- Codelivery of Doxorubicin and shAkt1 by Poly(ethylenimine)-Glycyrrhetinic Acid Nanoparticles to Induce Autophagy-Mediated Liver Cancer Combination Therapy
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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.
- Wang, Feng-Zhen,Xing, Lei,Tang, Zheng-Hai,Lu, Jin-Jian,Cui, Peng-Fei,Qiao, Jian-Bing,Jiang, Lei,Jiang, Hu-Lin,Zong, Li
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- On-Demand Cascade Release of Hydrophobic Chemotherapeutics from a Multicomponent Hydrogel System
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A multicomponent hydrogel drug-delivery platform with covalent incorporation of core-cross-linked star (CCS) polymers has been fabricated through dual cross-linking reactions. The presence of amphiphilic CCS polymers enhances the mechanical stability of the network and allows for immobilization of hydrophobic chemotherapeutics (e.g., doxorubicin: DOX) within a hydrophilic matrix. Thanks to thiol-responsive disulfide segments, the hybrid network is selectively degradable upon exposure to the glutathione-rich tumor environment, leading to an on-demand cascade release of payloads in a prolonged manner. After network degradation, the integrity of the therapeutic cargos is still well-protected by the CCS polymeric carriers. A cellular study demonstrated efficient internalization of released drug-containing CCS polymers by HeLa cells, intracellular delivery of encapsulated drugs following pH-mediated erosion of the CCS containers, and excellent cytocompatibility of this hydrogel system.
- Gu, Dunyin,Tan, Shereen,O'Connor, Andrea J.,Qiao, Greg G.
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- Reduction-sensitive mixed micelles assembled from amphiphilic prodrugs for self-codelivery of DOX and DTX with synergistic cancer therapy
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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.
- Wu, Jilian,Zhang, Huiyuan,Hu, Xu,Liu, Ruiling,Jiang, Wei,Li, Zhonghao,Luan, Yuxia
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- Cephalosporin Derivatives of Doxorubicin as Prodrugs for Activation by Monoclonal Antibody-β-Lactamase Conjugates
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The synthesis of a series of cephalosporin doxorubicin derivatives that differ with respect to the substituent at position 7 of the cephem nucleus is described.These compounds are designed as prodrugs of doxorubicin for activation by monoclonal antibody-β-lactamase conjugates.The key step in the synthesis of this series of compounds involves the use of the phenylacetamido group as an enzymatically removable protecting group for the 7-amino group on the cephem.In vitro cytotoxicity assays with H2981 lung adenocarcinoma cells revealed that cephalosporin doxorubicin derivatives were all less toxic than the released drug.Prodrugs containing negatively charged groups in the side chain, such as the δ-carboxybutanamido derivative 4 and the α-sulfophenylacetyl derivative 5, displayed the least cytotoxic activity and were 46- and 26-fold less toxic than doxorubicin, respectively.The efficiency of activation of all the prodrugs was evaluated in cytotoxicity assays on H2981 cells with the β-lactamases from Enterobacter cloacae P99, Escherichia coli TEM-1, and Bacillus cereus (type II).In general, the E. cloacae enzyme was found to most rapidly activate the majority of these prodrugs.Phenylacetamido prodrug 2 and δ-carboxybutanamido prodrug 4 were both activated in an immunospecific manner by L6-E. cloacae β-lactamase, a monoclonal antibody conjugate that binds to receptore on H2981 lung adenocarcinoma cells.
- Vrudhula, Vivekananda M.,Svensson, Hakan P.,Senter, Peter D.
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- Intracellular trafficking of nuclear localization signal conjugated nanoparticles for cancer therapy
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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.
- Misra, Ranjita,Sahoo, Sanjeeb K.
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- Lipid nanoemulsions loaded with doxorubicin-oleic acid ionic complex: Characterization, in vitro and in vivo studies
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This study aimed at developing a novel lipid nanoemulsion formulation of doxorubicin (DOX) which is feasible for scale-up production, exhibits good parenteral acceptability, and further improves the therapeutic index of the drug. Oleic acid was used to form ionic complex with DOX in order to enhance its lipophilicity. The lipid nanoemulsions loaded with doxorubicin-oleic acid complex (DOX-OA-LNs) were prepared using a simple high-pressure homogenization method and fully characterized from physicochemical and in vitro release standpoint. Afterwards, the DOX-OA-LNs and free DOX were compared with respect to their in vitro cellular uptake and cytotoxicity, and their in vivo pharmacokinetics and biodistribution behavior in mice were also investigated. The obtained DOX-OA-LNs could achieve high encapsulation efficiency of 93.7±1.2% under optimal conditions. The in vitro release behavior displayed biphasic drug release pattern with rapid release at the initial stage and prolonged release afterwards. The DOX-OA-LNs exhibited higher growth inhibitory effect than free DOX by MTT assay. Flow cytometry and confocal microscopy studies showed that the cellular uptake of free DOX and DOX-OA-LNs were comparable. Pharmacokinetics and in vivo distribution studies in mice showed that DOX-OA-LNs demonstrated significantly higher DOX level in blood and longer circulation time than free DOX. Moreover, DOX-OA-LNs significantly decreased DOX concentration in heart, lung and kidney. These results suggested that DOX-OA-LNs could be a promising formulation for the delivery of DOX in tumor chemotherapy.
- Zhang, Xuanmiao,Sun, Xun,Li, Jilong,Zhang, Xiaoning,Gong, Tao,Zhang, Zhirong
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- Small Molecule-Based Fluorescent Organic Nanoassemblies with Strong Hydrogen Bonding Networks for Fine Tuning and Monitoring Drug Delivery in Cancer Cells
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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.
- Boucard, Joanna,Linot, Camille,Blondy, Thibaut,Nedellec, Steven,Hulin, Philippe,Blanquart, Christophe,Lartigue, Léna?c,Ishow, Eléna
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- Indomethacin-guided cancer selective prodrug conjugate activated by histone deacetylase and tumour-associated protease
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An indomethacin-guided drug delivery conjugate (IGDDC) has been designed by utilizing cancer associated elevated HDAC and CTSL activities as consecutive demasking ventures for drug activation. IGDDC exhibited preferential uptake by COX-2 positive cells bo
- Jang, Joo Hee,Lee, Hoyeon,Sharma, Amit,Lee, Sang Min,Lee, Tae Hoon,Kang, Chulhun,Kim, Jong Seung
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- Understanding of real alternative redox partner of Streptomyces peucetius DoxA: Prediction and validation using in silico and in vitro analyses
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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.
