- A two-photon responsive naphthyl tagged: P -hydroxyphenacyl based drug delivery system: Uncaging of anti-cancer drug in the phototherapeutic window with real-time monitoring
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We report a two-photon responsive drug delivery system (DDS), namely, p-hydroxyphenacyl-naphthalene-chlorambucil (pHP-Naph-Cbl), having a two-photon absorption (TPA) cross-section of ≥20 GM in the phototherapeutic window (700 nm). Our DDS exhibited both AIE and ESIPT phenomena, which were utilized for the real-time monitoring of anti-cancer drug release.
- Kundu, Moumita,Mondal, Mahitosh,Nair, Asha V,Pal, Bipul,Roy, Biswajit,Roy, Samrat,Shah, Sk. Sheriff,Singh, Amit Kumar,Singh, N. D. Pradeep
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- Upconversion-like Photolysis of BODIPY-Based Prodrugs via a One-Photon Process
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Photochemical reactions at lower energy than the absorption window are currently achieved by multi-photon processes, including two-photon absorption and photon upconversion, which have limited energy utilization efficiency. Here, we report a one-photon strategy based on triplet-triplet energy transfer (TTET) between a photosensitizer and a photocleavable molecule to achieve photolysis at low energy. To verify this concept, we chose platinum(II) tetraphenyltetrabenzoporphyrin (PtTPBP) as the photosensitizer and synthesized a boron-dipyrromethene (BODIPY)-based prodrug as the photocleavable molecule. Photolysis of the prodrug is achieved by TTET upon excitation of PtTPBP at 625 nm with a photolysis quantum yield of 2.8%. Another demonstration shows an unexpected higher photolysis quantum yield than the direct excitation at 530 nm. This strategy opens a new path for achieving photolysis at long wavelengths, benefiting the applications in biological studies, photopharmacology, and photoresponsive drug delivery.
- Lv, Wen,Li, Yafei,Li, Feiyang,Lan, Xin,Zhang, Yaming,Du, Lili,Zhao, Qiang,Phillips, David L.,Wang, Weiping
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- Single component photoresponsive fluorescent organic nanoparticles: a smart platform for improved biomedical and agrochemical applications
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In the last two decades, light responsive nano drug delivery systems (DDSs) have gained considerable importance, particularly in the area of biology and medicine. In general, light responsive nano DDSs are bicomponent and constructed using two ingredients, namely a nanocarrier and a phototrigger. The synthesis of these bicomponent nano DDSs requires multiple steps, which limits their applications. Hence, we have reported single component light responsive nano DDSs using fluorescent organic nanoparticles (FONPs) which acted both as a nanocarrier and a phototrigger. This feature article provides an overview of recently developed light responsive single component FONPs and their applications in the regulated release of anticancer drugs, gasotransmitters, antibacterial agents, and pesticides, and also as efficient PDT agents. We have summarised the synthesis, characterisation, and photophysical, photochemical, andin vitrobehaviours of these light responsive FONPs. In addition, we also discussed the advantages of using FONPs as a nano DDS for cellular studies like: excellent biocompatibility, efficient cellular internalisation, real time monitoring of the drug release ability inside the cells, and enhanced cytotoxicity due to regulated release of bioactive molecules inside the cells.
- Chaudhuri, Amrita,Paul, Amrita,Sikder, Antara,Pradeep Singh
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- Three-Arm, Biotin-Tagged Carbazole–Dicyanovinyl–Chlorambucil Conjugate: Simultaneous Tumor Targeting, Sensing, and Photoresponsive Anticancer Drug Delivery
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The design, synthesis, and in vitro biological studies of a biotin–carbazole–dicyanovinyl–chlorambucil conjugate (Bio-CBZ-DCV-CBL; 6) are reported. This conjugate (6) is a multifunctional single-molecule appliance composed of a thiol-sensor DCV functionality, a CBZ-derived phototrigger as well as fluorescent reporter, and CBL as the anticancer drug, and Bio as the cancer-targeting ligand. In conjugate 6, the DCV bond undergoes a thiol–ene click reaction at pH7 with intracellular thiols, thereby shutting down internal charge transfer between the donor CBZ and acceptor DCV units, resulting in a change of the fluorescence color from green to blue, and thereby, sensing the tumor microenvironment. Subsequent photoirradiation results in release of the anticancer drug CBL in a controlled manner.
