betadex and Lung-Neoplasms

Targeted drug delivery by nanocarriers molecules can increase the efficiency of cancer treatment. One of the targeting ligands is folic acid (FA), which has a high affinity for the folic acid receptors, which are overexpressed in many cancers. Herein, we describe the preparation of the nanoconjugates containing quantum dots (QDs) and

Topics: Acridines; Antineoplastic Agents; beta-Cyclodextrins; Cell Line, Tumor; Drug Carriers; Drug Delivery Systems; Folic Acid; Humans; Lung; Lung Neoplasms; Male; Nanoconjugates; Nanostructures; Prostate; Prostatic Neoplasms; Quantum Dots

Aurisin A (AA), an aristolane dimer sesquiterpene isolated from the luminescent mushroom Neonothopanus nambi, exhibits various biological and pharmacological effects. However, its poor solubility limits its use for further medicinal applications. This study aimed to improve the water solubility of AA via complexation with β-cyclodextrin (βCD) and its derivatives (2,6-di-O-methyl-βCD (DMβCD) and 2-hydroxypropyl-βCD (HPβCD). A phase solubility analysis demonstrated that the solubility of AA linearly enhanced with increasing concentrations of βCDs (ranked in the order of AA/DMβCD > AA/HPβCD > AA/βCD). Notably, βCDs, especially DMβCD, increased the thermal stability of the inclusion complexes. The thermodynamic study indicated that the complexation between AA and βCD(s) was a spontaneous endothermic reaction, and AA/DMβCD possesses the highest binding strength. The complex formation between AA and DMβCD was confirmed by means of FT-IR, DSC, and SEM. Molecular dynamics simulations revealed that the stability and compactness of the AA/DMβCD complex were higher than those of the DMβCD alone. The encapsulation of AA led to increased intramolecular H-bond formations on the wider rim of DMβCD, enhancing the complex stability. The antiproliferative activity of AA against A549 and H1975 lung cancer cells was significantly improved by complexation with DMβCD. Altogether, the satisfactory water solubility, high thermal stability, and enhanced antitumor potential of the AA/DMβCD inclusion complex would be useful for its application as healthcare products or herbal medicines.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Cyclodextrins; Humans; Lung Neoplasms; Solubility; Spectroscopy, Fourier Transform Infrared; Water

Topics: A549 Cells; Administration, Inhalation; Antibiotics, Antineoplastic; Antitubercular Agents; beta-Cyclodextrins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Diarylquinolines; Drug Carriers; Drug Repositioning; Humans; Lung Neoplasms; Models, Molecular

The purpose of this study was to investigate the impact of anticancer drug erlotinib-randomly methylated-

Topics: A549 Cells; Animals; Antineoplastic Agents; beta-Cyclodextrins; Caco-2 Cells; Calorimetry, Differential Scanning; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Liberation; Erlotinib Hydrochloride; Humans; Intestinal Absorption; Lung Neoplasms; Methylation; Mice; Microscopy, Electron, Scanning; Solubility; Treatment Outcome

Platforms for enzyme delivery must simultaneously have plasma stability, high catalytic activity, and low/no immunogenicity of the enzyme. Here, we designed a novel biomimetic membrane-structured nanovesicle (BNV) to efficiently carry supramolecular enzymes to meet the above requirements. We complexed l-asparaginase (Aase) with hydroxypropyl-β-cyclodextrin (HPCD) to form a supramolecular amphiphile (AS) by self-assembly via noncovalent reversible interactions. We then used the first synthesized polyethylene glycol (PEG 2 kDa)-decorated hyaluronan (12 kDa) and HPCD to self-assemble a semipermeable biomimetic membrane-structured nanovesicle (BNV) together with AS loading. As compared to native Aase, AS@BNV exhibited superior catalytic activity preservation, improved catalytic activity, better pharmacokinetics in rats, enhanced cytotoxic effects, increased antitumor efficacy, and decreased side effects. The underlying mechanisms, such as the autophagy inhibition action against tumor cells, protein-protein docking of the interaction between Aase-serum albumin, and decreased hepatic enzymatic activity, were investigated. This approach paves the way for new types of powerful biomimetic-, supramolecular-, and nanocarrier-based enzymatic therapies.

