosis; Energy Metabolism; Humans; Hydrogen-Ion Concentration; Membrane Potential, Mitochondrial; Nanomedicine; Nanoparticles; Neoplasms; Paclitaxel; Rhodamine 123

In this work, we developed a simple, novel method for constructing gold nanocomposite supramolecular hybrid hydrogels for drug delivery, in which gold nanocrystals were utilized as building blocks. First, methoxypoly(ethylene glycol) thiol (mPEG-SH, molecular weight (MW)=5 K) capped gold nanocrystals (nanospheres and nanorods) were prepared via a facile one-step ligand-exchange procedure. Then, the homogeneous supramolecular hybrid hydrogels were formed, after adding α-cyclodextrin (α-CD) into PEG-modified gold nanocrystal solutions, due to the host-guest inclusion. Both gold nanoparticles and inclusion complexes formed between α-CD and PEG chain provided the supra-cross-links, which are beneficial to the gelation formation. The resulting hybrid hydrogels were fully characterized by a combination of techniques including X-ray diffraction, rheology studies, and scanning electron microscopy. Meanwhile, the hybrid hydrogel systems demonstrated unique reversible gel-sol transition properties at a certain temperature caused by the temperature-responsive reversible supramolecular assembly. The drug delivery applications of such hybrid hydrogels were further investigated in which doxorubicin was selected as a model drug for in vitro release, cytotoxicity, and intracellular release studies. We believe that the development of such hybrid hydrogels will provide new and therapeutically useful means for medical applications.

Topics: alpha-Cyclodextrins; Doxorubicin; Drug Delivery Systems; Gold; Humans; Hydrogel, Polyethylene Glycol Dimethacrylate; Microscopy, Electron, Scanning; Nanoparticles; Neoplasms; Polyethylene Glycols; X-Ray Diffraction

Engineering of pH-responsive nanoplatforms can be facilely achieved from acetalated α-cyclodextrin materials. The hydrolysis period of nanoparticles can be precisely tailored by using materials with various acetal types that can be easily controlled by acetalation time. These nanomaterials with pH-modulated hydrolysis and pH-triggered drug delivery capability show good biocompatibility in vitro and in vivo. Incorporation of anticancer drug paclitaxel (PTX) into newly developed pH-sensitive nanosystems leads to nanotherapeutics with significantly improved cytotoxic activity against various tumor cells. Importantly, thus formulated nanomedicines can reverse the multidrug resistance of PTX-resistant cancer cells. In vivo antitumor studies also reveal the superior of pH-sensitive nanosystems over pristine PTX and pH-insensitive PLGA nanoformulations. Moreover, comparison with other two acid-labile materials evidenced the advantages of cyclodextrin-based nanovehicles with respect to drug loading capacity, in vitro and in vivo activity as well as alleviated adverse effects. These pH-responsive nanoparticles may serve as new generation nanocarriers for drug delivery.

Topics: Acetylation; alpha-Cyclodextrins; Animals; Apoptosis; Cell Line, Tumor; Drug Carriers; Drug Delivery Systems; Drug Resistance, Neoplasm; Female; Humans; Hydrogen-Ion Concentration; Intracellular Space; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Paclitaxel; Toxicity Tests, Acute; Xenograft Model Antitumor Assays

The antitumor sulfonylurea LY237868 (N-(4-aminophenyl-sulfonyl)-N'-(4-chlorophenyl)urea) was conjugated through the A ring to alpha-cyclodextrin or agarose bead material (Affigel 10) to prepare impermeant conjugates for activity measurements and affinity isolation of binding proteins from serum. When conjugated to alpha-cyclodextrin, the resulting LY237868 conjugate inhibited both NADH oxidase activity and growth of HeLa cells in culture. The conjugate was at least one order of magnitude more potent as an inhibitor than the parent compound. These findings confirm previous results that demonstrate an antitumor sulfonylurea-binding protein with NADH oxidase activity at the external plasma membrane surface of HeLa cells that is shed into culture media conditioned by growth of HeLa cells. A comparable activity, responsive to sulfonylurea, was present in sera of cancer patients. LY237868 conjugated to agarose beads as the affinity support bound a large number of serum proteins. However, compared to serum from normal patients, the affinity support bound two proteins of M(r) approx. 33.5 and 29.5 not found in sera of normal patients. The 33.5 kDa protein from human sera reacted with antisera to a 33.5 kDa protein from culture media conditioned by growth of HeLa cells that blocked and immunoprecipitated the sulfonylurea-responsive activity from HeLa cell plasma membranes. The results point to the 33.5 kDa protein from cancer patient sera that bound to the sulfonylurea affinity support as representing the circulating equivalent of the previously identified 34 kDa sulfonylurea-binding protein, with NADH oxidase activity at the external cell surface of cultured HeLa cells and a corresponding 33.5 kDa protein shed into culture media conditioned by growth of HeLa cells.

Topics: alpha-Cyclodextrins; Antineoplastic Agents; Blood Proteins; Cell Division; Cell Membrane; Chromatography, Affinity; Cyclodextrins; Enzyme Inhibitors; HeLa Cells; Humans; Molecular Weight; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Neoplasm Proteins; Neoplasms; Protein Binding; Sulfonylurea Compounds