Reversal of Multidrug Resistance by Apolipoprotein A1-Modified Doxorubicin Liposome for Breast Cancer Treatment

Multidrug resistance (MDR) remains a major problem in cancer therapy and is characterized by the overexpression of p-glycoprotein (P-gp) efflux pump, upregulation of anti-apoptotic proteins or downregulation of pro-apoptotic proteins. In this study, an Apolipoprotein A1 (ApoA1)-modified cationic liposome containing a synthetic cationic lipid and cholesterol was developed for the delivery of a small-molecule chemotherapeutic drug, doxorubicin (Dox) to treat MDR tumor. The liposome-modified by ApoA1 was found to promote drug uptake and elicit better therapeutic effects than free Dox and liposome in MCF-7/ADR cells. Further, loading Dox into the present ApoA1-liposome systems enabled a burst release at the tumor location, resulting in enhanced anti-tumor effects and reduced off-target effects. More importantly, ApoA1-lip/Dox caused fewer adverse effects on cardiac function and other organs in 4T1 subcutaneous xenograft models. These features indicate that the designed liposomes represent a promising strategy for the reversal of MDR in cancer treatment.     

Non-alkaloids extract from Stemona sessilifolia enhances the activity of chemotherapeutic agents through P-glycoprotein-mediated multidrug-resistant cancer cells

One of the major impediments to the successful treatment of cancer is the development of resistant cancer cells, which could cause multidrug resistance (MDR), and overexpression of ABCB1/P-glycoprotein (P-gp) is one of the most common causes of MDR in cancer cells. Recently, natural products or plant-derived chemicals have been investigated more and more widely as potential multidrug-resistant (MDR) reversing agents. The current study demonstrated for the first time that non-alkaloids extract from Stemona sessilifolia significantly reversed the resistance of chemotherapeutic agents, adriamycin, paclitaxel and vincristine to MCF-7/ADR cells compared with MCF-7/S cells in a dose-dependent manner. The results obtained from these studies indicated that the non-alkaloids extract from S. sessilifolia plays an important role in reversing MDR of cancer as a P-gp modulator in vitro and may be effective in the treatment of multidrug-resistant cancers.     

具有肿瘤多药耐药逆转作用的金雀异黄素衍生物的合成及生物活性研究

细胞膜P-糖蛋白(P-gp)介导的药物外流是肿瘤多药耐药(MDR)产生的重要机制,异黄酮类化合物可以通过抑制P-gp活性发挥MDR逆转作用.通过对P-gp抑制剂进行结构分析,以金雀异黄素为母体,在其7位、8位及4'位分别引进碱性边链,设计、合成了20个金雀异黄素衍生物(其中16个未见文献报道),并检测了其多药耐药逆转活性.结果表明,大多数目标化合物对人白血病耐药细胞株K562/A02具有不同程度的耐药逆转作用.其中目标化合物8a,8b,8d,8e逆转作用较强,逆转倍数分别为8.97,6.36,5.19和5.82.     

Preparation of pH-Responsive Doxorubicin Nanocapsules by Combining High-gravity Antisolvent Precipitation with In-situ Polymerization for Intracellular Anticancer Drug Delivery

Owing to the low pH value in tumor and cancer cells, drug delivery systems based on pH-responsive polymer nanocarriers have been extensively explored for anticancer chemotherapy. Herein, we developed a pH-responsive doxorubicin(DOX) nanocapsule(named as DNanoCapsule) prepared by combining in-situ polymerization technique with high-gravity antisolvent precipitation technique through an amphiphilic polymerized surface ligand. DNanoCapsules show an obvious spherical core-shell structure with a single DOX nanoparticle encapsulated in the polymer layer. Dissolution rate studies prove that the DNanoCapsules have robust drug-release profiles under acidic environments due to the division of the pH-sensitive cross-linker, which triggers the collapse of the polymer layer. The in vitro investigations demonstrated that the DNanoCapsules exhibited high cellular uptake efficiency and cytotoxicity for both HeLa and MCF-7 cancer cells. Therefore, this work may provide a promising strategy to design and develop various stimuli-responsive drug nanocapsules for the treatment of cancer or other diseases.     