Topics: Animals; Antineoplastic Agents; Asparaginase; beta-Cyclodextrins; Biomimetics; Drug Delivery Systems; Hydrogen-Ion Concentration; Lung Neoplasms; Polyethylene Glycols; Rats

Resveratrol (RES), a natural polyphenol in fruits, has shown promising anti-cancer properties. Due to its relative low toxicity which limits the adverse effects observed for conventional chemotherapeutics, RES has been proposed as an alternative. However, the therapeutic applications of RES have been limited due to low water solubility, as well as chemical and physical instability. This study investigated enhancing the anti-cancer activity of RES against non-small-cell-lung-cancer (NSCLC) by complexing with sulfobutylether-β-cyclodextrin (CD-RES) and loading onto polymeric nanoparticles (NPs). The physicochemical properties of the CD-RES NPs were then characterized. The CD-RES inclusion complex increased the water solubility of RES by ~66-fold. CD-RES NPs demonstrated very good aerosolization potential with a mass median aerodynamic diameter of 2.20 μm. Cell-based studies demonstrated improved therapeutic efficacy of CD-RES NPs compared to RES. This included enhanced cellular uptake, cytotoxicity, and apoptosis, while retaining antioxidant activity. The 3D spheroid study indicated an intensified anti-cancer effect of CD-RES NPs. Altogether, these findings marked CD-RES NPs as a potential inhalable delivery system of RES for the treatment NSCLC.

Topics: A549 Cells; Administration, Inhalation; beta-Cyclodextrins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Stability; HEK293 Cells; Humans; Lung Neoplasms; Nanoparticles; Particle Size; Resveratrol

Activation of c-Met, a receptor tyrosine kinase, induces radiation therapy resistance in non-small cell lung cancer (NSCLC). The activated residual of c-Met is located in lipid rafts (Duhon et al. Mol Carcinog 49:739-49, 2010). Therefore, we hypothesized that disturbing the integrity of lipid rafts would restrain the activation of the c-Met protein and reverse radiation resistance in NSCLC. In this study, a series of experiments was performed to test this hypothesis.. NSCLC A549 and H1993 cells were incubated with methyl-β-cyclodextrin (MβCD), a lipid raft inhibitor, at different concentrations for 1 h before the cells were X-ray irradiated. The following methods were used: clonogenic (colony-forming) survival assays, flow cytometry (for cell cycle and apoptosis analyses), immunofluorescence microscopy (to show the distribution of proteins in lipid rafts), Western blotting, and biochemical lipid raft isolation (purifying lipid rafts to show the distribution of proteins in lipid rafts).. Our results showed that X-ray irradiation induced the aggregation of lipid rafts in A549 cells, activated c-Met and c-Src, and induced c-Met and c-Src clustering to lipid rafts. More importantly, MβCD suppressed the proliferation of A549 and H1993 cells, and the combination of MβCD and radiation resulted in additive increases in A549 and H1993 cell apoptosis. Destroying the integrity of lipid rafts inhibited the aggregation of c-Met and c-Src to lipid rafts and reduced the expression of phosphorylated c-Met and phosphorylated c-Src in lipid rafts.. X-ray irradiation induced the aggregation of lipid rafts and the clustering of c-Met and c-Src to lipid rafts through both lipid raft-dependent and lipid raft-independent mechanisms. The lipid raft-dependent activation of c-Met and its downstream pathways played an important role in the development of radiation resistance in NSCLC cells mediated by c-Met. Further studies are still required to explore the molecular mechanisms of the activation of c-Met and c-Src in lipid rafts induced by radiation.

Topics: A549 Cells; Apoptosis; beta-Cyclodextrins; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; CSK Tyrosine-Protein Kinase; Humans; Lung Neoplasms; Membrane Microdomains; Phosphorylation; Proto-Oncogene Proteins c-met; Radiation Tolerance; Radiation-Sensitizing Agents; src-Family Kinases

The aim of the present study was to use a combinatorial approach of inclusion complexation and dendrimer synthesization of gefitinib using solvent-free technique for targeting EGFR-TK to treat Non-Small-Cell Lung Cancer (NSCLC). The inclusion complex of gefitinib with β-cyclodextrin was prepared by trituration method. This complex encapsulated G4 PAMAM dendrimers were synthesized by Michael addition and amidation reactions using green chemistry and then PEGylated by conjugation reaction. FTIR and DSC confirmed the formation of inclusion complex of gefitinib and β-cyclodextrin and PEGylation of G4 PAMAM dendrimers. Gefitinib showed higher solubility, encapsulation efficiency and controlled release profile from PEGylated dendrimers compared to inclusion complex. The PEGylated dendrimers of inclusion complex of gefitinib were found to reduce hemolytic toxicity and lesser GI 50 value on Human lung cancer cell line A-549 by effective targeting EGFR-TK. A combinatorial approach of inclusion complexation and dendrimer synthesization is one of the alternative advanced approaches to treat NSCLC.

