23214-92-8Relevant articles and documents
Codelivery of Doxorubicin and shAkt1 by Poly(ethylenimine)-Glycyrrhetinic Acid Nanoparticles to Induce Autophagy-Mediated Liver Cancer Combination Therapy
Wang, Feng-Zhen,Xing, Lei,Tang, Zheng-Hai,Lu, Jin-Jian,Cui, Peng-Fei,Qiao, Jian-Bing,Jiang, Lei,Jiang, Hu-Lin,Zong, Li
, p. 1298 - 1307 (2016)
Combination therapy has been developed as a promising therapeutic approach for hepatocellular carcinoma therapy. Here we report a low toxicity and high performance nanoparticle system that was self-assembled from a poly(ethylenimine)-glycyrrhetinic acid (PEI-GA) amphiphilic copolymer as a versatile gene/drug dual delivery nanoplatform. PEI-GA was synthesized by chemical conjugation of hydrophobic GA moieties to the hydrophilic PEI backbone via an acylation reaction. The PEI-GA nanocarrier could encapsulate doxorubicin (DOX) efficiently with loading level about 12% and further condense DNA to form PEI-GA/DOX/DNA complexes to codeliver drug and gene. The diameter of the complexes is 102 ± 19 nm with zeta potential of 19.6 ± 0.2 mV. Furthermore, the complexes possess liver cancer targeting ability and could promote liver cancer HepG2 cell internalization. Apoptosis of cells could be induced by chemotherapy of DOX, and PI3K/Akt/mTOR signaling pathway acts a beneficial effect on the modulation of autophagy. Here, it is revealed that utilizing PEI-GA/DOX/shAkt1 complexes results in effective autophagy and apoptosis, which are useful to cause cell death. The induction of superfluous autophagy is reported to induce type-II cell death and also could increase the sensity of chemotherapy to tumor cells. In this case, combining autophagy and apoptosis is meaningful for oncotherapy. In this study, PEI-GA/DOX/shAkt1 has demonstrated favorable tumor target ability, little side effects, and ideal antitumor efficacy.
Reduction-sensitive mixed micelles assembled from amphiphilic prodrugs for self-codelivery of DOX and DTX with synergistic cancer therapy
Wu, Jilian,Zhang, Huiyuan,Hu, Xu,Liu, Ruiling,Jiang, Wei,Li, Zhonghao,Luan, Yuxia
, p. 449 - 456 (2018)
Clinically, codelivery of chemotherapeutics has been limited by poor water-solubility and severe systemic toxicity. In this work, we developed a new reduction-sensitive mixed micellar system for self-codelivery of doxorubicin (DOX) and docetaxel (DTX). Biodegradable methoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) was coupled with DOX and DTX by a reduction-sensitive disulfide bond, resulting in mPEG-PCL-SS-DOX and mPEG-PCL-SS-DTX, respectively. mPEG-PCL-SS-DOX was mixed with mPEG-PCL-SS-DTX at a mole ratio of 1:1 in water, forming a mixed micellar system. The mixed micelles had a diameter of 223.7 nm and a low critical micelle concentration. Reductive-triggered drug release revealed a “smart” characteristic of the mixed micelles. A cellular uptake and cytotoxicity assay in vitro showed that the mixed micelles could efficiently accumulate in MCF-7 cells and suppress the growth of tumour cells. The proposed reduction-sensitive mixed micelles assembled from amphiphilic prodrugs can be used as a promising drug codelivery system for cancer therapy.
Intracellular trafficking of nuclear localization signal conjugated nanoparticles for cancer therapy
Misra, Ranjita,Sahoo, Sanjeeb K.