Nanocarrier based on the assembly of protein and antisense oligonucleotide to combat multidrug resistance in tumor cells

Chemotherapy-induced multi-drug resistance(MDR) in tumors poses a huge challenge for clinical treatment of tumors. The downregulation of the multi-drug resistance relative protein, represented by P-glycoprotein(P-gp), can reverse MDR of cancer cells. In this study, we developed doxorubicin-loading nanocarrier based on the assembly of protein and antisense oligonucleotide(ASO) to combat MDR of cancer cells. The data demonstrate that the nanocarrier can efficiently deliver ASO to cytoplasm and downregulate the P-glycoprotein expression, subsequently improving the therapeutic effects of Dox in doxorubicin-resistant MCF-7/ADR cancer cells. The preparation is simple and effective, providing a powerful tool for gene delivery. Therefore, our nanocarrier shows high promise in cancer treatment.     

Two-dimensional LDH nanodisks modified with hyaluronidase enable enhanced tumor penetration and augmented chemotherapy

The condensed tumor extracellular matrix(ECM) consisting of cross-linked hyaluronic acid(HA) is one of the key factors that result in the aberrant tumor microenvironment and severely impair drug delivery and tumor penetration. Herein, we report a simple design of a hyaluronidase(HAase)-modified layered double hydroxide(LDH) nanoplatform loaded with anticancer drug doxorubicin(DOX) for enhanced tumor penetration and augmented chemotherapy. In our approach, LDH nanodisks were synthesized via a co-precipitation method, modified with HAase by electrostatic attraction, and finally physically loaded with DOX. The formulated DOX/LDH-HAase complexes show a high DOX loading percentage of 34.2% with good colloidal stability, retain 86.1% of the enzyme activity, and release DOX in a pH-responsive manner having a faster release rate under slightly acidic tumor microenvironment than that under a physiological condition. With the catalytic activity of HAase to digest the HA nearby the cancer cells, the developed DOX/LDH-HAase complexes enable more significant uptake by cancer cells and penetration in 3-dimensional tumor spheroids than enzyme-free DOX/LDH complexes, thus displaying much better antitumor efficacy in vitro than the latter. The more significant tumor penetration and inhibition of the DOX/LDH-HAase complexes than that of the DOX/LDH complexes was further demonstrated by in vivo tumor imaging and therapeutic activity assessments. Our study suggests a unique nanomedicine platform combined with both anticancer drug and enzyme for improved tumor penetration and chemotherapy, which is promising for effective chemotherapy of different types of stroma-rich tumors.     

NIR-triggered drug delivery system based on phospholipid coated ordered mesoporous carbon for synergistic chemo-photothermal therapy of cancer cells

Chemo-photothermal treatment is one of the most efficient strategies for cancer therapy. However, traditional drug carriers without near-infrared absorption capacity need to be loaded with materials behaving photothermal properties, as it results in complicated synthesis process, inefficient photothermal effects and hindered NIR-mediated drug release. Herein we report a facile synthesis of a polyethylene glycol (PEG) linked liposome (PEG-liposomes) coated doxorubicin (DOX)-loaded ordered mesoporous carbon (OMC) nanocomponents (PEG-LIP@OMC/DOX) by simply sonicating DOX and OMC in PEG-liposomes suspensions. The as-obtained PEG-LIP@OMC/DOX exhibits a nanoscale size (600±15 nm), a negative surface potential (-36.70 mV), high drug loading (131.590 mg/g OMC), and excellent photothermal properties. The PEG-LIP@OMC/DOX can deliver loaded DOX to human MCF-7 breast cancer cells (MCF-7) and the cell toxicity viability shows that DOX unloaded PEG-LIP@OMC has no cytotoxicity, confirming the PEG-LIP@OMC itself has excellent biocompatibility. The NIR-triggered release studies demonstrate that this NIR-responsive drug delivery system enables on-demand drug release. Furthermore, cell viability results using human MCF-7 cells demonstrated that the combination of NIR-based hyperthermal therapy and triggered chemotherapy can provide higher therapeutic efficacy than respective monotherapies. With these excellent features, we believe that this phospholipid coating based multifunctional delivery system strategy should promote the application of OMC in nanomedical applications.     