- Rimal, Hemraj,Lee, Seung-Won,Lee, Joo-Ho,Oh, Tae-Jin
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- Doxazolidine, a proposed active metabolite of doxorubicin that cross-links DNA
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A crystal structure establishes doxoform as a dimeric formaldehyde conjugate of the oxazolidine of doxorubicin. Doxoform is a prodrug of doxazolidine, a monomeric doxorubicin formaldehyde-oxazolidine. Both doxoform and doxazolidine inhibit the growth of cancer cells at 1-4 orders of magnitude lower concentration than doxorubicin. They also inhibit the growth of cancer cells better than doxsaliform, a prodrug for an acyclic doxorubicin-formaldehyde conjugate. Doxoform rapidly hydrolyzes to doxazolidine, which then hydrolyzes to doxorubicin with a half-life of 3 min in human serum at 37 °C. Both doxoform and doxazolidine are taken up by multidrug-resistant MCF-7/Adr cells 3- to 4-fold better than doxorubicin. A molecular model suggests that doxazolidine can cross-link DNA by direct reaction with a G-base in a tautomeric form with synchronous ring opening of the oxazolidine. These results point to doxoform being a prodrug for doxazolidine that is the reactive species that directly cross-links DNA.
- Post, Glen C.,Barthel, Benjamin L.,Burkhart, David J.,Hagadorn, John R.,Koch, Tad H.
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- A Peptide-Based Supramolecular Hydrogel for Controlled Delivery of Amine Drugs
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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.
- Wang, Youzhi,Zhang, Yiming,Li, Xinxin,Li, Can,Yang, Zhimou,Wang, Ling
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- Multistimuli-responsive supramolecular vesicles based on water-soluble pillar[6]arene and SAINT complexation for controllable drug release
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Supramolecular binary vesicles based on the host-guest complexation of water-soluble pillar[6]arene (WP6) and SAINT molecule have been successfully constructed, which showed pH-, Ca2+-, and thermal-responsiveness. These supramolecular vesicles can efficiently encapsulate model substrate calcein, which then can be efficiently released either by adjusting the solution pH to acidic condition due to the complete disruption of vesicular structure, or particularly, by adding a certain amount of Ca2+ due to the Ca2+-induced vesicle fusion and accompanied by the structure disruption. More importantly, drug loading and releasing experiments demonstrate that an anticancer drug, DOX, can be successfully encapsulated by the supramolecular vesicles, and the resulting DOX-loaded vesicles exhibit efficient release of the encapsulated DOX with the pH adjustment or the introduction of Ca2+. Cytotoxicity experiments suggest that the resulting DOX-loaded supramolecular vesicles exhibit comparable therapeutic effect for cancer cells as free DOX and the remarkably reduced damage for normal cells as well. The present multistimuli-responsive supramolecular vesicles have great potential applications in the field of controlled drug delivery. In addition, giant supramolecular vesicles (～3 μm) with large internal volume and good stability can be achieved by increasing the temperature of WP6 ? SAINT vesicular solution, and they might have potential applications for bioimaging.
- Cao, Yu,Hu, Xiao-Yu,Li, Yan,Zou, Xiaochun,Xiong, Shuhan,Lin, Chen,Shen, Ying-Zhong,Wang, Leyong
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- A novel doxorubicin prodrug with controllable photolysis activation for cancer chemotherapy
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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.
- Ibsen, Stuart,Zahavy, Eran,Wrasdilo, Wolf,Berns, Michael,Chan, Michael,Esener, Sadik
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- Vinylboronic acid-caged prodrug activation using click-to-release tetrazine ligation
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Bioorthogonal reactions can be performed selectively in the presence of any biological functional group and are widely used to achieve site-selective chemical modifications of biomolecules. The click-to-release reaction is a bioorthogonal bond-cleavage variant that has gained much interest over the last few years. The bioorthogonal reaction between tetrazines and trans-cyclooctenes or vinyl ethers, for example, initiates the release of a small molecule immediately after the cycloaddition with tetrazines. Recently, our group reported that vinylboronic acids (VBAs) give exceptionally high reaction rates in the bioorthogonal inverse electron-demand Diels-Alder reaction with tetrazines that are substituted with boron-coordinating ligands. In the present study, we show that VBAs can be used in a click-to-release variant and demonstrate its bioorthogonality with a VBA-protected doxorubicin prodrug. We show that the cytotoxicity of doxorubicin is silenced by the attachment of the VBA, and activity can be largely restored upon the reaction with a tetrazine, inducing cell death.
- Lelieveldt, Lianne P.W.M.,Eising, Selma,Wijen, Abel,Bonger, Kimberly M.
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- Conjugation with α-linolenic acid improves cancer cell uptake and cytotoxicity of doxorubicin
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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
- Huan, Meng-lei,Zhou, Si-yuan,Teng, Zeng-hui,Zhang, Bang-le,Liu, Xin-you,Wang, Jie-pin,Mei, Qi-bing
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- A prodrug nanoassembly entrapping drugs as a tumor-targeted delivery system
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We presented here a targeted drug delivery system, biotinylated polyethylene glycol prodrug loading with free drugs (doxorubicin or camptothecin), which showed high drug loading capacity and superior targeted therapeutic efficacy for cancerous cells.
- Yuan, Zhefan,Yi, Xiaoqing,Zhang, Jing,Cheng, Sixue,Zhuo, Renxi,Li, Feng
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- Redox-responsive polymer-drug conjugates based on doxorubicin and chitosan oligosaccharide- g -stearic acid for cancer therapy
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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.