- Venkatesh, Yarra,Karthik,Rajesh,Mandal, Mahitosh,Jana, Avijit,Singh, N. D. Pradeep
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- Targeted photoresponsive carbazole–coumarin and drug conjugates for efficient combination therapy in leukemia cancer cells
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Phototriggered drug delivery systems (PTDDSs) facilitate controlled delivery of drugs loaded on photoactive platform to the target region under light stimulation. The present study investigated the synthesis and efficacy of carbazole–coumarin (CC)-fused heterocycles as a PTDDS platform for the photocontrolled release of a chemotherapeutic agent, chlorambucil, in an in vitro model of human breast and leukemia cancer cells. CC-fused heterocycles were constructed using 4-hydroxycarbazole as the starting material, and further modification of these heterocycles yielded two CC derivatives. CC-7 with an additional ? COOH group and CC-8 with the triphenylphosphonium (TPP) group, a mitochondria-targeting ligand introduced in the carbazole ring, dissolved in polar solvents and exhibited emission bands at 360 and 450 nm, respectively. The results indicate that visible light of 405 nm triggers the photolysis of the CC–drug conjugate and efficiently delivers the drug in both in vitro cancer cell models. Cytotoxicity evaluation indicates the suppression of proliferation of both types of cells treated with CC-8 under synergy effect combining drug potency and photosensitization. Further, the lower IC50 of CC-8 toward leukemia cells suggests the efficacy of the TPP ligand in increasing the bioavailability of CC–drug conjugates in leukemia treatment. Studies on mitochondria-targeting drug delivery systems are required for improving the performance of anticancer drugs.
- Chang, Wen-Wei,Chu, Chih-Chien,Lai, Yi-Ting,Lin, Yen-Cheng,Ou, Jia-Yu,Wang, Bing-Yen
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- A dual-analyte probe: Hypoxia activated nitric oxide detection with phototriggered drug release ability
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A new strategy for the detection of hypoxia and NO succeeded by photocontrolled delivery of an anticancer agent has been demonstrated. The developed system is able to produce distinct responses (dual channel) upon interaction with hypoxia and NO. This probe can also release anticancer drugs upon photoirradiation acting potentially as both a dual-analyte imaging agent and a prodrug.
- Biswas, Sandipan,Rajesh,Barman, Shrabani,Bera, Manoranjan,Paul, Amrita,Mandal, Mahitosh,Pradeep Singh
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- Cys fluorescent molecular probe for detecting DNA targeting under reduction stress as well as preparation method and application of Cys fluorescent molecular probe
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The invention relates to a Cys fluorescent molecular probe for detecting DNA targeting under reduction stress as well as a preparation method and application of the Cys fluorescent molecular probe. The structural formula of the fluorescent molecular probe is as shown in the formula (1). The prominent light control characteristic of the fluorescent molecular probe is beneficial to real-time monitoring of diseases caused by errors in the DNA replication process due to abnormal expression of Cys under DNA peripheral reduction stress, and the fluorescent molecular probe is expected to be applied to prevention, treatment and the like of gene diseases caused by abnormal expression of Cys.
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Paragraph 0067-0068
(2021/06/26)
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- Method for synthesizing chlorambucil
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The invention discloses a method for synthesizing chlorambucil, which relates to the technical field of organic chemistry, and comprises the following steps: S1, adding a mixture of 4-bromo-N, N-bis (2-chloroethyl) aniline, N-(quinolin-8-yl) butyl 3-enamide, palladium chloride, tri-n-butylphosphine tetrafluoroborate, potassium carbonate and benzoic acid at ratio of 10.83%: 10.83%-32.50%: 0.22%-2.17%: 0.43%-2.17%: 10.83%-54.17%: 10.83%-54.17% and dimethyl sulfoxide at molar volume ratio of 0.1 mmol: 2 mL to a reaction vessel for uniform mixing; and S2, placing the reaction container in an oil bath at 135-145 DEG C, and violently stirring to react for 24 hours. According to the invention, through the coupling reaction, 8-aminoquinoline is designed as a compound of a leaving group to control regioselectivity and chemical selectivity in the reaction, so that the problem of excessive steps in the existing synthesis process of chlorambucil is effectively solved; the method has the characteristics of high reaction region selectivity and yield, mild reaction conditions and simple reaction and post-treatment purification processes.