NIR-triggered drug delivery system based on phospholipid coated ordered mesoporous carbon for synergistic chemo-photothermal therapy of cancer cells

Chemo-photothermal treatment is one of the most efficient strategies for cancer therapy. However, traditional drug carriers without near-infrared absorption capacity need to be loaded with materials behaving photothermal properties, as it results in complicated synthesis process, inefficient photothermal effects and hindered NIR-mediated drug release. Herein we report a facile synthesis of a polyethylene glycol (PEG) linked liposome (PEG-liposomes) coated doxorubicin (DOX)-loaded ordered mesoporous carbon (OMC) nanocomponents (PEG-LIP@OMC/DOX) by simply sonicating DOX and OMC in PEG-liposomes suspensions. The as-obtained PEG-LIP@OMC/DOX exhibits a nanoscale size (600 ± 15 nm), a negative surface potential (−36.70 mV), high drug loading (131.590 mg/g OMC), and excellent photothermal properties. The PEG-LIP@OMC/DOX can deliver loaded DOX to human MCF-7 breast cancer cells (MCF-7) and the cell toxicity viability shows that DOX unloaded PEG-LIP@OMC has no cytotoxicity, confirming the PEG-LIP@OMC itself has excellent biocompatibility. The NIR-triggered release studies demonstrate that this NIR-responsive drug delivery system enables on-demand drug release. Furthermore, cell viability results using human MCF-7 cells demonstrated that the combination of NIR-based hyperthermal therapy and triggered chemotherapy can provide higher therapeutic efficacy than respective monotherapies. With these excellent features, we believe that this phospholipid coating based multifunctional delivery system strategy should promote the application of OMC in nanomedical applications.     

Effect of meta-tetra(hydroxyphenyl)chlorin (mTHPC)-mediated photodynamic therapy on sensitive and multidrug-resistant human breast cancer cells

Meta-tetra(hydroxyphenyl)chlorin (mTHPC) is in clinical trials for the photodynamic therapy (PDT) of localized-stage cancer. The PDT susceptibility of cells expressing multidrug resistance (MDR) phenotype is an attractive possibility to overcome the resistance to cytotoxic drugs observed during cancer chemotherapy. The accumulation, photocytotoxicity and intracellular localization of mTHPC were examined using the doxorubicin selected MCF-7/DXR human breast cancer cells, expressing P-glycoprotein (P-gp), and the wild-type parental cell line, MCF-7. No significant difference in mTHPC accumulation was observed between the two cell lines up to 3 h contact. The photodynamic activity of mTHPC, measured 24 h after irradiation with red laser light (lambda=650 nm), was significantly greater in MCF-7/DXR as compared to MCF-7 cells. A light dose of 2.5 J cm(-2) inducing 50% of cytotoxicity in MCF-7, resulted in 85% cytotoxicity in MCF-7/DXR. The presence of P-gp inhibitors SDZ-PSC-833 and cyclosporin A did not modify the mTHPC-induced cytotoxicity. The difference in intracellular mTHPC distribution pattern between two cell lines may contribute to different photocytotoxicity. Our results indicate that mTHPC mediated PDT could be useful in killing cells expressing MDR phenotype.     

Co-Inhibition of P-gp and Hsp90 by an Isatin-Derived Compound Contributes to the Increase of the Chemosensitivity of MCF7/ADR-Resistant Cells to Doxorubicin