- Su, Yigang,Hu, Yingwen,Du, Yongzhong,Huang, Xuan,He, Jiabei,You, Jian,Yuan, Hong,Hu, Fuqiang
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- Localized in vivo activation of a photoactivatable doxorubicin prodrug in deep tumor tissue
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Sparing sensitive healthy tissue from chemotherapy exposure is a critical challenge in the treatment of cancer. The work described here demonstrates the localized in vivo photoactivation of a new chemotherapy prodrug of doxorubicin (DOX). The DOX prodrug (DOX-PCB) was 200 times less toxic than DOX and was designed to release pure DOX when exposed to 365 nm light. This wavelength was chosen because it had good tissue penetration through a 1 cm diameter tumor, but had very low skin penetration, due to melanin absorption, preventing uncontrolled activation from outside sources. The light was delivered specifically to the tumor tissue using a specialized fiber-optic LED system. Pharmacokinetic studies showed that DOX-PCB had an α circulation half-life of 10 min which was comparable to that of DOX at 20 min. DOX-PCB demonstrated resistance to metabolic cleavage ensuring that exposure to 365 nm light was the main mode of in vivo activation. Tissue extractions from tumors exposed to 365 nm light in vivo showed the presence of DOX-PCB as well as activated DOX. The exposed tumors had six times more DOX concentration than nearby unexposed control tumors. This in vivo proof of concept demonstrates the first preferential activation of a photocleavable prodrug in deep tumor tissue.
- Ibsen, Stuart,Zahavy, Eran,Wrasidlo, Wolf,Hayashi, Tomoko,Norton, John,Su, Yongxuan,Adams, Stephen,Esener, Sadik
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- Hyaluronic acid ion-pairing nanoparticles for targeted tumor therapy
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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.
- Li, Wenhao,Yi, Xiaoli,Liu, Xing,Zhang, Zhirong,Fu, Yao,Gong, Tao
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- The use of new quinazolinone derivative and doxorubicin loaded solid lipid nanoparticles in reversing drug resistance in experimental cancer cell lines: A systematic study
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The aim of this research is to study the feasibility of using carnauba wax as a new carrier for anticancer agents to deliver doxorubicin (DOX) as a model drug and a novel quinazolinone derivative (QZO-DER) to different types of normal and resistant cancer cell lines. A Box-Behnken design was implemented to investigate the influence of high melting point carnauba wax stabilized with cell membrane lipid (lecithin) and non-ionic biocompatible surfactant (span 60) in different concentration on particle size, entrapment efficiency of each drug and percent drug release. The solid lipid nanoparticles (SLNPs) were produced via the hot-melting homogenization technique. SLNPS particle size was from 16.58 ± 4 to 72.45 ± 1.21 nm and from 7.93 ± 1.67 to 174.31 ± 4.86 nm for DOX and QZO-DER respectively. Entrapment efficiency was from 51.78 ± 1.68% to 92.52 ± 2.47% and from 50.21 ± 1.8 to 82.95 ± 3.56% for DOX and QZO-DER respectively. While the percentage of release after 36 h was from 29.28 ± 3.89% to 78.08 ± 3.78% and from 37.5 ± 1.09 to 100 ± 1.25% for DOX and QZO-DER respectively. Selected formulations for DOX (OFX1 and OFX4) and QZO-DER (OFR4 and OFR6) were generated after validation of design. The in vitro anticancer activity was tested against both a panel of wild type and DOX-resistant human cancer cell lines. Cancer cell lines included colorectal cancer (HCT-116), breast cancer (MCF-7 and MDA-231), and lung adenocarcinoma (A549). Most of the tested SLNPs improved the efficacy of QZO-DER and DOX against the different cancer cell lines and have extended the spectrum to cover those accruing resistance during chemotherapy. QZO-DER loaded SLNPs exhibited the highest ability to reverse the drug resistance of MDA-231 cells compared to MDA-231/ADR cells was 19.7-fold, while DOX loaded SLNPs that showed reversal power was 1.8 fold for the same cells. Additionally, SLNPs showed a broad safety margin in normal cells. This study presented the use of SLNPs with carnauba wax as a potential therapeutic strategy to improve anticancer activity and overcome cancer resistance for clinical use.
- Abou Taleb, Heba A.,El-Menshawe, Shahira F.,Omar, Hany A.,Saweris, Mina A.,Sayed, Ossama M.,Zaher, Dana M.
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- Stimulus-Responsive Short Peptide Nanogels for Controlled Intracellular Drug Release and for Overcoming Tumor Resistance
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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.
- Lyu, Linna,Liu, Fang,Wang, Xiaoyong,Hu, Ming,Mu, Jing,Cheong, Haolun,Liu, Gang,Xing, Bengang
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- A light-responsive, self-immolative linker for controlled drug delivery: Via peptide- and protein-drug conjugates
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When designing prodrugs, choosing an appropriate linker is the key to achieving efficient, controlled drug delivery. Herein, we report the use of a photocaged C4′-oxidized abasic site (PC4AP) as a light-responsive, self-immolative linker. Any amine- or hydroxyl-bearing drug can be loaded onto the linker via a carbamate or carbonate bond, and the linker is then conjugated to a carrier peptide or protein via an alkyl chain. The PC4AP linker is stable under physiologically relevant conditions. However, photodecaging of the linker generates an active intermediate that reacts intramolecularly with a primary amine (the ?-amine of a lysine residue and the N-terminal amine) on the carrier, leading to rapid and efficient release of the drug via an addition-elimination cascade, without generating any toxic side products. We demonstrated that the use of this self-immolative linker to conjugate the anticancer drug doxorubicin to a cell-penetrating peptide or an antibody enabled targeted, controlled delivery of the drug to cells. Our results suggest that the linker can be used with a broad range of carriers, such as cell-penetrating peptides, proteins, antibodies, and amine-functionalized polymers, and thus will find a wide range of practical applications.
- Zang, Chuanlong,Wang, Huawei,Li, Tiantian,Zhang, Yingqian,Li, Jiahui,Shang, Mengdi,Du, Juanjuan,Xi, Zhen,Zhou, Chuanzheng
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- PH triggered doxorubicin delivery of PEGylated glycolipid conjugate micelles for tumor targeting therapy
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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.
- Hu, Fu-Qiang,Zhang, Yin-Ying,You, Jian,Yuan, Hong,Du, Yong-Zhong
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- A thioether-directed palladium-cleavable linker for targeted bioorthogonal drug decaging
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We describe the development of a bifunctional linker that simultaneously allows site-specific protein modification and palladium-mediated bioorthogonal decaging. This was enabled by a thioether binding motif in the propargyl carbamate linker and a readily available palladium complex. We demonstrate the efficiency of this reaction by controlled drug release from a PEGylated doxorubicin prodrug in cancer cells. The linker can be easily installed into cysteine bearing proteins which we demonstrated for the construction of an anti-HER2 nanobody-drug conjugate. Targeted delivery of the nanobody drug conjugate showed effective cell killing in HER2+ cells upon palladium-mediated decaging.