Topics: beta-Cyclodextrins; Dendrimers; Humans; Lung Neoplasms; Solubility

Paclitaxel (PTX) is one of the drugs of choice in the treatment of breast and lung cancer. However, its severe side effects, including mielosuppression, cardiotoxicity and neurotoxicity, frequently cause treatment to be discontinued. Solid lipid nanoparticles (NPs) of glyceril tripalmitate (tripalmitin) loaded with PTX (Tripalm-NPs-PTX) including modifications by the addition of hexa(ethylene glycol), β-cyclodextrin and macelignan were developed. All NPs-PTX formulations displayed excellent hemocompatibility and significantly enhanced PTX antitumor activity in human breast (MCF7, MDAMB231, SKBR3 and T47D) and lung (A549, NCI-H520 and NCI-H460) cancer cells. Tripalm-NPs-PTX decreased PTX IC

Topics: Antineoplastic Agents; beta-Cyclodextrins; Breast Neoplasms; Cell Line; Female; Humans; Lignans; Lung Neoplasms; MCF-7 Cells; Nanoparticles; Neoplastic Stem Cells; Paclitaxel; Polyethylene Glycols; Spheroids, Cellular; Triglycerides; Tumor Cells, Cultured

Topics: Animals; beta-Cyclodextrins; Breast Neoplasms; Cytokines; Female; Inflammasomes; Inflammation; Injections, Intraperitoneal; Liver; Liver Neoplasms; Lung Neoplasms; Macrophages, Peritoneal; Mammary Neoplasms, Experimental; Mice, Inbred C57BL; Nanoparticles; NLR Family, Pyrin Domain-Containing 3 Protein; Polyethyleneimine; Spleen

Camptothecin (CPT) is a potent chemotherapeutic agent that shows a broad spectrum of anticancer activities. However, it is clinically inactive because of poor aqueous solubility, rapid aqueous hydrolysis, and unexpected side effects. Three strategies have extensively been adopted to improve its dissolution rate including reduction of drug particle size to a nanoscale, use of an amorphous state, and the formation of inclusion compounds. In our study, we combined these three strategies together by constructing CPT nanoparticles by creating an inclusion complex with β-cyclodextrin (BCD). This new CPT formulation showed a rod-like structure of nanoscaled size and with semiamorphous or amorphous CPT. These BCD-CPT nanoparticles showed improved dissolution rate, stability, dispersion, and cellular uptake. When tested on cancer cells, BCD-CPT nanoparticles showed a much higher anticancer activity (IC50=14-28 μmol/l) in comparison with free CPT (IC50>500 μmol/l) and CPT nanocrystals (IC50>200 μmol/l). In addition, BCD-CPT nanoparticles can be physically mixed with CPT nanocrystals, leading to CPT formulations with tailored drug-release profiles to achieve customized therapeutics and flexible treatments in clinics.

Topics: A549 Cells; Antineoplastic Agents, Phytogenic; beta-Cyclodextrins; Camptothecin; Drug Stability; Humans; Lung Neoplasms; Nanoparticles; Solubility

Cancer metastasis is the leading reason for the high mortality of breast cancer. Herein, we report on a pH-responsive host-guest nanosystem of succinobucol (PHN) with pH-stimuli controlled drug release behavior to improve the therapeutic efficacy on lung metastasis of breast cancer. PHN was composed of the host polymer of β-cyclodextrin linked with multiple arms of N,N-diisopropylethylenediamine (βCD-DPA), the guest polymer of adamantyl end-capped methoxy poly(ethylene glycol) (mPEG-Ad), and the active agent of succinobucol. PHN comprises nanometer-sized homogenous spherical particles, and exhibits specific and rapid drug release in response to the intracellular acidic pH-stimuli. Then, the anti-metastatic efficacy of PHN is measured in metastatic 4T1 breast cancer cells, which effectively confirms the superior inhibitory effects on cell migration and invasion activities, VCAM-1 expression and cell-cell binding of RAW 264.7 to 4T1 cells. Moreover, PHN can be specifically delivered to the sites of metastatic nodules in lungs, and result in an obviously improved therapeutic efficacy on lung metastasis of breast cancer. Thereby, the pH-responsive host-guest nanosystem can be a promising drug delivery platform for effective treatment of cancer metastasis.

Topics: Animals; Antineoplastic Agents; beta-Cyclodextrins; Breast Neoplasms; Cell Movement; Disease Models, Animal; Drug Delivery Systems; Female; Hydrogen-Ion Concentration; Lung Neoplasms; Mice, Inbred BALB C; Nanostructures; Neoplasm Invasiveness; Polyethylene Glycols; Probucol; Treatment Outcome

The inclusion complex of GA-13316 with β-cyclodextrin (β-CD) is one of a unique series of gibberellin derivatives possessed of potential anticancer activities. The complex with β-CD was characterized by means of UV, XRD, DSC, TG, (1)H, and 2D NMR spectroscopy. In addition, we investigated the main aspects of the interaction between GA-13316 and β-CD using both experimental and molecular modeling approaches. The complex still maintained its anticancer activity, as shown by in vitro cell survival assay on the human colon carcinoma cell line (HCT116) and the human lung cancer cell line (H460). The results showed that the use of β-CD could be obviously improved the water solubility and stability of GA-13316, implying that the inclusion complex could be a promising future therapeutic agent.