Breast cancer is a complex and multi-drug resistant (MDR) disease, which could result in the failure of many chemotherapeutic clinical agents. Discovering effective molecules from natural products or by derivatization from known compounds is the interest of many research studies. The first objective of the present study is to investigate the cytotoxic combinatorial, chemosensitizing, and apoptotic effects of an isatin derived compound (5,5-diphenylimidazolidine-2,4-dione conjugated with 5-substituted isatin, named HAA₂₀₂₁ in the present study) against breast cancer cells (MCF7) and breast cancer cells resistant to doxorubicin (MCF7/ADR) when combined with doxorubicin. The second objective is to investigate the binding mode of HAA₂₀₂₁ withP-glycoprotein (P-gp) and heat shock protein 90 (Hsp90), and to determine whether their co-inhibition by HAA₂₀₂₁ contribute to the increase of the chemosensitization of MCF7/ADR cells to doxorubicin. The combination of HAA₂₀₂₁, at non-toxic doses, with doxorubicin synergistically inhibited the proliferation while inducing significant apoptosis in MCF7 cells. Moreover, HAA₂₀₂₁ increased the chemosensitization of MCF7/ADR cells to doxorubicin, resulting in increased cytotoxicity/selectivity and apoptosis-inducing efficiency compared with the effect of doxorubicin or HAA₂₀₂₁ alone against MCF7/ADR cells. Molecular modeling showed that two molecules of HAA₂₀₂₁ bind to P-gp at the same time, causing P-gp inhibitory effect of the MDR efflux pump, and accumulation of Rhodamine-123 (Rho123) in MCF7/ADR cells. Furthermore, HAA₂₀₂₁ stably interacted with Hsp90α more efficiently compared with 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), which was confirmed with the surface plasmon resonance (SPR) and molecular modeling studies. Additionally, HAA₂₀₂₁ showed multi-target effects via the inhibition of Hsp90 and nuclear factor kappa B (NF-𝜅B) proteins in MCF7 and MCF7/ADR cells. Results of real time-PCR also confirmed the synergistic co-inhibition of P-gp/Hsp90α genes in MCF7/ADR cells. Further pharmacokinetic and in vivo studies are warranted for HAA₂₀₂₁ to confirm its anticancer capabilities.     

METTL3 promotes adriamycin resistance in MCF-7 breast cancer cells by accelerating pri-microRNA-221-3p maturation in a m6A-dependent manner

Breast cancer (BC) is the most prevalent malignant neoplasm among women and is the fifth most common cause of cancer-associated death worldwide. Acquired chemoresistance driven by genetic and epigenetic alterations is a significant clinical challenge in treating BC. However, the mechanism of BC cell resistance to adriamycin (ADR) remains to be elucidated. In this study, we identified the methyltransferase-like 3/microRNA-221-3p/homeodomain-interacting protein kinase 2/Che-1 (METTL3/miR-221-3p/HIPK2/Che-1) axis as a novel signaling event that may be responsible for resistance of BC cells to ADR. A dual-luciferase reporter gene assay was employed to test the presence of miR-221-3p binding sites in the 3′UTR of HIPK2. Drug resistance was evaluated by immunoblotting multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP). Cultured ADR-resistant MCF-7 cells were assayed for their half maximal inhibitory concentration (IC50) values and apoptosis using an MTT assay and Annexin V-FITC/PI-labeled flow cytometry, and the cells were then xenografted into nude mice. METTL3 knockdown was shown to reduce the expression of miR-221-3p by reducing pri-miR-221-3p m6A mRNA methylation, thereby reducing the IC50 value of ADR-resistant MCF-7 cells, reducing the expression of MDR1 and BCRP, and inducing apoptosis. Mechanistically, miR-221-3p was demonstrated to negatively regulate HIPK2 and upregulate its direct target Che-1, thus leading to enhanced drug resistance in ADR-resistant MCF-7 cells. In vitro results were reproduced in nude mice xenografted with ADR-resistant MCF-7 cells. Our work elucidates an epigenetic mechanism of acquired chemoresistance in BC, in support of the METTL3/miR-221-3p/HIPK2/Che-1 axis as a therapeutic target for the improvement of chemotherapy.Subject terms: Breast cancer, Cell biology     

5-Aminolaevulinic acid-mediated photodynamic therapy in multidrug resistant leukemia cells