- Stenton, Benjamin J.,Oliveira, Bruno L.,Matos, Maria J.,Sinatra, Laura,Bernardes, Gon?alo J. L.
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- Synthesis, characterization, and in vitro and in vivo evaluation of a novel pectin-adriamycin conjugate
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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.
- Tang, Xiao-Hai,Xie, Ping,Ding, Yi,Chu, Liang-Yin,Hou, Jing-Ping,Yang, Jin-Liang,Song, Xin,Xie, Yong-Mei
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- Impairment of myocardial contractility by anticancer anthracyclines: Role of secondary alcohol metabolites and evidence of reduced toxicity by a novel disaccharide analogue
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1 The anticancer anthracycline doxorubicin (DOX) causes cardiotoxicity. Enzymatic reduction of a side chain carbonyl group converts DOX to a secondary alcohol metabolite that has been implicated in cardiotoxicity. We therefore monitored negative inotropism, assessed as inhibition of post-rest contractions, in rat right ventricle strips exposed to DOX or to analogues forming fewer amounts of their alcohol metabolites (epirubicin, EPI, and the novel disaccharide anthracycline Men 10755). 2 Thirty μM EPI exhibited higher uptake than equimolar DOX, but formed comparable amounts of alcohol metabolite due to its resistance to carbonyl reduction. MEN 10755 exhibited also an impaired uptake, and consequently formed the lowest levels of alcohol metabolite. Accordingly, DOX and EPI inhibited post-rest contractions by ～40-50%, whereas MEN 10755 inhibited by ～6%. 3 One hundred μM EPI exhibited the same uptake as equimolar DOX, but formed ～50% less alcohol metabolite. One hundred μM MEN 10755 still exhibited the lowest uptake, forming ～60% less alcohol metabolite than EPI. Under these conditions DOX inhibited post-rest contractions by 88%. EPI and MEN 10755 were ～18% (P0.05) or ～80% (P0.001) less inhibitory than DOX, respectively. 4 The negative inotropism of 30-100 μM DOX, EPI, or MEN 10755 correlated with cellular levels of both alcohol metabolites (r=0.88, P0.0001) and carbonyl anthracyclines (r=0.79, P0.0001). Nonetheless, multiple comparisons showed that alcohol metabolites were ～20-40 times more effective than carbonyl anthracyclines in inhibiting contractility. The negative inotropism of MEN 10755 was therefore increased by chemical procedures, like side chain valeryl esterification, that facilitated its uptake and conversion to alcohol metabolite but not its retention in a carbonyl form. 5 These results demonstrate that secondary alcohol metabolites are important mediators of cardiotoxicity. A combination of reduced uptake and limited conversion to alcohol metabolite formation might therefore render MEN 10755 more cardiac tolerable than DOX and EPI.
- Minotti, Giorgio,Parlani, Massimo,Salvatorelli, Emanuela,Menna, Pierantonio,Cipollone, Amalia,Animati, Fabio,Maggi, Carlo A.,Manzini, Stefano
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- Development of a theranostic prodrug for colon cancer therapy by combining ligand-targeted delivery and enzyme-stimulated activation
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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.
- Sharma, Amit,Kim, Eun-Joong,Shi, Hu,Lee, Jin Yong,Chung, Bong Geun,Kim, Jong Seung
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Read Online
- Iridium-Triggered Allylcarbamate Uncaging in Living Cells
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Designing a metal catalyst that addresses the major issues of solubility, stability, toxicity, cell uptake, and reactivity within complex biological milieu for bioorthogonal controlled transformation reactions is a highly formidable challenge. Herein, we report an organoiridium complex that is nontoxic and capable of the uncaging of allyloxycarbonyl-protected amines under biologically relevant conditions and within living cells. The potential applications of this uncaging chemistry have been demonstrated by the generation of diagnostic and therapeutic agents upon the activation of profluorophore and prodrug in a controlled fashion within HeLa cells, providing a valuable tool for numerous potential biological and therapeutic applications.
- Gupta, Ajay,Gupta, Shalini,Mahawar, Pritam,Prasad, Puja,Sasmal, Pijus K.,Singh, Neelu
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p. 12644 - 12650
(2021/09/06)
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- A triple-targeting delivery system carrying two anticancer agents
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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.
- Lee, Chang-Hee,Li, Hui,Shin, Injae
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supporting information
p. 8009 - 8013
(2021/10/04)
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- REVERSING THE UNDESIRABLE pH-PROFILE OF DOXORUBICIN VIA ACTIVATION OF A DISUBSTITUTED MALEAMIC ACID PRODRUG AT TUMOR ACIDITY
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A pre-prodrug, comprising a drug, e.g., doxorubicin, which has off-target toxicity (e.g., cardiotoxicity) with respect to its antineoplastic activity, and an amine functionality of the drug incorporated into a disubstituted maleimide (DMI). The pre-prodrug may be linked to a targeting or de-targeting agent or a polar modulator, e.g., charged ligand, amino acid, peptide, etc., to increase therapeutic index. The pre-prodrug is hydrolyzed to the prodrug, having a disubstituted maleamic acid (DMA). A polar modulator such as glutamic acid prevents cellular uptake of the prodrug, but not the doxorubicin drug released from the prodrug after dissociation. The prodrug is pH sensitive, and below pH 7.0, tends to cleave to form free drug and cyclized maleic anhydride. Tumor environments tend to be more acidic, e.g., pH 6.8, than cardiac tissue, e.g., pH 7.4, and therefore the heart is spared while the drug is selectively released within a tumor.
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Paragraph 0165; 0267; 0272-0277; 0352; 0354-0356
(2021/05/07)
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- Switching on prodrugs using radiotherapy
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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.].
- Geng, Jin,Zhang, Yichuan,Gao, Quan,Neumann, Kevin,Dong, Hua,Porter, Hamish,Potter, Mark,Ren, Hua,Argyle, David,Bradley, Mark
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p. 805 - 810
(2021/06/14)
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- Photoactivatable Prodrug of Doxazolidine Targeting Exosomes
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Natural lipid nanocarriers, exosomes, carry cell-signaling materials such as DNA and RNA for intercellular communications. Exosomes derived from cancer cells contribute to the progression and metastasis of cancer cells by transferring oncogenic signaling molecules to neighboring and remote premetastatic sites. Therefore, applying the unique properties of exosomes for cancer therapy has been expected in science, medicine, and drug discovery fields. Herein, we report that an exosome-targeting prodrug system, designated MARCKS-ED-photodoxaz, could spatiotemporally control the activation of an exquisitely cytotoxic agent, doxazolidine (doxaz), with UV light. The MARCKS-ED peptide enters a cell by forming a complex with the exosomes in situ at its plasma membrane and in the media. MARCKS-ED-photodoxaz releases doxaz under near-UV irradiation to inhibit cell growth with low nanomolar IC50 values. The MARCKS-ED-photodoxaz system targeting exosomes and utilizing photochemistry will potentially provide a new approach for the treatment of cancer, especially for highly progressive and invasive metastatic cancers.