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Paragraph 0028; 0031-0032; 0035-0036
(2021/07/17)
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- PHOTOLYTIC COMPOUNDS AND TRIPLET-TRIPLET ANNIHILATION MEDIATED PHOTOLYSIS
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The invention provides novel photolytic compounds and prodrugs, nanoparticles and compositions thereof, and methods of conducting photolysis mediated by triplet-triplet annihilation.
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Paragraph 0026; 00254
(2021/04/17)
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- Iridium-Catalysed Reductive Deoxygenation of Ketones with Formic Acid as Traceless Hydride Donor
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An iridium-catalysed deoxygenation of ketones and aldehydes is achieved, with formic acid as hydride donor and water as co-solvent. At low catalyst loading, a number of 4-(N,N-disubstituted amino) aryl ketones are readily deoxygenated in excellent yields and chemoselectivity. Numerous functional groups, especially phenolic and alcoholic hydroxyls, secondary amine, carboxylic acid, and alkyl chloride, are well tolerable. Geminally dideuterated alkanes are obtained with up to 90% D incorporation, when DCO2D and D2O are used in place of their hydrogenative counterparts. The activating 4-(N,N-disubstituted amino)aryl groups have been demonstrated to undergo a variety of useful transformations. The deoxygenative deuterations have been used to prepare a deuterated drug molecule Chlorambucil-4,4-d2. (Figure presented.).
- Yang, Zhiheng,Zhu, Xueya,Yang, Shiyi,Cheng, Weiyan,Zhang, Xiaojian,Yang, Zhanhui
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p. 5496 - 5505
(2020/10/22)
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- Selective modification of sulfamidate-containing peptides
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Hybrid peptides whose N-terminal residues are activated in the form of α-methylisoserine-derived cyclic sulfamidates exhibit rich reactivity as electrophiles, allowing site- and stereoselective modifications at different backbone and side chain positions.
- Busto, Jesús H.,Jiménez-Osés, Gonzalo,Mazo, Nuria,Navo, Claudio D.,Peregrina, Jesús M.
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supporting information
p. 6265 - 6275
(2020/09/07)
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- Mitochondria-localized: In situ generation of rhodamine photocage with fluorescence turn-on enabling cancer cell-specific drug delivery triggered by green light
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In this work, we have developed a rhodamine dye based water-soluble, mitochondria-indicating photocage, which gets activated in the mitochondria producing a fluorescent signal and on-demand releases the caged anticancer drug, chlorambucil, in the cancer cells selectively upon irradiation of green light.
- Bera, Manoranjan,Jana, Avijit,Mengji, Rakesh,Ojha, Mamata,Paul, Amrita,Singh, N. D. Pradeep
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p. 8412 - 8415
(2020/08/13)
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- TRIPLET-TRIPLET ENERGY TRANSFER WITH LIGHT EXCITATION AT LONG WAVELENGTHS AND METHODS THEREOF
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The field of various phototriggered drug release and photoreactions, including reactions generally based on triplet-triplet energy transfer with light excitation at long wavelengths. Systems and methods for absorbing energy in a photosensitizer, and methods for making or using such systems, kits including such systems. The systems and methods comprise transferring that energy by triplet-triplet energy transfer to cleave a cleavable or other active moiety, for instance, in order to cause the release of a releasable moiety. In some cases, these may be contained within a suitable carrier material, for example, a particle or a micelle. Such systems and methods may be used in a variety of applications, including various biological or physical applications. For example, such systems and methods may be useful for delivering drugs or other releasable moieties to regions of a subject.