Topics: Antineoplastic Agents; beta-Cyclodextrins; Cell Line, Tumor; Colonic Neoplasms; Gibberellins; Humans; Lung Neoplasms; Magnetic Resonance Spectroscopy; Molecular Docking Simulation; Solubility

The vasculature in tumor microenvironment plays important roles in the tumor growth and metastasis, and the combination of vascular disrupting agents with chemotherapeutic drugs should be effective in inhibiting tumor progression. But the dosing schedules are essential to achieve a balance between vascular collapse and intratumoral uptake of chemotherapeutic agents. In the current study, emulsion and blend electrospinning were used to create compartmental fibers accommodating both combretastatin A-4 (CA4) and hydroxycamptothecin (HCPT). The release durations of CA4 and HCPT were modulated through the structure of fibers for dual drug loadings and the inoculation of 2-hydroxypropyl-β-cyclodextrin in fiber matrices. Under a noncontact cell coculture in Transwell, the sequential release of CA4 and HCPT indicated a sequential killing of endothelial and tumor cells. In an orthotopic breast tumor model, all the CA4/HCPT-loaded fibers showed superior antitumor efficacy and higher survival rate than fibers with loaded individual drug. Compared with fibrous mats with infiltrated free CA4 and fibers with extended release of CA4 for over 30 days, fibers with sustained release of CA4 for 3-7 days from CA4/HCPT-loaded fibers resulted in the most significant antitumor efficacy, tumor vasculature destruction, and the least tumor metastasis to lungs. A judicious selection of CA4 release durations in the combination therapy should be essential to enhance the tumor suppression efficacy and antimetastasis activity.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; beta-Cyclodextrins; Breast Neoplasms; Camptothecin; Drug Carriers; Drug Liberation; Female; Lactates; Lung Neoplasms; Mice; Mice, Inbred BALB C; Polyethylene Glycols; Stilbenes

We previously reported that glucuronylglucosyl-β-cyclodextrin (GUG-β-CyD) conjugate with polyamidoamine starburst dendrimer (GUG-β-CDE conjugate) with the average degree of substitution (DS) of cyclodextrin (CyD) of 1.8 (GUG-β-CDE conjugate (DS 1.8)), showed remarkably higher gene transfer activity than α-CyD/dendrimer conjugate (α-CDE conjugate (DS 1.2)) and β-CyD/dendrimer conjugate (β-CDE conjugate (DS 1.3)) in vitro and in vivo. In this study, to clarify the enhancing mechanism for high gene transfer activity of GUG-β-CDE conjugate (DS 1.8), we investigated the physicochemical properties, cellular uptake, endosomal escape and nuclear translocation of the plasmid DNA (pDNA) complexes as well as pDNA release from the complexes. The particle size, ζ-potential and cellular uptake of GUG-β-CDE conjugate (DS 1.8)/pDNA complex were mostly comparable to those of α-CDE conjugate (DS 1.2) and β-CDE conjugate (DS 1.3). Meanwhile, GUG-β-CDE conjugate (DS 1.8)/pDNA complex was likely to have high endosomal escaping ability and nuclear localization ability in A549 and RAW264.7 cells. In addition, the pDNA condensation and decondensation abilities of GUG-β-CDE conjugate (DS 1.8) were lower and higher than that of α-CDE conjugate (DS 1.2) or β-CDE conjugate (DS 1.3), respectively. These results suggest that high gene transfer activity of GUG-β-CDE conjugate (DS 1.8) could be, at least in part, attributed to high endosomal escaping ability, nuclear localization ability and suitable pDNA release from its complex.

Topics: Active Transport, Cell Nucleus; Adenocarcinoma; Adenocarcinoma of Lung; alpha-Cyclodextrins; Animals; beta-Cyclodextrins; Buffers; Cell Line, Tumor; Cell Nucleus; Dendrimers; DNA; Endocytosis; Endosomes; Humans; Hydrogen-Ion Concentration; Lung Neoplasms; Mice; Nucleic Acid Conformation; Particle Size; Transfection