- Tamura, Ryo,Balabanova, Alla,Frakes, Samuel A.,Bargmann, Austin,Grimm, Jan,Koch, Tad H.,Yin, Hang
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p. 1959 - 1970
(2019/02/26)
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- Stabilizing p-Dithiobenzyl Urethane Linkers without Rate-Limiting Self-Immolation for Traceless Drug Release
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Exploiting the redox sensitivity of disulfide bonds is a prevalent strategy in targeted prodrug designs. In contrast to aliphatic disulfides, p-thiobenzyl-based disulfides have rarely been used for prodrug designs, given their intrinsic instability caused by the low pKa of aromatic thiols. Here, we examined the interplay between steric hindrance and the low-pKa effect on thiol–disulfide exchange reactions and uncovered a new thiol–disulfide exchange process for the self-immolation of p-thiobenzyl-based disulfides. We observed a central leaving group shifting effect in the α,α-dimethyl-substituted p-dithiobenzyl urethane linkers (DMTB linkers), which leads to increased disulfide stability by more than two orders of magnitude, an extent that is significantly greater than that observed with typical aliphatic disulfides. In particular, the DMTB linkers display not only high stability, but also rapid self-immolation kinetics due to the low pKa of the aromatic thiol, which can be used as a general and robust linkage between targeting reagents and cytotoxic drugs for targeted prodrug designs. The unique and promising stability characteristics of the present DMTB linker will likely inspire the development of novel targeted prodrugs to achieve traceless release of drugs into cells.
- Zheng, Yiwu,Shen, Yang,Meng, Xiaoting,Wu, Yaqi,Zhao, Yibing,Wu, Chuanliu
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p. 1196 - 1203
(2019/05/28)
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- ENRICHMENT-TRIGGERED CHEMICAL DELIVERY SYSTEM
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Disclosed herein is a chemical delivery system having: i) a cargo compound comprising a first reactive moiety covalently bonded to a first enrichment moiety and a tethered cargo moiety, wherein the first reactive moiety is bonded to the tethered cargo moiety via a cleavable linker; and ii) a trigger compound comprising a second reactive moiety covalently bonded to a second enrichment moiety and a cargo-releasing moiety. The first enrichment moiety and the second enrichment moiety cause an increase in concentration of the cargo compound and the concentration of the trigger compound at a target site, causing a bimolecular reaction between the first reactive moiety and the second reactive moiety to form a cyclization precursor compound. The cargo moiety is then released from the cyclization precursor compound in a unimolecular cyclization reaction. Methods for treating conditions such as cancer, inflammatory conditions, and infections with the chemical delivery systems are also described.
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Paragraph 0179-0186
(2019/05/15)
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- Thiourea Modified Doxorubicin: A Perspective pH-Sensitive Prodrug
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A novel approach to the synthesis of pH-sensitive prodrugs has been proposed: thiourea drug modification. Resulting prodrugs can release the cytotoxic agent and the biologically active 2-thiohydantoin in the acidic environment of tumor cells. The concept of acid-catalyzed cyclization of thioureas to 2-thiohydantoins has been proven using a FRET model. Dual prodrugs of model azidothymidine, cytotoxic doxorubicin, and 2-thiohydantoin albutoin were obtained, which release the corresponding drugs in the acidic environment. The resulting doxorubicin prodrug was tested on prostate cancer cells and showed that the thiourea-modified prodrug is less cytotoxic (average IC50 ranging from 0.5584 to 0.9885 μM) than doxorubicin (IC50 ranging from 0.01258 to 0.02559 μM) in neutral pH 7.6 and has similar toxicity (average IC50 ranging from 0.4970 to 0.7994 μM) to doxorubicin (IC50 ranging from 0.2303 to 0.8110 μM) under mildly acidic conditions of cancer cells. Cellular and nuclear accumulation in PC3 tumor cells of Dox prodrug is much higher than accumulation of free doxorubicin.
- Krasnovskaya, Olga O.,Malinnikov, Vladislav M.,Dashkova, Natalia S.,Gerasimov, Vasily M.,Grishina, Irina V.,Kireev, Igor I.,Lavrushkina, Svetlana V.,Panchenko, Pavel A.,Zakharko, Marina A.,Ignatov, Pavel A.,Fedorova, Olga A.,Jonusauskas, Gediminas,Skvortsov, Dmitry A.,Kovalev, Sergey S.,Beloglazkina, Elena K.,Zyk, Nikolay V.,Majouga, Alexander G.
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p. 741 - 750
(2019/03/02)
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- High Drug Loading and Sub-Quantitative Loading Efficiency of Polymeric Micelles Driven by Donor-Receptor Coordination Interactions
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Polymeric micelles are extensively used for the delivery of hydrophobic drugs, which, however, suffer from unsatisfactory drug loading, colloidal uniformity, formulation stability, and drug release. Herein, we demonstrate a convenient strategy to prepare micelles with ultrahigh drug loading via the incorporation of polymer-drug coordination interactions. An amphiphilic copolymer containing pendant phenylboronic acid as electron acceptor unit was synthesized, which afforded donor-acceptor coordination with doxorubicin to obtain micelles with ultrahigh drug loading (～50%), nearly quantitative loading efficiency (>95%), uniform size, and colloidal stability. Besides, the encapsulated drug can be effectively and selectively released in response to the high reactive oxygen species levels in cancer cells, which potentiated the anticancer efficacy and reduced systemic toxicity. Apart from doxorubicin, the current platform could be extended to other drugs with electron-donating groups (e.g., epirubicin and irinotecan), rendering a simple and robust strategy for enabling high drug loading in polymeric micelles and cancer-specific drug release.