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Page/Page column 5; 18-19
(2020/03/15)
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- Enzyme-responsive sulfatocyclodextrin/prodrug supramolecular assembly for controlled release of anti-cancer drug chlorambucil
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Supramolecular drug delivery systems are becoming an increasingly important part in controlled drug release. In this work, we report a novel enzyme-responsive supramolecular assembly directly constructed using biocompatible sulfato-β-cyclodextrin (SCD) and an anti-cancer prodrug, i.e. choline modified anti-cancer drug chlorambucil (QA-Cbl). The supramolecular assembly acts as an effective drug delivery system via the controlled drug loading and enzyme-responsive drug release, because the butyrylcholinesterase (BChE) can cleave the ester bond of QA-Cbl prodrug, resulting in the release of anti-cancer drug chlorambucil (Cbl). Compared to other sophisticated drug delivery systems, the present system provides a feasible and functional approach for achievement of controlled drug release.
- Guan, Xinran,Chen, Yong,Wu, Xuan,Li, Peiyu,Liu, Yu
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supporting information
p. 953 - 956
(2019/01/24)
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- Peptide-Driven Targeted Drug-Delivery System Comprising Turn-On Near-Infrared Fluorescent Xanthene–Cyanine Reporter for Real-Time Monitoring of Drug Release
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Targeted drug delivery (TDD) is an efficient strategy for cancer treatment. However, the real-time monitoring of drug delivery is still challenging because of a pronounced lack of TDD systems capable of providing a near-infrared (NIR) fluorescence signal for the detection of drug-release events. Herein, a new TDD system, comprising a turn-on NIR fluorescent reporter attached to an anticancer drug and targeting peptide, is reported. This system provides both TDD and NIR fluorescence monitoring of drug-release events in target tissue. In this TDD system, a new carboxy-derivatized xanthene–cyanine (XCy) dye is attached to an anticancer drug, chlorambucil (CLB), through a hydrolytically cleavable ester linker and coupled to a targeting peptide, octreotide amide (OCTA), which is specific to somatostatin receptors SSTR-2 and STTR-5 overexpressed on many tumor cells. This OCTA-G-XCy-CLB (G: γ-aminobutyric acid) conjugate exhibits no detectable fluorescence, whereas, upon the hydrolytic cleavage of the ester linker, a bright NIR fluorescence appears at λ≈710 nm; this signals release of the drug. Real-time TDD monitoring is demonstrated for the example of the human pancreatic cancer cell line overexpressing SSTR-2 and STTR-5, in comparison with the noncancerous Chinese hamster ovary cell line, which contains a reduced number of these receptors.
- Ebaston,Rozovsky, Alex,Zaporozhets, Alisa,Bazylevich, Andrii,Tuchinsky, Helena,Marks, Vered,Gellerman, Gary,Patsenker, Leonid D.
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supporting information
p. 1727 - 1734
(2019/09/12)
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- Preparation method of anti-tumor medicine chlorambucil
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The invention belongs to the field of compound preparation, and specifically discloses a preparation method of an anti-tumor medicine chlorambucil. The preparation method comprises the steps of performing a Vilsmeier reaction on a raw material N,N-dihydroxyethylaniline and phosphorus oxychloride and DMF so as to prepare 4-[bi(2-chloroethyl)amino]benzaldehyde, then performing a witting reaction on4-[bi(2-chloroethyl)amino]benzaldehyde and methoxymethyl triphenylphosphonium chloride so as to prepare 4-[bi(2-chloroethyl)amino]-BETA-methoxystyrene, reacting under an acid condition so as to obtain4-[bi(2-chloroethyl)amino]phenylacetaldehyde, and finally, reacting with Meldrum's acid in triethylamine and formic acid systems so as to prepare a target product. The raw material N,N-dihydroxyethylaniline is cheap, has a wide source and is easy to obtain; the whole reaction process has high yield, production conditions are mild, the steps are short, and post treatment and purification are easyto operate, so that the preparation method is applicable to commercial large scale production, and meets the rapidly growing market demands.