To verify if photodynamic therapy (PDT) could overcome multidrug resistance (MDR) when it it applied to eradicate minimal residual disease in patients with leukemia, we investigated the fluorescence kinetics of 5-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PpIX) and the effect of subsequent photodynamic therapy on MDR leukemia cells, which express P-glycoprotein (P-gp), as well as on their parent cells. Evaluation of PpIX accumulation by flow cytometry showed that PpIX accumulated at higher levels in mdr-1 gene-transduced MDR cells (NB4/MDR) and at lower levels in doxorubicin-induced MDR cells (NOMO-1/ADR) than in their parent cells. A P-gp inhibitor could not increase PpIX accumulation. Measurement of extracellular PpIX concentration by fluorescence spectrometry showed that P-gp did not mediate the fluorescence kinetics of ALA-induced PpIX production. Assessment of ferrochelatase activity using high-performance liquid chromatography indicated that PpIX accumulation in drug-induced MDR cells was probably regulated by this enzyme. Assessment of phototoxicity of PDT using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that PDT was effective in NB4, NB4/MDR, NOMO-1 and NOMO-1/ADR cells, which accumulated high levels of PpIX, but not effective in K562 and K562/ADR cell lines, which accumulated relatively low levels of PpIX. These findings demonstrate that P-gp does not mediate the ALA-fluorescence kinetics, and multidrug resistant leukemia cells do not have cross-resistance to ALA-PDT.     

Molecular-scale drug delivery systems loaded with oxaliplatin for supramolecular chemotherapy

Smart strategies that can decrease the side effect and enhance the therapeutic efficacy of chemotherapy are in urgent need to meet the special demands of cance r therapy.Herein,two wate r-soluble macrocyclic hosts,i.e.,a carboxylated leaning tower[6]arene(CLT6) and a carboxylated [2]biphenyl-extended pillar[6]arene(CBpP6),are used to load chemotherapy drug oxaliplatin(OxPt) by forming inclusion complexes(OxPt■CLT6 and OxPt■CBpP6) through host-guest interactions.Interestingly,OxPt can be released from the macrocyclic cavities of these drug delivery systems(DDSs) via the competitive binding effect of spermine(SPM) because of the stronger binding abilities of CLT6/CBpP6 toward SPM as compared with OxPt,leading to enhanced cytotoxicity on SPM-overexpressed cancer cells,such as breast cancer MCF-7 cells.Moreover,compared to free OxPt,due to the low concentration of SPM in normal cells,OxPt■CGT6 and OxPt■CBpP6 demonstrated a decreased cytotoxicity on liver L02 cells,which is beneficial fo r reducing the side effect of anticancer drug during chemotherapy.Such a strategy might be extended to other antitumor drugs and water-soluble macrocycles with suitable cavity sizes to achieve controllable drug delivery and enhanced anticancer ability in supramolecular chemotherapy     

Inhibitory Effect of Ursolic Acid on the Migration and Invasion of Doxorubicin-Resistant Breast Cancer

The cause of death in most breast cancer patients is disease metastasis and the occurrence of multidrug resistance (MDR). Ornithine decarboxylase (ODC), which is involved into multiple pathways, is closely related to carcinogenesis and development. Ursolic acid (UA), a natural triterpenoid compound, has been shown to reverse the MDR characteristics of tumor cells. However, the effect of UA on the invasion and metastasis of tumor cells with MDR is not known. Therefore, we investigated the effects of UA on invasion and metastasis, ODC-related polyamine metabolism, and MAPK-Erk-VEGF/MMP-9 signaling pathways in a doxorubicin-resistant breast cancer cell (MCF-7/ADR) model. The obtained results showed that UA significantly inhibited the adhesion and migration of MCF-7/ADR cells, and had higher affinities with key active cavity residues of ODC compared to the known inhibitor di-fluoro-methyl-ornithine (DFMO). UA could downregulate ODC, phosphorylated Erk (P-Erk), VEGF, and matrix metalloproteinase-9 (MMP-9) activity. Meanwhile, UA significantly reduced the content of metabolites of the polyamine metabolism. Furthermore, UA increased the intracellular accumulation of Dox in MCF-7/ADR cells. Taken together, UA can inhibit against tumor progression during the treatment of breast cancer with Dox, and possibly modulate the Erk-VEGF/MMP-9 signaling pathways and polyamine metabolism by targeting ODC to exert these effects.     