, p. 152 - 163 (2010)
Doxorubicin (DOX) is an anticancer drug with an intracellular site of action in the nucleus. For high antitumour activity, it should be effectively internalized into the cancer cells and accumulate in the nucleus. In this study, we have prepared a nuclear localization signal conjugated doxorubicin loaded Poly (d,l-lactide-co-glycolide) nanoparticles (NPs), to deliver doxorubicin to the nucleus efficiently. Physico-chemical characterization of these NPs showed that the drug is molecularly dispersed in spherical and smooth surfaced nanoparticles. NPs (~226 nm in diameter, 46% encapsulation efficiency) under in vitro conditions exhibited sustained release of the encapsulated drug (63% release in 60 days). Cell cytotoxicity results showed that NLS conjugated NPs exhibited comparatively lower IC50 value (2.3 μM/ml) than drug in solution (17.6 μM/ml) and unconjugated NPs (7.9 μM/ml) in breast cancer cell line MCF-7 as studied by MTT assay. Cellular uptake studies by confocal laser scanning microscopy (CLSM) and fluorescence spectrophotometer showed that greater amount of drug is targeted to the nucleus with NLS conjugated NPs as compared to drug in solution or unconjugated NPs. Flow cytometry experiments results showed that NLS conjugated NPs are showing greater cell cycle (G2/M phase) blocking and apoptosis than native DOX and unconjugated NPs. In conclusion, these results suggested that NLS conjugated doxorubicin loaded NPs could be potentially useful as novel drug delivery system for breast cancer therapy.
Small Molecule-Based Fluorescent Organic Nanoassemblies with Strong Hydrogen Bonding Networks for Fine Tuning and Monitoring Drug Delivery in Cancer Cells
Boucard, Joanna,Linot, Camille,Blondy, Thibaut,Nedellec, Steven,Hulin, Philippe,Blanquart, Christophe,Lartigue, Léna?c,Ishow, Eléna
, (2018)
Bright supramolecular fluorescent organic nanoassemblies (FONs), based on strongly polar red-emissive benzothiadiazole fluorophores containing acidic units, are fabricated to serve as theranostic tools with large colloidal stability in the absence of a polymer or surfactant. High architectural cohesion is ensured by the multiple hydrogen-bonding networks, reinforced by the dipolar and hydrophobic interactions developed between the dyes. Such interactions are harnessed to ensure high payload encapsulation and efficient trapping of hydrophobic and hydrogen-bonding drugs like doxorubicin, as shown by steady state and time-resolved measurements. Fine tuning of the drug release in cancer cells is achieved by adjusting the structure and combination of the fluorophore acidic units. Notably delayed drug delivery is observed by confocal microscopy compared to the entrance of hydrosoluble doxorubicin, demonstrating the absence of undesirable burst release outside the cells by using FONs. Since FON-constituting fluorophores exhibit a large emission shift from red to green when dissociating in contact with the lipid cellular content, drug delivery could advantageously be followed by dual-color spectral detection, independently of the drug staining potentiality.
Understanding of real alternative redox partner of Streptomyces peucetius DoxA: Prediction and validation using in silico and in vitro analyses
Rimal, Hemraj,Lee, Seung-Won,Lee, Joo-Ho,Oh, Tae-Jin
, p. 64 - 74 (2015)
Streptomyces peucetius ATCC27952 contains the cytochrome P450 monoxygenase DoxA that is responsible for the hydroxylation of daunorubicin into doxorubicin. Although S. peucetius ATCC27952 contains several potential redox partners, the most suitable endogenous electron-transport system is still unclear; therefore, we conducted a study of potential redox partners using Accelrys Discovery Studio 3.5. Recombinant DoxA along with its redox partners from S. peucetius FDX1, FDR2, and FDX3, and the putidaredoxin and putidaredoxin reductase from Pseudomonas putida that are essential equivalents of the class I type of bacterial electron-transport system were over-expressed and purified. The successful development of an efficient redox system was achieved by an in vitro enzymatic catalysis reaction with DoxA. The optimal pH for the activation of the heme was 7.6 and the optimal temperature was 30°C. Our findings suggest a two-fold increase of DoxA activity via the NADH → FDR2 → FDX1 → DoxA pathway for the hydroxylation of the daunorubicin, and indicate that the usage of a native redox partner may increase daunorubicin-derived doxorubicin production due to the inclusion of DoxA.
A Peptide-Based Supramolecular Hydrogel for Controlled Delivery of Amine Drugs
Wang, Youzhi,Zhang, Yiming,Li, Xinxin,Li, Can,Yang, Zhimou,Wang, Ling
, p. 3460 - 3463 (2018)
Supramolecular hydrogels hold great promise for controlled drug delivery. Herein we report a supramolecular hydrogel based on a peptide bearing a terminal aldehyde. The hydrogel was prepared via an enzyme instructed self-assembly (EISA) process, and the resulting hydrogels showed ultra-stable properties in highly acidic or basic aqueous solutions. The hydrogelator could form Schiff bases with amine drugs. Owing to the pH-responsive properties of Schiff bases, the hydrogels could be used for controlled release of encapsulated amine drugs. Our study provides a peptide-based hydrogel that may be applied for controlled drug delivery.