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- Improving the Potency of Cancer Immunotherapy by Dual Targeting of IDO1 and DNA
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Herein we report the first exploration of a dual-targeting drug design strategy to improve the efficacy of small-molecule cancer immunotherapy. New hybrids of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and DNA alkylating nitrogen mustards that respectively target IDO1 and DNA were rationally designed. As the first-in-class examples of such molecules, they were found to exhibit significantly enhanced anticancer activity in vitro and in vivo with low toxicity. This proof-of-concept study has established a critical step toward the development of a novel and effective immunotherapy for the treatment of cancers.
- Fang, Kun,Dong, Guoqiang,Wang, Hongyu,He, Shipeng,Wu, Shanchao,Wang, Wei,Sheng, Chunquan
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- Novel enmein-type diterpenoid hybrids coupled with nitrogen mustards: Synthesis of promising candidates for anticancer therapeutics
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Natural derived enmein-type diterpenoids exert cytotoxicity against a wide range of human cancer cells. Yet their medicinal applications are hindered by insufficient potency for chemotherapy. Hence, a series of novel enmein-type diterpenoid hybrids coupled with nitrogen mustards were designed and synthesized to increase antitumor efficacy while reducing systemic toxicity. Most conjugates exhibited stronger antiproliferative activities than parent diterpenoids and nitrogen mustards, especially for multidrug-resistant tumor cell line Bel-7402/5-FU. Among them, compound E2 showed the most potent inhibitory activities in human leukemia HL-60 cells, human prostate cancer PC-3 cells, human liver cancer Bel-7402 cells and drug-resistant human liver cancer Bel-7402/5-FU cells with IC50 values of 7.83 μM, 3.97 μM, 0.77 μM and 2.07 μM, respectively. Additionally, high selectivity with selectivity index over 130 was also observed from cytotoxic evaluation between L-02 human normal liver cells and Bel-7402 malignant liver cells. Further studies on mechanism of action indicated that E2 induced both apoptosis and G1 phase cell cycle arrest in Bel-7402 hepatoma cells. Moreover, the dysfunction in mitochondrial pathway was also involved in E2 initiated apoptotic activation, which entailed the loss of mitochondrial membrane potential followed by upregulating the bax/bcl-2 ratio and increasing the expression of cytochrome c, p53, caspase-3 and -9. Overall, E2 has the potential to emerge as a promising drug candidate for cancer therapy.
- Gao, Xiang,Li, Jia,Wang, Mingying,Xu, Shengtao,Liu, Weiwei,Zang, Linghe,Li, Zhanlin,Hua, Huiming,Xu, Jinyi,Li, Dahong
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p. 588 - 598
(2018/02/09)
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- Redox-responsive xanthene-coumarin-chlorambucil-based FRET-guided theranostics for "activatable" combination therapy with real-time monitoring
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A FRET donor-acceptor xanthene-coumarin conjugate has been designed for redox-regulated synergic treatment of photodynamic therapy and chemotherapy with real-time monitoring. The "locked" FRET pair was selectively "unlocked" by biological reducing thiols via rupture of a sacrificial disulfide linker. A distinct change in fluorescence color and selective cancer cell toxicity were observed in vitro.
- Gangopadhyay, Moumita,Mengji, Rakesh,Paul, Amrita,Venkatesh, Yarra,Vangala, Venugopal,Jana, Avijit,Singh, N. D. Pradeep
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supporting information
p. 9109 - 9112
(2017/08/17)
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- Targeted combinational therapy inducing mitochondrial dysfunction
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We report on a mitochondria-specific combinational theranostic agent, 1. This system contains a chlorambucil prodrug and an aggregation induced emission dye. In addition, compound 1 bears both an intracellular thiol-triggered moiety and a mitochondria targeting unit (triphenylphosphonium). Glutathione (GSH) is the most abundant thiol and its concentrations are significantly higher in a great number of cancer cell lines, compared to normal cells. The GSH-induced prodrug 1 upon activation releases chlorambucil and exhibits mitochondria targeted aggregation induced emission (AIE) fluorescence, resulting in cell apoptosis via the caspase pathway due to mitochondrial dysfunction.