Gefitinib is a promising agent for the treatment of non-small cell lung cancer. The purpose of this study was to develop a novel liposomal formulation for gefitinib (L-GEF) to improve its therapeutic index.. Several L-GEF formulations were prepared and characterized for their physical chemical properties and cytotoxicity. The pharmacokinetic parameters of the liposomes were determined in mice. The effect of lipid composition, transmembrane pH gradient, and incorporation of hydroxypropyl-β-cyclodextrin (HPβCD) on drug-loading efficiency, liposomal stability, and the rate of drug release were investigated.. The L-GEF formulation composed of hydrogenated soy phosphatidylcholine (HSPC)/cholesterol (Chol)/monomethoxy polyethylene glycol 2000-distearoyl phosphatidyl-ethanolamine (mPEG-DSPE) encapsulating 0.3 M (NH4)2SO4 and 0.1 M HPβCD (L-GEF-HSPC), had a drug-loading efficiency (DLE) of 85.5%. In vitro release studies showed that gefitinib release from L-GEF-HSPC in the presence of human plasma was slow and exhibited non-Fickian kinetics. Pharmacokinetic study in mice after i.v. bolus administration of L-GEF-HSPC showed that the area under the plasma concentration time curve (AUC) for gefitinib was 32.41 μg·h /ml and six times that of free gefitinib. The elimination half life (t(1/2β)) of L-GEF-HSPC was 7.29 h, while that of free gefitinib was 2.26 h.. It was shown that gefitinib can be efficiently loaded into L-GEF-HSPC composed of HSPC/Chol/mPEG-DSPE (55/40/5 mol/mol) with 0.3 M (NH(4))(2)SO(4) and 0.1 M HPβCD as trapping agents. Compared with the free drug, L-GEF-HSPC had high drug loading, good stability, and long-circulating properties.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antineoplastic Agents; beta-Cyclodextrins; Cell Line, Tumor; Drug Stability; Gefitinib; Humans; Liposomes; Lung Neoplasms; Mice; Mice, Inbred ICR; Particle Size; Quinazolines

The success of gene therapy relies largely on an effective targeted gene delivery system. Till recently, more and more targeted delivery carriers, such as liposome, nanoparticles, microbubbles, etc., have been developed. However, the clinical applications of these systems were limited for their several disadvantages. Therefore, design and development of novel drug/gene delivery vehicles became a hot topic. Cell-based delivery systems are emerging as an alternative for the targeted delivery system as we described previously. Mesenchymal stem cells (MSCs) are an attractive cell therapy carrier for the delivery of therapeutic agents into tumor sites mainly for their tumor-targeting capacities. In the present study, a nonviral vector, PEI(600)-Cyd, prepared by linking low molecular weight polyethylenimine (PEI) and β-cyclodextrin (β-CD), was used to introduce the therapeutical gene, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), to MSCs. Meanwhile, the characterization, transfection efficiency, cytotoxicity, cellular internalization, and its mechanism of this nonviral vector were evaluated. The in vitro expression of TRAIL from MSCs-TRAIL was demonstrated by both enzyme-linked immunosorbent assay and Western blot analysis. The lung tumor homing ability of MSCs was further confirmed by the in vitro and in vivo model. Moreover, the therapeutic effects as well as the safety of MSCs-TRAIL on lung metastases bearing C57BL/6 mice and normal C57BL/6 mice were also demonstrated. Our results supported both the effectiveness of nonviral vectors in transferring the therapeutic gene to MSCs and the feasibility of using MSCs as a targeted gene delivery carrier, indicating that MSCs could be a promising tumor target delivery vehicle in cancer gene therapy based on nonviral gene recombination.

Topics: Animals; beta-Cyclodextrins; Cell Movement; Female; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Lung Neoplasms; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Polyethyleneimine; Rats; Rats, Sprague-Dawley; TNF-Related Apoptosis-Inducing Ligand; Transfection; Xenograft Model Antitumor Assays

CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid) is a novel synthetic retinoic acid derivative that has been shown to selectively induce apoptosis in human lung cancer cells. This compound, however, is limited in its application due to its low solubility in aqueous solutions. One technique for increasing the solubility and bioavailability of a cytotoxic agent is the formation of inclusion complexes with cyclodextrins. Herein, we report the formation and characterization of a 2:1 complex between β-cyclodextrin (β-CD) and CD437. It is shown that CD437 is a tight binder of β-CD with an overall association constant of 2.6±0.6×10(7)M(-2). In addition, we demonstrate (a) that β-CD-derived complexation enhances the aqueous solubility of CD437, and (b) that a significant increase in the toxicity of CD437 against a human lung adenocarcinoma cell line can be achieved by co-treatment with β-CD.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; beta-Cyclodextrins; Cell Line, Tumor; Cell Proliferation; Humans; Lung Neoplasms; Models, Molecular; Retinoids; Solubility