Therapeutic Potential of DNAzyme Loaded on Chitosan/Cyclodextrin Nanoparticle to Recovery of Chemosensitivity in the MCF-7 Cell Line

Commonly, acquired resistances to anticancer drug are mediated by overexpression of a membrane-associated protein that encode via multi-drug resistance gene-1 (MDR1). Herein, the mRNA-cleaving DNAzyme that targets the mRNA of MDR1 gene in doxorubicin-resistant breast cancer cell line (MCF-7/DR) loaded on the chitosan β-cyclodextrin complexes was used as a tropical agent. Chitosan/β-cyclodextrin complexes were used to deliver DNAzymes into cancer cells. Determination of the physicochemical characteristics of the particles was done by photon correlation spectroscopy and scanning electron microscopy. The encapsulation efficiency of the complexes was tested by using gel retardation assay. Positively charged nanoparticles interacted with DNAzyme that could perform as an efficient DNAzyme transfection system. The rationale usage of this platform is to sensitize MCF-7/DR to doxorubicin by downregulating the drug-resistance gene MDR1. Results demonstrated a downregulation of MDR1 mRNAs in MCF-7/DR/DNZ by real-time PCR, compared to the MCF-7/DR as control. WST1 assay showed the 22-fold decrease in drug resistance on treated cells 24 h after transfection. Results showed the intracellular accumulation of Rh123 increased in the treated cells with DNAzyme. Results suggested a potential platform in association with chemotherapy drug for cancer therapy and indicated extremely efficient at delivery of DNAzyme in restoring chemosensitivity.

     

Short and simple peptide-based pH-sensitive hydrogel for antitumor drug delivery

Since self-assembled peptide hydrogels can solve the problems such as low solubility, poor selectivity and serious adverse effects of traditional chemotherapy drugs, they have been widely used as carrier materials for drug delivery. In this study, we developed a novel and injectable drug delivery platform for the antitumor drug doxorubicin(DOX) using a p H-responsive ionic-complementary octapeptide FOE.This octapeptide could self-assemble into stable hydrogel under neutral conditions, while disa...     

A pH-response multifunctional nanoplatform based on NaGdF4:Yb,Er,Fe@Ce6@mSiO2-DOX for synergistic photodynamic/chemotherapy of cancer cells

Cancer is one of the major diseases that seriously threaten human health. Drug delivery nanoplatforms for tumor treatment have attracted increasing attention owing to their unique advantages such as good specificity and few side effects. This study aimed to fabricate a pH-responsive drug release multifunctional nanoplatform NaGdF₄:Yb,Er,Fe@Ce6@mSiO₂-DOX. In the platform, Fe³⁺ doping enhanced the fluorescence intensity of NaGdF₄:Yb, Er by 5.8 folds, and the mSiO₂ shell substantially increased the specific surface area of nanomaterials (559.257 m²/g). The loading rates of chlorin e6 and doxorubicin hydrochloride (DOX) on NaGdF₄:Yb,Er,Fe@Ce6@mSiO₂-DOX reached 28.58 ± 0.85% and 87.53 ± 5.53%, respectively. Additionally, the DOX release rate from the nanoplatform was only 24.4% after 72 h at pH 7.4. However, under tumor microenvironment conditions (pH 5.0), the release rate of DOX increased to 85.3% after 72 h. The nanoplatform could generate reactive oxygen species (ROS) under 980 nm near-infrared excitation. Moreover, the nanoplatform exhibited a strong comprehensive killing efficiency against cancer cells. The viabilities of HeLa, MCF-7, and HepG2 cancer cells were only 18.5, 11.4, and 9.3%, respectively, after being treated with a combination of photodynamic therapy and chemotherapy. The constructed nanoplatform exhibits great application potential in cancer treatment.     