- Shin, Weon Sup,Park, Soon Ki,Verwilst, Peter,Koo, Seyoung,Lee, Joung Hae,Chi, Sung-Gil,Kim, Jong Seung
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p. 1281 - 1284
(2017/02/05)
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- Photocaging of Single and Dual (Similar or Different) Carboxylic and Amino Acids by Acetyl Carbazole and its Application as Dual Drug Delivery in Cancer Therapy
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A new fluorescent photoremovable protecting group (FPRPG) based on acetylcarbazole framework has been explored for the first time release of single and dual (similar or different) substrates from single chromophore. Mechanistic studies of the photorelease process revealed that photorelease of two (similar or different) substrates from acetyl carbazole proceeds via a stepwise pathway. Further, we constructed photoresponsive dual drug delivery system (DDS) to release two different anticancer drugs (caffeic acid and chlorambucil, 1 equiv each). In vitro study reveals that our DDS exhibit excellent properties like biocompatibility, cellular uptake, and photoregulated dual drug release.
- Venkatesh, Yarra,Rajesh,Karthik,Chetan,Mandal, Mahitosh,Jana, Avijit,Singh, N.D. Pradeep
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supporting information
p. 11168 - 11175
(2016/11/28)
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- A process for synthesizing phenylbutyric acid nitrogen mustard antineoplastic agent
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The invention relates to a synthesis process of an antineoplastic drug chlorambucil. The synthesis process comprises the following steps: (1) amino protection reaction; (2) acylation reaction; (3) reduction reaction; (4) carboxyl protection reaction; (5) substitution reaction; (6) chlorination reaction; and (7) deprotection reaction. According to the synthesis process, the amino group is protected by use of acetic anhydride, and then acylation, reduction, carboxyl protection, substitution, chlorination and aqueous hydrochloric acid solution hydrolysis are performed to obtain the chlorambucil. The synthesis process of the antineoplastic drug chlorambucil has the characteristics of low cost, mild reaction conditions, low toxicity, convenience in process operation, and suitability for industrial production.
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Paragraph 0040-0041; 0043-0044
(2018/02/04)
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- Coumarin-benzothiazole-chlorambucil (Cou-Benz-Cbl) conjugate: An ESIPT based pH sensitive photoresponsive drug delivery system
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We have developed an ESIPT based drug delivery system (DDS), Cou-Benz-Cbl conjugate, by incorporating a benzothiazole group at the 8th position of the 7-hydroxy-coumarin moiety for pH sensitive fluorescence properties and photocontrolled release of the anticancer drug chlorambucil. The Cou-Benz-Cbl conjugate exhibited unique photophysical properties like good absorbance at around 350 nm, a large Stokes shift (～151 nm) and pH sensitive fluorescence properties. The pH sensitive fluorescence properties of the Cou-Benz-Cbl conjugate can be ascribed to an ESIPT turn "on and off" mechanism. At physiological pH, the ESIPT gets turned "off" and a blue fluorescence of the coumarin moiety was observed, but at acidic pH, the ESIPT gets turned "on" and a green fluorescence was noted. Photolysis of the Cou-Benz-Cbl conjugate using UV light of wavelength ≥365 nm resulted in the efficient release of the anticancer drug chlorambucil. Cellular uptake studies revealed that the Cou-Benz-Cbl conjugate was easily internalized inside the cancer cells. Further, an MTT assay showed that the Cou-Benz-Cbl conjugate has a good biocompatibility and low cytotoxicity towards the MDA-MB-231 cell line, whereas upon exposure to UV light, the Cou-Benz-Cbl conjugate exhibited enhanced cytotoxicity compared to the free drug due to the effective release of the anticancer drug chlorambucil inside the cancer cell.
- Barman, Shrabani,Mukhopadhyay, Sourav K.,Gangopadhyay,Biswas, Sandipan,Dey, Satyahari,Singh, N.D.Pradeep
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p. 3490 - 3497
(2015/05/05)
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- A pillararene-based ternary drug-delivery system with photocontrolled anticancer drug release
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A study was conducted to report a supramolecular system that met these design criteria. Specifically, a photodegradable anticancer prodrug ( Py-Cbl ) containing the anticancer drug chlorambucil and fluorophore pyrene was designed and synthesized. The photo-cleavable group here performed two important functions, such as providing photoresponsive control over the drug release and serving as a linker between the fluorophore and the drug. The absorption and emission spectra of Py-Cbl were first investigated by using UV and fluorescence spectroscopy. The band at 340 nm corresponding to Py-Cbl was similar to that of PyOH in water.