Tubulysins are naturally occurring tetrapeptides with potent antiproliferative activity against multiple cancer cell lines. However, they are also highly toxic in animal models. In order to improve the therapeutic index of this class of compounds, a nanoparticle prodrug of tubulysin A (TubA) was synthesized and evaluated in vitro and in vivo.. A thiol derivative of TubA was covalently attached to a linear, beta-cyclodextrin based polymer through a disulfide linker (CDP-TubA). The polymer conjugate assembled into stable nanoparticles. Inhibition of tubulin polymerization and antiproliferative activity of the polymer conjugate were evaluated in vitro. The preclinical efficacy of CDP-TubA administered i.v. was evaluated in nude mice bearing s.c. implanted human HT29 colorectal and H460 non-small cell lung carcinoma tumors.. The IC(50) of CDP-TubA (in Tub A equivalents) was 24, 5, and 10 nmol/L versus 3, 1, and 2 nmol/L for Tub A in NCI-H1299 (lung), HT-29 (colon), and A2780 (ovarian) cell lines, respectively. Tub A and the active thiol derivative were potent inhibitors of tubulin polymerization, whereas CDP-TubA showed minimal inhibition, indicating that target inhibition requires release of the peptide drug from the nanoparticles. The maximum tolerated dose of CDP-TubA was 6 mg/kg (in TubA equivalents) versus 0.05 mg/kg for TubA in nude mice. In vivo, a single treatment cycle of three weekly doses of CDP-TubA showed a potent antitumor effect and significantly prolonged survival compared with TubA alone.. Cyclodextrin polymerized nanoparticles are an enabling technology for the safe and effective delivery of tubulysins for the treatment of cancer.

Topics: Animals; beta-Cyclodextrins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Evaluation, Preclinical; HT29 Cells; Humans; Inhibitory Concentration 50; Lung Neoplasms; Maximum Tolerated Dose; Mice; Mice, Nude; Nanoparticles; Oligopeptides; Polymers; Prodrugs; Solubility; Tubulin; Xenograft Model Antitumor Assays

To analyze mechanisms for cancer metastasis, we established high metastatic sublines from mouse Lewis lung cancer (P29) by repeated injection. Sublines established from the two subclones H7 and C4 commonly exhibited increased proliferation and invasion activity and reduced expression of ganglioside GM1, although they showed different preferences in their target organs of metastasis. The high metastatic sublines secreted higher levels of activated matrix metalloprotease (MMP)-9 as well as pro-MMP-9 in the culture medium than the parent lines. Furthermore, they contained MMP-9 at the glycolipid-enriched microdomain (GEM)/rafts fractionated by the sucrose density gradient ultracentrifugation of Triton X-100 extracts, whereas the parent cells showed faint bands at the fraction. When high metastatic sublines were treated with methyl-beta-cyclodextrin, their invasion activities were dramatically suppressed, and the MMP-9 secretion was also suppressed. All these results indicated that GEM/rafts play crucial roles in the increased invasion and high metastatic potential. To clarify the implication of reduced GM1 expression, low GM1-expressing cell lines were established using an RNA interference-expression vector of the GM1 synthase. Low GM1-expressing cell lines showed increased proliferation and invasion, enrichment in the GEM/rafts, and increased secretion of MMP-9. Among adhesion molecules, only integrin beta1 was detected in GEM/rafts with stronger intensity in high metastatic lines and low GM1-expressing cells. Taken together, integrins seemed to be enriched in the GEM/rafts by reduced GM1 levels, and subsequently MMP-9 was recruited to the GEM/rafts, resulting in its efficient secretion and activation, and eventually in the increased invasion and metastatic potentials.

Topics: Animals; beta-Cyclodextrins; Carcinoma, Lewis Lung; Cell Line, Tumor; Down-Regulation; G(M1) Ganglioside; Immunohistochemistry; Integrins; Lung Neoplasms; Matrix Metalloproteinase 9; Membrane Microdomains; Membrane Proteins; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Transplantation; RNA, Small Interfering; Transfection