- Lv, Shixian,Wu, Yuchen,Cai, Kaimin,He, Hua,Li, Yongjuan,Lan, Min,Chen, Xuesi,Cheng, Jianjun,Yin, Lichen
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p. 1235 - 1238
(2018/02/09)
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- A unimolecular theranostic system with H2O2-specific response and AIE-activity for doxorubicin releasing and real-time tracking in living cells
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A theranostic drug delivery system composed of tetraphenyl-ethene (AIEgen), benzyl boronic ester (trigger), and doxorubicin (drug) was designed and synthesized; its utilities for cell imaging, drug delivery tracking, and cancer cell cytociding were evalua
- Gao, Xiaoying,Cao, Jie,Song, Yinuo,Shu, Xiao,Liu, Jianzhao,Sun, Jing Zhi,Liu, Bin,Tang, Ben Zhong
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p. 10975 - 10979
(2018/03/26)
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- P-Sulfocalix[6]arene as Nanocarrier for Controlled Delivery of Doxorubicin
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Given the high toxicity of the anthracycline antibiotic doxorubicin (DOX), it is relevant to search for nanocarriers that decrease the side effects of the drug and are able to transport it towards a therapeutic target Here, the encapsulation of DOX by p-sulfocalix[6]arene (calix) has been studied. The interaction of DOX with the macrocycle, as well as with DNA, has been investigated and the equilibrium constant for each binding process estimated. The results showed that the binding constant of DOX to DNA, KDNA, is three orders of magnitude higher than that to calix, Kcalix. The ability of calixarenes to encapsulate DOX molecules, as well as the capability of the DOX molecules included into the inner cavity of the macrocycle to bind with DNA have been examined. Cytotoxicity measurements were done in different cancer and normal cell lines to probe the decrease in the toxicity of the encapsulated DOX. The low toxicity of calixarenes has also been demonstrated for different cell lines.
- Ostos, Francisco J.,Lebrón, José A.,Moyá, Maria L.,López-López, Manuel,Sánchez, Antonio,Clavero, Amparo,García-Calderón, Clara B.,Rosado, Iván V.,López-Cornejo, Pilar
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p. 679 - 689
(2017/03/22)
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- Mechanistically elucidating the in vitro safety and efficacy of a novel doxorubicin derivative
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Doxorubicin is an effective anticancer drug; however, it is cardiotoxic and has poor oral bioavazilability. Quercetin is a plant-based flavonoid with inhibitory effects on P-glycoprotein (P-gp) and CYP3A4 and also antioxidant properties. To mitigate these therapeutic barriers, DoxQ, a novel derivative of doxorubicin, was synthesized by conjugating quercetin to doxorubicin. The purpose of this study is to mechanistically elucidate the in vitro safety and efficacy of DoxQ. Drug release in vitro and cellular uptake by multidrug-resistant canine kidney (MDCK-MDR) cells were quantified by HPLC. Antioxidant activity, CYP3A4 inhibition, and P-gp inhibitory effects were examined using commercial assay kits. Drug potency was assessed utilizing triple-negative murine breast cancer cells, and cardiotoxicity was assessed utilizing adult rat and human cardiomyocytes (RL-14). Levels of reactive oxygen species and gene expression of cardiotoxicity markers, oxidative stress markers, and CYP1B1 were determined in RL-14. DoxQ was less cytotoxic to both rat and human cardiomyocytes and retained anticancer activity. Levels of ROS and markers of oxidative stress demonstrate lower oxidative damage induced by DoxQ compared to doxorubicin. DoxQ also inhibited the expression and catalytic activity of CYP1B1. Additionally, DoxQ inhibited CYP3A4 and demonstrated higher cellular uptake by MDCK-MDR cells than doxorubicin. DoxQ provides a novel therapeutic approach to mitigate the cardiotoxicity and poor oral bioavailability of doxorubicin. The cardioprotective mechanism of DoxQ likely involves scavenging ROS and CYP1B1 inhibition, while the mechanism of improving the poor oral bioavailability of doxorubicin is likely related to inhibiting CYP3A4 and P-gp.
- Alrushaid, Samaa,Zhao, Yunqi,Sayre, Casey L.,Maayah, Zaid H.,Laird Forrest,Senadheera, Sanjeewa N.,Chaboyer, Kevin,Anderson, Hope D.,El-Kadi, Ayman O. S.,Davies, Neal M.
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p. 582 - 597
(2017/07/27)
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- Modular Integration of Upconverting Nanocrystal-Dendrimer Composites for Folate Receptor-Specific NIR Imaging and Light-Triggered Drug Release
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Upconversion nanocrystals (UCNs) display near-infrared (NIR)-responsive photoluminescent properties for NIR imaging and drug delivery. The development of effective strategies for UCN integration with other complementary nanostructures for targeting and drug conjugation is highly desirable. This study reports on a core/shell-based theranostic system designed by UCN integration with a folate (FA)-conjugated dendrimer for tumor targeting and with photocaged doxorubicin as a cytotoxic agent. Two types of UCNs (NaYF4:Yb/Er (or Yb/Tm); diameter = ≈50 to 54 nm) are described, each displaying distinct emission properties upon NIR (980 nm) excitation. The UCNs are surface modified through covalent attachment of photocaged doxorubicin (ONB-Dox) and a multivalent FA-conjugated polyamidoamine (PAMAM) dendrimer G5(FA)6 to prepare UCNat(ONB-Dox)(G5FA). Surface plasmon resonance experiments performed with G5(FA)6 dendrimer alone show nanomolar binding avidity (KD = 5.9 × 10-9m) to the folate binding protein. This dendrimer binding corresponds with selective binding and uptake of UCNat(ONB-Dox)(G5FA) by FAR-positive KB carcinoma cells in vitro. Furthermore, UCNat(ONB-Dox)(G5FA) treatment of FAR(+) KB cells inhibits cell growth in a light dependent manner. These results validate the utility of modularly integrated UCN-dendrimer nanocomposites for cell type specific NIR imaging and light-controlled drug release, thus serving as a new theranostic system.
- Wong, Pamela T.,Chen, Dexin,Tang, Shengzhuang,Yanik, Sean,Payne, Michael,Mukherjee, Jhindan,Coulter, Alexa,Tang, Kenny,Tao, Ke,Sun, Kang,Baker, James R.,Choi, Seok Ki
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p. 6078 - 6090
(2015/12/18)
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- Selective arylthiolane deprotection by singlet oxygen: A promising tool for sensors and prodrugs
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A routine thioketal protecting group reacts rapidly and selectively with singlet oxygen to reveal ketone products in good (aryl 1,3-dithiolane) to excellent (aryl 1,3-oxathiolane) yields. Arylthiolanes are stable to biologically relevant reactive oxygen species and can be used as a light-activated gating mechanism for activating fluorescent sensors or small molecule prodrugs.