A novel doxorubicin prodrug with controllable photolysis activation for cancer chemotherapy
Ibsen, Stuart,Zahavy, Eran,Wrasdilo, Wolf,Berns, Michael,Chan, Michael,Esener, Sadik
, p. 1848 - 1860 (2010)
Purpose: Doxorubicin (DOX) is a very effective anticancer agent. However, in its pure form, its application is limited by significant cardiotoxic side effects. The purpose of this study was to develop a controllably activatable chemotherapy prodrug of DOX created by blocking its free amine group with a biotinylated photocleavable blocking group (PCB). Methods: An n-hydroxy succunamide protecting group on the PCB allowed selective binding at the DOX active amine group. The PCB included an ortho-nitrophenyl group for photo cleavability and a water-soluble glycol spacer arm ending in a biotin group for enhanced membrane interaction. Results: This novel DOX-PCB prodrug had a 200-fold decrease in cytotoxicity compared to free DOX and could release active DOX upon exposure to UV light at 350 nm. Unlike DOX, DOX-PCB stayed in the cell cytoplasm, did not enter the nucleus, and did not stain the exposed DNA during mitosis. Human liver microsome incubation with DOX-PCB indicated stability against liver metabolic breakdown. Conclusions: The development of the DOX-PCB prodrug demonstrates the possibility of using light as a method of prodrug activation in deep internal tissues without relying on inherent physical or biochemical differences between the tumor and healthy tissue for use as the trigger.
Conjugation with α-linolenic acid improves cancer cell uptake and cytotoxicity of doxorubicin
Huan, Meng-lei,Zhou, Si-yuan,Teng, Zeng-hui,Zhang, Bang-le,Liu, Xin-you,Wang, Jie-pin,Mei, Qi-bing
, p. 2579 - 2584 (2009)
The synthetic DOX-LNA conjugate was characterized by proton nuclear magnetic resonance and mass spectrometry. In addition, the purity of the conjugate was analyzed by reverse-phase high-performance liquid chromatography. The cellular uptake, intracellular distribution, and cytotoxicity of DOX-LNA were assessed by flow cytometry, fluorescence microscopy, liquid chromatography/electrospray ionization tandem mass spectrometry, and the tetrazolium dye assay using the in vitro cell models. The DOX-LNA conjugate showed substantially higher tumor-specific cytotoxicity compared with DOX. Crown Copyright
Redox-responsive polymer-drug conjugates based on doxorubicin and chitosan oligosaccharide- g -stearic acid for cancer therapy
Su, Yigang,Hu, Yingwen,Du, Yongzhong,Huang, Xuan,He, Jiabei,You, Jian,Yuan, Hong,Hu, Fuqiang
, p. 1193 - 1202 (2015)
Here, a biodegradable polymer-drug conjugate of doxorubicin (DOX) conjugated with a stearic acid-grafted chitosan oligosaccharide (CSO-SA) was synthesized via disulfide linkers. The obtained polymer-drug conjugate DOX-SS-CSO-SA could self-assemble into nanosized micelles in aqueous medium with a low critical micelle concentration. The size of the micelles was 62.8 nm with a narrow size distribution. In reducing environments, the DOX-SS-CSO-SA could rapidly disassemble result from the cleavage of the disulfide linkers and release the DOX. DOX-SS-CSO-SA had high efficiency for cellular uptake and rapidly released DOX in reductive intracellular environments. In vitro antitumor activity tests showed that the DOX-SS-CSO-SA had higher cytotoxicity against DOX-resistant cells than free DOX, with reversal ability up to 34.8-fold. DOX-SS-CSO-SA altered the drug distribution in vivo, which showed selectively accumulation in tumor and reduced nonspecific accumulation in hearts. In vivo antitumor studies demonstrated that DOX-SS-CSO-SA showed efficient suppression on tumor growth and relieved the DOX-induced cardiac injury. Therefore, DOX-SS-CSO-SA is a potential drug delivery system for safe and effective cancer therapy.