Tetrahydrocortisol, beta-cyclodextrin tetradecasulfate, and minocycline used alone or in combination are not very cytotoxic toward EMT-6 mouse mammary tumor cells growing in monolayer. Tetrahydrocortisol (100 microM, 24 h) and beta-cyclodextrin tetradecasulfate (100 microM, 24 h) protected EMT-6 cells from the cytotoxicity of CDDP, melphalan, 4-hydroperoxycyclophosphamide, BCNU, and X-rays under various conditions of oxygenation and pH. Minocycline (100 microM, 24 h) either had no effect upon or was additive with the antitumor alkylating agents or X-rays in cytotoxic activity toward the EMT-6 cells in culture. The combination of the three modulators either had no effect upon or was to a small degree protective against the cytotoxicity of the antitumor alkylating agents or X-rays. The Lewis lung carcinoma was chosen for primary tumor growth-delay studies and tumor lung-metastases studied. Tetrahydrocortisol and beta-cyclodextrin tetradecasulfate were given in a 1:1 molar ratio by continuous infusion over 14 days, and minocycline was given i.p. over 14 days, from day 4 to day 18 post tumor implantation. The combination of tetrahydrocortisol/beta-cyclodextrin tetradecasulfate diminished the tumor growth delay induced by CDDP and melphalan and produced modest increases in the tumor growth delay produced by cyclophosphamide and radiation. Minocycline co-treatment increased the tumor growth delay produced by CDDP, melphalan, radiation, bleomycin, and, especially cyclophosphamide, where 4 of 12 animals receiving minocycline (14 x 5 mg/kg, days 4-18) and cyclophosphamide (3 x 150 mg/kg, days 7, 9, 11) were long-term survivors. The 3 modulators given in combination produced further increases in tumor growth delay with all of the cytotoxic therapies, and 5 of 12 of the animals treated with the 3-modulator combination and cyclophosphamide were long-term survivors. Although neither tetrahydrocortisol/beta-cyclodextrin tetradecasulfate, minocycline, nor the three modulator combination impacted the number of lung metastases, there was a decrease in the number of large lung metastases. Treatment with the cytotoxic therapies alone reduced the number of lung metastases. Addition of the modulators to treatment with the cytotoxic therapies resulted in a further reduction in the number of lung metastases. These results indicate that agents that inhibit the breakdown of the extracellular matrix can be useful additions to the treatment of solid tumors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; beta-Cyclodextrins; Cell Division; Cell Hypoxia; Cyclodextrins; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C57BL; Minocycline; Tetrahydrocortisol; Tumor Cells, Cultured

The formation of a blood supply (angiogenesis) is critical to the growth of solid tumors. The naturally occurring steroid tetrahydrocortisol, the synthetic cyclodextrin derivative beta-cyclodextrin tetradecasulfate, and the tetracycline derivative minocycline have antiangiogenic activity. Tetrahydrocortisol and beta-cyclodextrin tetradecasulfate in a 1:1 molar ratio by continuous infusion over 14 days and minocycline administered i.p. over 14 days from day 4 to day 18 postimplantation of the Lewis lung carcinoma significantly increased the growth delay of the primary tumor after treatment with cis-diamminedichloroplatinum(II), melphalan, cyclophosphamide, Adriamycin, bleomycin, and radiation therapy administered in standard regimens. Addition of the antiangiogenic agents to treatment with the cytotoxic therapies not only reduced the number of lung metastases formed from the primary tumor but also reduced the number of large metastases. Five of 12 animals treated with the antiangiogenic modulators and cyclophosphamide were long-term survivors (> 120 days). Thus, antiangiogenic therapies can potentiate the efficacy of standard anticancer therapies.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; beta-Cyclodextrins; Bleomycin; Cisplatin; Cyclodextrins; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Lung Neoplasms; Mice; Mice, Inbred C57BL; Minocycline; Neoplasm Transplantation; Tetrahydrocortisol; Tumor Cells, Cultured

We investigated the effect of beta-cyclodextrin-benzaldehyde (CDBA) on lymphokine-activated killer (LAK) cell activity of spleen cells from normal or RCT(+)H-2(+)-sarcoma-bearing C3H/He mice. CDBA augmented the induction of LAK cytotoxicity in vitro against RCT(+)H-2+ tumor cells by IL-2, whereas the culture with CDBA alone did not. In a LAK cytotoxicity assay in vitro, the augmentative effect of CDBA was strongly exerted against spleen cells originating from 2-week-tumor-bearing mice, rather than those from normal mice or mice that had born tumors for 5 weeks. Such an augmentative effect was not observed against other tumor cells (YAC-1, D-6, Colon-26 and EL-4 cells) non-specifically. When the intravenous adoptive transfer of LAK cells was carried out in the mice, LAK cells from tumor-bearing mice induced by combined culture with interleukin-2 (IL-2) and CDBA markedly inhibited the pulmonary metastases of RCT(+)H-2+ tumor, while neither LAK cells from the same tumor-bearing mice induced by only IL-2 nor those from normal mice inhibited the pulmonary metastasis. The majority of LAK cells induced either by IL-2 plus CDBA or by IL-2 alone were found to be Thy1.2+ and asialoGM1+ cells by flow-cytometric analysis, but no obvious phenotypical difference was observed between them. However, the most significant effect of CDBA might be the maintenance of the Lyt-2+ cell level in the spleen cells from tumor-bearing mice. These results suggested that the costimulation of spleen cells with IL-2 and CDBA might induce cytotoxic T cells specific for syngeneic tumor cells.