- Lamb, Brian M.,Barbas, Carlos F.
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supporting information
p. 3196 - 3199
(2015/05/27)
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- PH-responsive dendritic core-multishell nanocarriers
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In this paper we describe novel pH-responsive core-multishell (CMS) nanocarrier (pH-CMS), obtained by introducing an aromatic imine linker between the shell and the core. At a pH of 5 and lower the used imine linker was rapidly cleaved as demonstrated by NMR studies. The CMS nanocarriers were loaded with the dye Nile red (NR) and the anticancer drug doxorubicin (DOX), respectively. The transport capacities were determined using UV/Vis spectroscopy, and the sizes of the loaded and unloaded CMS nanocarriers were investigated using dynamic light scattering (DLS). We could show that CMS nanocarriers efficiently transported NR in supramolecular aggregates, while DOX was transported in a unimolecular fashion. After cellular uptake the DOX-loaded pH-responsive nanocarriers showed higher toxicities than the stable CMS nanocarriers. This is due to a more efficient DOX release caused by the cleavage of the pH-labile imine bond at lower pH within the intracellular compartments.
- Fleige, Emanuel,Achazi, Katharina,Schaletzki, Karolina,Triemer, Therese,Haag, Rainer
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- Targeted Delivery of Doxorubicin by Folic Acid-Decorated Dual Functional Nanocarrier
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Doxorubicin (DOX) is one of the most commonly used antineoplastic agents, but its clinical application is oftentimes coupled with severe side effects. Selective delivery of DOX to tumors via nanosized drug carrier represents an attractive approach to this problem. Previously, we developed a dual functional nanomicellar carrier, PEG5K-embelin2 (PEG5K-EB2), which was able to deliver paclitaxel (PTX) selectively to tumors and to achieve an enhanced therapeutic effect. In the present study, we examined the utility of PEG5K-EB2 to deliver DOX to tumors. In addition, folic acid (FA) was coupled to the surface of the PEG5K-EB2 micelles (FA-PEG5K-EB2) to further improve the selective targetability of the system. DOX-loaded PEG5K-EB2 micelles were uniformly spherical particles with a diameter of approximately 20 nm. Incorporation of FA had minimal effect on the size of the particles. The DOX loading efficiency was as high as 91.7% and 93.5% for PEG5K-EB2 and FA-PEG5K-EB2, respectively. DOX formulated in PEG5K-EB2 micelles (with or without FA decoration) demonstrated sustained kinetics of DOX release compared to free DOX. FA-PEG5K-EB2 significantly facilitated the intracellular uptake of DOX over free DOX and PEGylated liposomal DOX (Doxil) in breast cancer cells, 4T1.2, and drug resistant cells, NCI/ADR-RES. P-gp ATPase assay showed that PEG5K-EB2 significantly inhibited the function of the P-gp efflux pump. The maximum tolerated dose of DOX-loaded PEG5K-EB2 micelles was 15 mg/kg in mice, which was 1.5-fold greater than that for free DOX. Pharmacokinetics (PK) and biodistribution studies showed that both types of DOX-loaded micelles, especially FA-PEG5K-EB2, were able to significantly prolong the blood circulation time of DOX and facilitate its preferential accumulation at the tumor tissue. Finally, DOX/PEG5K-EB2 mixed micelles demonstrated significantly enhanced tumor growth inhibitory effect with minimal toxicity in comparison to free DOX and Doxil and the antitumor activity was further enhanced after the decoration by folic acid. Our data suggest that FA-PEG5K-EB2 micelles represent a promising DOX delivery system that warrants more study in the future.
- Lu, Jianqin,Zhao, Wenchen,Huang, Yixian,Liu, Hao,Marquez, Rebecca,Gibbs, Robert B.,Li, Jiang,Venkataramanan, Raman,Xu, Liang,Li, Shulin,Li, Song
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p. 4164 - 4178
(2015/09/28)
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- Synthesis of doxorubicin α-linolenic acid conjugate and evaluation of its antitumor activity
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Doxorubicin (DOX) is a broad-spectrum antitumor drug used in the clinic. However, it can cause serious heart toxicity. To increase the therapeutic index of DOX and to attenuate its toxicity toward normal tissues, we conjugated DOX with either α-linolenic acid (LNA) or palmitic acid (PA) by a hydrazone or an amide bond to produce DOX-hyd-LNA, DOX-ami-LNA, DOX-hyd-PA, and DOX-ami-PA. The cytotoxicity of DOX-hyd-LNA on HepG2, MCF-7, and MDA-231 cells was higher compared to that of DOX, DOX-ami-LNA, DOX-hyd-PA, and DOX-ami-PA. The cytotoxicity of DOX-hyd-LNA on HUVECs was lower than that of DOX. DOX-hyd-LNA released significantly more DOX in pH 5.0 medium than it did in pH 7.4 medium. DOX-hyd-LNA induced more apoptosis in MCF-7 and HepG2 cells than DOX or DOX-ami-LNA. Significantly more DOX was released from DOX-hyd-LNA in both MCF-7 and HepG2 cells compared with DOX-ami-LNA. Compared to free DOX, a biodistribution study showed that DOX-hyd-LNA greatly increased the content of DOX in tumor tissue and decreased the content of DOX in heart tissue after it was intravenously administered. DOX-hyd-LNA improved the survival rate, prolonged the life span, and slowed the growth of the tumor in tumor-bearing nude mice. These results indicate that DOX-hyd-LNA improved the therapeutic index of DOX. Therefore, DOX-hyd-LNA is a potential compound for use as a cancer-targeting therapy.
- Liang, Chun-Hui,Ye, Wei-Liang,Zhu, Chun-Lai,Na, Ren,Cheng, Ying,Cui, Han,Liu, Dao-Zhou,Yang, Zhi-Fu,Zhou, Si-Yuan
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p. 1378 - 1390
(2014/05/20)
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- BIO-ORTHOGONAL DRUG ACTIVATION
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Disclosed is a kit for the administration and activation of a Prodrug. The kit comprises a Masking Moiety linked, directly or indirectly, to a Trigger moiety, which in turn is linked to a Drug, and an Activator for the Trigger moiety. The Trigger moiety comprises a dienophile and the Activator comprises a diene, whereby the dienophile is an eight-membered non- aromatic cyclic alkenylene group, preferably a cyclooctene group, and more preferably a trans-cyclooctene group. The Trigger and the Activator undergo a fast, bio-orthogonal reaction resulting in the release of the Masking Moiety, and activation of the drug.