A non-radioactive assay for precise determination of intracellular levels of imatinib and its main metabolite in Bcr-Abl positive cells

Multidrug resistance (MDR) is often associated with overexpression of the P-glycoprotein (P-gp, ABCB1). It was demonstrated that the P-gp mediated efflux decreases the drug concentration in cancer cells which results in the failure of chemotherapy. However, the MDR phenotype in cancer cells obviously involves various mechanisms. Therefore, if we want to estimate a contribution of the P-gp expression to the MDR phenotype, a clear quantitative relationship between the intracellular drug level and cell sensitivity must be established. To achieve this goal, a sensitive and non-radioactive assay for precise determination of intracellular levels of imatinib and its main metabolite N-desmethyl imatinib (CGP 74588) has been developed. The assay is based on an optimised extraction of cells with 4% formic acid after their separation from the growth medium by centrifugation through a layer of silicone oil. Cell extracts are subsequently analyzed by LC/MS/MS. Calibration curves were linear from 1 to 500 nmol/l for imatinib and from 2 to 500 nmol/l for CGP 74588, with correlation coefficients (r²) better than 0.998 and 0.996, respectively. The limit of quantitation (LOQ) was 1 nmol/l for imatinib and 2 nmol/l for CGP 74588. Our method has been successfully applied to the determination of intracellular levels of imatinib in sensitive K562 and their resistant variant, K562/Dox cells.     

Loading-free supramolecular organic framework drug delivery systems (sof-DDSs)for doxorubicin: normal plasm and multidrug resistant cancer cell-adaptive delivery and release

Four water-soluble porous supramolecular organic framework drug delivery systems(sof-DDSs)have been used to adsorb doxorubicin(DOX)in water at physiological pH of 7.4,which is driven exclusively by hydrophobicity.The resulting complexes DOX@SOFs are formed instantaneously upon dissolving the components in water.The drug-adsorbed sof-DDSs can undergo plasm circulation with important maintenance of the drug and overcome the multidrug resistance of human breast MCF-7/Adr cancer cells. DOX is released readily in the cancer cells due to the protonation of its amino group in the acidic medium of cancer cells.In vitro and in vivo experiments reveal that the delivery of SOF-a-d remarkably improve the cytotoxicity of DOX for the MCF-7/Adr cells and tumors,leading to 13-19-fold reduction of the IC50 values as compared with that of DOX.This new sof-DDSs strategy omits the indispensable loading process required by most of reported nano-scaled carriers for neutral hydrophobic chemotherapeutic agents,and thus should be highly valuable for future development of low-cost delivery systems.     

Synthesis of self-assemble pH-responsive cyclodextrin block copolymer for sustained anticancer drug delivery

Well-defined p H-responsive poly(ε-caprolactone)-graft-β-cyclodextrin-graft-poly(2-(dimethylamino)ethylmethacrylate)-co-poly(ethylene glycol) methacrylate amphiphilic copolymers(PCL-g-β-CD-g-P(DMAEMA-co-PEGMA)) were synthesized using a combination of atom transfer radical polymerization(ATRP),ring opening polymerization(ROP) and "click" chemistry.Successful synthesis of polymers was confirmed by Fourier transform infrared spectroscopy(FTIR),proton nuclear magnetic resonance(1H-NMR),and gel permeation chromatography(GPC).Then,the polymers could selfassemble into micelles in aqueous solution,which was demonstrated by dynamic light scattering(DLS) and transmission electron microscopy(TEM).The p H-responsive self-assembly behavior of these copolymers in water was investigated at different p H values of 7.4 and 5.0 for controlled doxorubicin(DOX) release,and these results revealed that the release rate of DOX could be effectively controlled by altering the p H,and the release of drug loading efficiency(DLE) was up to 88%(W/W).CCK-8 assays showed that the copolymers had low toxicity and possessed good biodegradability and biocompatibility,whereas the DOX-loaded micelles remained with high cytotoxicity for He La cells.Moreover,confocal laser scanning microscopy(CLSM) images revealed that polymeric micelles could actively target the tumor site and the efficient intracellular DOX release from polymeric micelles toward the tumor cells further confirmed the anti-tumor effect.The DOX-loaded micelles could easily enter the cells and produce the desired pharmacological action and minimize the side effect of free DOX.These results successfully indicated that p H-responsive polymeric micelles could be potential hydrophobic drug delivery carriers for cancer targeting therapy with sustained release.