Topics: Animals; Benzaldehydes; beta-Cyclodextrins; Cyclodextrins; Cytotoxicity, Immunologic; Drug Synergism; Flow Cytometry; Immunotherapy, Adoptive; Interleukin-2; Killer Cells, Lymphokine-Activated; Lung Neoplasms; Male; Mice; Mice, Inbred C3H; Sarcoma

The effect of beta-cyclodextrin-benzaldehyde (CDBA) on the pulmonary metastasis in C3H/He mice was examined. When mice were treated daily with CDBA, 3 weeks later the number of lung nodules developed after i.v. inoculation of 1 X 10(6) RCT (+) cells was significantly decreased. The mean numbers of the lung nodules were 69.9 and 73.4 in the water-and cyclodextrin (CD)-treated mice, respectively. However, these were 17.8, 9.8 and 2.9 in 0.5, 5 and 25 mg/mouse per day CDBA-treated mice, respectively. And also, daily treatment of CDBA prolonged the survival time of the tumor bearing mice in both experimental and spontaneous metastasis studies. Two or three weeks after subcutaneous inoculation of RCT (+) cells (1 X 10(6) cells) to the foot pad, left hindlimbs were amputated and then mice were daily treated or untreated with CDBA. Five weeks after tumor inoculation, the number of lung nodules was counted. Twenty eight point six and 100% of untreated mice had lung metastases when amputation was carried out 2 (earlier operation group) and 3 (latero peration group) weeks after tumor inoculation. However, in CDBA-treated mice, these values were noticeably decreased, that is, 6.7% and 60% in earlier and later operation groups, respectively. Furthermore, in the later operation group, mean number of the lung nodules in CDBA-treated mice was only 2.7 while this was 12.9 in untreated mice. These data suggest that CDBA improve the survival time of tumor bearing mice through the inhibition of the lung metastasis.

Topics: Administration, Oral; Animals; Benzaldehydes; beta-Cyclodextrins; Cyclodextrins; Dextrins; Lung Neoplasms; Male; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Starch

The effect of beta-cyclodextrin-benzaldehyde (CDBA) on pulmonary metastasis in C3H/He mice was examined. In experimental metastasis that was induced by iv injection of 1 X 10(6) RCT (+) cells, the highest inhibition was observed in the mice that were treated daily with CDBA (5 mg/day) for 1 week before tumor cell inoculation and further treated for 3 weeks after inoculation, when compared with those in other experimental groups that were given only pretreatment or posttreatment. The inhibitory effect was dose-dependent. In spontaneous metastasis that was induced by sc injection of 3 X 10(6) RCT (+) cells, the inhibition of metastasis was also observed in the mice treated with CDBA (5 mg/day) in the same manner as described above. However, the development of the primary tumor was not inhibited. CDBA-treated tumor-bearing mice showed almost as much NK activity as normal mice. Furthermore, although injection of 5-fluorouracil suppressed this activity to about 50% of that in normal mice, the combined treatment with CDBA could maintain the NK cell activity at the normal level. The results suggested that the inhibition of pulmonary metastasis might be induced by a combined effect of CDBA; that is, the direct inhibition of tumors and the maintenance of NK cell activity.

Topics: Animals; Antineoplastic Agents; Benzaldehydes; beta-Cyclodextrins; Cyclodextrins; Cytotoxicity, Immunologic; Dextrins; Dose-Response Relationship, Drug; Killer Cells, Natural; Lung Neoplasms; Male; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Sarcoma, Experimental; Starch

The effect of beta-cyclodextrin-benzaldehyde (CDBA) on experimental pulmonary metastasis in C3H/He mice was examined. In an in vitro assay, the growth of RCT(+) cells was inhibited by 1200 micrograms/ml CDBA using unrenewed media, and by 600 micrograms/ml CDBA in that using daily renewed media. When mice were treated daily with CDBA, 3 weeks later the number of lung nodules developing after i.v. injection of 1 X 10(6) RCT(+) cells was significantly decreased in a dose-dependent manner, i.e., 73.8%, 85.6%, and 95.7% inhibition was observed following 0.5, 5, and 25 mg CDBA/mouse per day p.o. administration, respectively. The same mice showed almost as much natural killer (NK) activity as normal mice. Therefore, experiments were designed to evaluate the effect of CDBA on the NK activity of tumor-free mice whose immunity had been suppressed by 5-fluorouracil (5FU). Injections of 5FU only suppressed this activity to about 50% of normal mice, but the combined treatment with CDBA negated the suppressive effect of 5FU on NK activity. The results suggested that the inhibition of experimental pulmonary metastasis might be induced by the possible combined effects of CDBA; that is, the direct inhibition of tumors and the augmentation of NK cell activity.

Topics: Animals; Benzaldehydes; beta-Cyclodextrins; Cyclodextrins; Cytotoxicity, Immunologic; Dextrins; Fluorouracil; Immunosuppression Therapy; Killer Cells, Natural; Lung Neoplasms; Male; Mice; Mice, Inbred C3H; Neoplasm Metastasis; Neoplasms, Experimental; Starch