Hyaluronic acid ion-pairing nanoparticles for targeted tumor therapy
Li, Wenhao,Yi, Xiaoli,Liu, Xing,Zhang, Zhirong,Fu, Yao,Gong, Tao
, p. 170 - 182 (2016)
Hyaluronic acid (HA)-based doxorubicin (DOX) nanoparticles (HA-NPs) were fabricated via ion-pairing between positively charged DOX and negatively charged HA, which displayed near-spherical shapes with an average size distribution of 180.2 nm (PDI = 0.184). Next, HA-NPs were encapsulated in liposomal carriers to afford HA-based DOX liposomes (HA-LPs), which also showed near-spherical morphology with an average size of 130.5 nm (PDI = 0.201). HA-NPs and HA-LPs displayed desirable sustained-release profiles compared to free DOX, and moreover, HA-LPs were proven to prevent premature release of DOX from HA-NPs. Cell based studies demonstrated HA-NPs and HA-LPs were selectively taken up by CD44+ tumor cells, and DOX was released intracellularly to target the cell nuclei. Both HA-NPs and HA-LPs showed comparable levels of penetration efficiency in tumor spheroids. In vivo studies revealed that HA-NPs and HA-LPs significantly prolonged the blood circulation time of DOX, decreased accumulation in the normal tissues and enriched drugs into the tumors. Furthermore, HA-NPs and HA-LPs greatly enhanced therapeutic efficacy of DOX in tumor-bearing mice and minimized systemic toxicity against vital organs. In sum, HA-NPs and HA-LPs represent promising nanocarriers for CD44+ tumor-targeted delivery.
Stimulus-Responsive Short Peptide Nanogels for Controlled Intracellular Drug Release and for Overcoming Tumor Resistance
Lyu, Linna,Liu, Fang,Wang, Xiaoyong,Hu, Ming,Mu, Jing,Cheong, Haolun,Liu, Gang,Xing, Bengang
, p. 744 - 752 (2017)
Multidrug resistance (MDR) poses a major burden to cancer treatment. As one important factor contributing to MDR, overexpression of P-glycoprotein (P-gp) results in a reduced intracellular drug accumulation. Hence, the ability to effectively block the efflux protein and to accumulate the therapeutics in cancer cells is of great significance in clinical practice. In this work, we successfully developed a smart stimulus-responsive short peptide-assembled system, termed as PD/VER nanogels, which synergistically combined the acid-activatable antitumor prodrug doxorubicin (Dox) with the P-gp inhibitor verapamil (VER) for reversing MDR. Systematic studies demonstrated that such an inhibitor-encapsulated nanogel could effectively enhance the accumulation of Dox in resistant cancer cells, thereby revealing significantly higher antitumor activity compared to free Dox molecules. This work showed that the assembly of bioactive agents with a synergistic effect into nano-drugs could provide a useful strategy to overcome cancer drug resistance.
PH triggered doxorubicin delivery of PEGylated glycolipid conjugate micelles for tumor targeting therapy
Hu, Fu-Qiang,Zhang, Yin-Ying,You, Jian,Yuan, Hong,Du, Yong-Zhong
, p. 2469 - 2478 (2012)
The main objective of this study was aimed at tumor microenvironment- responsive vesicle for targeting delivery of the anticancer drug, doxorubicin (DOX). A glucolipid-like conjugate (CS) was synthesized by the chemical reaction between chitosan and stearic acid, and polyethylene glycol (PEG) was then conjugated with CS via a pH-responsive cis-aconityl linkage to produce acid-sensitive PEGylated CS conjugates (PCCS). The conjugates with a critical micelle concentration (CMC) of 181.8 μg/mL could form micelles in aqueous phase, and presented excellent DOX loading capacity with a drug encapsulation efficiency up to 87.6%. Moreover, the PCCS micelles showed a weakly acid-triggered PEG cleavage manner. In vitro drug release from DOX-loaded PCCS micelles indicated a relatively faster DOX release in weakly acidic environments (pH 5.0 and 6.5). The CS micelles had excellent cellular uptake ability, which could be significantly reduced by the PEGylation. However, the cellular uptake ability of PCCS was enhanced comparing with insensitive PEGylated CS (PCS) micelles in weakly acidic condition imitating tumor tissue. Taking PCS micelles as a comparative group, the PCCS drug delivery system was demonstrated to show much more accumulation in tumor tissue, followed by a relatively better performance in antitumor activity together with a security benefit on xenograft tumor model.