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Page/Page column 87-88
(2014/06/11)
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- Click to release: Instantaneous doxorubicin elimination upon tetrazine ligation
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Eliminated without a trace: The fastest click reaction, the highly selective inverse-electron-demand Diels-Alder reaction, has been modified to enable selective bioorthogonal release. Thus, the click reaction of a tetrazine with a drug-bound trans-cyclooctene caused the instantaneous release of the drug and CO2 (see scheme). One possible application is the chemically triggered release, and thereby activation, of a drug from a tumor-bound antibody-drug conjugate. Copyright
- Versteegen, Ron M.,Rossin, Raffaella,Ten Hoeve, Wolter,Janssen, Henk M.,Robillard, Marc S.
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supporting information
p. 14112 - 14116
(2014/01/06)
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- Fluorescent polymeric micelles with aggregation-induced emission properties for monitoring the encapsulation of doxorubicin
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A new type of fluorescent polymeric micelles is developed by self-assembly from a series of amphiphilic block copolymers, poly(ethylene glycol)-b-poly[styrene-co-(2-(1,2,3,4,5-pentaphenyl-1H-silol-1-yloxy)ethyl methacrylate)] [PEG-b-P(S-co-PPSEMA)]. Their capability of loading doxorubicin (DOX) is investigated by monitoring the loading content, encapsulation efficiency, and photophysical properties of micelles. F?rster resonance energy transfer from PPSEMA to DOX is observed in DOX-loaded micelles, which can serve as an indication of successful encapsulation of DOX in these micelles. The application of this new type of fluorescent polymeric micelles as a fluorescent probe and an anticancer drug carrier simultaneously is explored by studying the intracellular uptake of DOX-loaded micelles.
- Chen, Jen-Ing,Wu, Wen-Chung
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p. 623 - 632
(2013/07/28)
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- CYTOTOXIC-DRUG DELIVERING MOLECULES TARGETING HIV (CDM-HS), CYTOTOXIC ACTIVITY AGAINST THE HUMAN IMMUNODEFICIENCY VIRUS AND METHODS OF USE
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The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as CDM-Hs, function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and by introducing cytotoxic moieties to gp120-expressing cells, thereby causing cell death and preventing cell infection and spread of HIV. It is shown that CDM-Hs bind to gp120 and gp-120 expressing cells competitively with CD4, and these compounds cause cell death of HIV-infected cells, thereby decreasing viral infectivity. Compounds and methods are described herein.
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Page/Page column 85
(2013/11/18)
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- Development of novel bisphosphonate prodrugs of doxorubicin for targeting bone metastases that are cleaved pH dependently or by cathepsin B: Synthesis, cleavage properties, and binding properties to hydroxyapatite as well as bone matrix
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Bone metastases are a frequent cause of morbidity in cancer patients. The present palliative therapeutic options are chemotherapy, hormone therapy, and the administration of bisphosphonates. The affinity between bisphosphonates and the apatite structure of bone metastases is strong. Thus, we designed two low-molecular-weight and water-soluble prodrugs which incorporate a bisphosphonate group as a bone targeting ligand, doxorubicin as the anticancer agent, and either an acid-sensitive bond (1) or a cathepsin B cleavable bond (3) for ensuring an effective release of doxorubicin at the site of action. Cleavage studies of both prodrugs showed a fast release of doxorubicin but sufficient stability over several hours in human plasma. Effective binding of prodrug 1 and 3 was demonstrated with hydroxyapatite and with native bone. In orientating toxicity studies in nude mice, the MTD of 1 was 3-fold higher compared to conventional doxorubicin, whereas 3 showed essentially the same MTD as doxorubicin.
- Hochd?rffer, Katrin,Abu Ajaj, Khalid,Sch?fer-Obodozie, Cynthia,Kratz, Felix
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p. 7502 - 7515
(2012/11/06)
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- DNA-templated release of functional molecules with an azide-reduction- triggered immolative linker
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Nucleic acid templated reactions have attracted significant attention for nucleic acid sensing. Herein we report a general design which extends the potential of nucleic acid templated reactions to unleash the function of a broad diversity of small molecules such as a transcription factor agonist, a cytotoxic or a fluorophore.
- Gorska, Katarzyna,Manicardi, Alex,Barluenga, Sofia,Winssinger, Nicolas
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supporting information; scheme or table
p. 4364 - 4366
(2011/06/19)
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- THERAPEUTIC FOR HEPATIC CANCER
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A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
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- FORMULATIONS AND METHODS OF USE
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The invention relates to the liquid and lyophilized formulations of small particulates, liposomes, and micelles, and methods for making and using the formulations. In particular, at least in some embodiments, the present invention relates to the production and lyophilization of PEGylated nanoparticles, microparticles, micelles, and liposomes for use and administration in to a subject.
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- Optimization of an albumin-binding prodrug of doxorubicin that is cleaved by prostate-specific antigen
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We have developed a novel albumin-binding prodrug of doxorubicin that incorporates p-aminobenzyloxycarbonyl (PABC) as a 1,6 self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, as a substrate for the prostate-specific antigen (PSA) that is overexpressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. The prodrug exhibited good water solubility and was bound rapidly to the cysteine-34 position of human serum albumin. Incubation studies with PSA demonstrated that the albumin-bound form of the prodrug was cleaved rapidly at the P1?P1? scissile bond, releasing H-Ser-Leu-PABC-DOXO, which was further degraded to release doxorubicin as a final cleavage product within a few hours in prostate tumor tissue homogenates as well as in PSA-positive LNCaP LN cell lysates. Moreover, our prodrug exhibited antiproliferative activity in a low micromolar range against a PSA-expressing prostate cancer cell line (LNCaP).
- Elsadek, Bakheet,Graeser, Ralph,Warnecke, Andre,Unger, Clemens,Saleem, Tahia,El-Melegy, Nagla,Madkor, Hafez,Kratz, Felix
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body text
p. 234 - 238
(2010/11/17)
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