Synthesis, characterization, and in vitro and in vivo evaluation of a novel pectin-adriamycin conjugate
Tang, Xiao-Hai,Xie, Ping,Ding, Yi,Chu, Liang-Yin,Hou, Jing-Ping,Yang, Jin-Liang,Song, Xin,Xie, Yong-Mei
, p. 1599 - 1609 (2010)
Adriamycin (ADM) has been widely used in the treatment of many types of solid malignant tumor. However, cardiotoxicity, multidrug resistance and a short half-life in vivo are significant problems that limit its clinical application. To resolve these problems, a novel pectin-adriamycin conjugate (PAC) was synthesized by attaching ADM to low-methoxylated pectin via an amide linkage. The ADM content and weight-average molecular weight (Mw) of PAC were greater than 25% (w/w) and 50,360 g/mol, respectively. PAC was highly stable in plasma, but 33.2% of ADM was released from PAC after incubation for 30 h with lysosomes derived from rat liver. PAC was distributed uniformly in the cytoplasm of most A549 cells and accumulated in the nucleus of a few A549 cells after incubation for 30 h. At concentrations equivalent to 0.125-1.000 μg of ADM/mL, PAC did not inhibit the growth of either A594 or B16 cells to the same extent as free ADM or a mixture of ADM and pectin. Interestingly, at all concentrations, PAC inhibited the growth of 2780cp cells in vitro significantly more effectively than ADM or the mixture of ADM and pectin. The anticancer effect of PAC in vivo was evaluated with C57BL/6 mice bearing pulmonary metastases of B16 cells. Compared with ADM and the mixture of ADM and pectin, PAC suppressed tumor growth significantly and prolonged the mean survival time of the B16-inoculated mice. PAC has great potential for development as a tumor targeting polymer-drug.
Development of a theranostic prodrug for colon cancer therapy by combining ligand-targeted delivery and enzyme-stimulated activation
Sharma, Amit,Kim, Eun-Joong,Shi, Hu,Lee, Jin Yong,Chung, Bong Geun,Kim, Jong Seung
, p. 145 - 151 (2018)
The high incidence of colorectal cancer worldwide is currently a major health concern. Although conventional chemotherapy and surgery are effective to some extent, there is always a risk of relapse due to associated side effects, including post-surgical complications and non-discrimination between cancer and normal cells. In this study, we developed a small molecule-based theranostic system, Gal-Dox, which is preferentially taken up by colon cancer cells through receptor-mediated endocytosis. After cancer-specific activation, the active drug Dox (doxorubicin) is released with a fluorescence turn-on response, allowing both drug localization and site of action to be monitored. The therapeutic potency of Gal-Dox was also evaluated, both in vivo and ex vivo, thus illustrating the potential of Gal-Dox as a colorectal cancer theranostic with great specificity.
A triple-targeting delivery system carrying two anticancer agents
Lee, Chang-Hee,Li, Hui,Shin, Injae
supporting information, p. 8009 - 8013 (2021/10/04)
To improve tumor selectivity, a triple-targeting delivery system (Oct-FK(PBA-Az)-Dox) carrying two anticancer agents (apoptozole (Az) and doxorubicin (Dox)) was designed and synthesized. The results showed that both anticancer agents in Oct-FK(PBA-Az)-Dox are liberated in the presence of both H2O2and cathepsin B, which are normally present at high levels in tumors.
Switching on prodrugs using radiotherapy
Geng, Jin,Zhang, Yichuan,Gao, Quan,Neumann, Kevin,Dong, Hua,Porter, Hamish,Potter, Mark,Ren, Hua,Argyle, David,Bradley, Mark
, p. 805 - 810 (2021/06/14)
Chemotherapy is a powerful tool in the armoury against cancer, but it is fraught with problems due to its global systemic toxicity. Here we report the proof of concept of a chemistry-based strategy, whereby gamma/X-ray irradiation mediates the activation of a cancer prodrug, thereby enabling simultaneous chemo-radiotherapy with radiotherapy locally activating a prodrug. In an initial demonstration, we show the activation of a fluorescent probe using this approach. Expanding on this, we show how sulfonyl azide- and phenyl azide-caged prodrugs of pazopanib and doxorubicin can be liberated using clinically relevant doses of ionizing radiation. This strategy is different to conventional chemo-radiotherapy radiation, where chemo-sensitization of the cancer takes place so that subsequent radiotherapy is more effective. This approach could enable site-directed chemotherapy, rather than systemic chemotherapy, with ‘real time’ drug decaging at the tumour site. As such, it opens up a new era in targeted and directed chemotherapy. [Figure not available: see fulltext.].