- Yu, Guocan,Yu, Wei,Mao, Zhengwei,Gao, Changyou,Huang, Feihe
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p. 919 - 925
(2015/03/30)
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- Benzo[a]acridinylmethyl esters as pH sensitive fluorescent photoactive precursors: Synthesis, photophysical, photochemical and biological applications
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A newsworthy class of carboxylate esters based on the (benzo[a]acridin-12- yl)methyl (BAM) chromophore has been shown to perform dual functions as a "pH sensitive fluorescent probe" and a "phototrigger" for acids. The photophysical properties of all the BAM ester conjugates were investigated and found to be highly sensitive to solvent polarity, H-bonding capability and pH of the environment. On irradiation using UV light (≥410 nm), BAM ester conjugates underwent heterolytic cleavage of C-O bonds resulting in efficient release of carboxylic and amino acids. Interestingly, the newly synthesized BAM chromophore was also explored for the construction of a drug delivery system (DDS). In the current DDS, the BAM chromophore plays two important roles: (i) a "fluorophore" for cell imaging and (ii) a "phototrigger" for the drug release. In vitro biological studies revealed that the newly developed BAM based DDS has a good biocompatibility, cellular uptake properties and efficient photoregulated anticancer drug release ability. the Partner Organisations 2014.
- Ikbal,Saha, Biswajit,Barman, Shrabani,Atta, Sanghamitra,Banerjee, Deb Ranjan,Ghosh, Sudip Kumar,Singh, N. D. Pradeep
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p. 3459 - 3469
(2014/05/20)
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- Long conjugated 2-nitrobenzyl derivative caged anticancer prodrugs with visible light regulated release: Preparation and functionalizations
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A series of anticancer prodrugs with different chemical functional groups were prepared, in which the styryl conjugated 2-nitrobenzyl derivatives were introduced as the phototrigger to regulate the drug (chlorambucil) release. Compared to the common 4,5-dimethoxy-2-nitrobenzyl caged compounds, most of the prodrugs exhibited large and redshifted one-photon absorption within the visible range. One-photon excitation for the drug release was studied by measuring UV-vis absorption, FT-IR, and HPLC spectra, which suggested that chlorambucil was released effectively and precisely by manipulating external light conditions. And the introduction of different functional groups made this type of prodrug a good platform to further react with some typical drug carriers and to further form excellent visible light responsive drug delivery systems. Moreover, the drug also could be effectively released under the excitation of two-photon at 800 nm with comparable photorelease efficiencies. The Royal Society of Chemistry 2012.
- Bao, Chunyan,Jin, Ming,Li, Bo,Xu, Yaodong,Jin, Jingyan,Zhu, Linyong
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experimental part
p. 5238 - 5244
(2012/08/08)
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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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- Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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- To determine the cytotoxicity of chlorambucil and one of its nitro-derivatives, conjugated to prasterone and pregnenolone, towards eight human cancer cell-lines
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Four ester prodrugs derived from the bifunctional alkylating agent chlorambucil, and one of its nitro-derivatives, 3-nitrochlorambucil conjugated to prasterone and pregnenolone, were synthesized and tested for their cytotoxic activity against eight human cell lines, using the standard MTT assay. A comparison between the esters and the controls, namely chlorambucil and 3-nitrochlorambucil would suggest that all four esters possess to varying degrees, specificity towards the breast adenocarcinoma cell line (MDA-mb468) than the other seven cells' lines tested. The overall findings are encouraging since it infers that these lipophilic esters not only have the ability to traverse specific cell membranes but also exhibit cytotoxicity towards most of the cell lines tested.
- Shervington, Leroy A.,Smith, Nigel,Norman, Emma,Ward, Timothy,Phillips, Roger,Shervington, Amal
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experimental part
p. 2944 - 2951
(2009/10/10)
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- Synthesis and pharmacokinetic profile of a quaternary ammonium derivative of chlorambucil, a potential anticancer drug for the chemotherapy of chondrosarcoma
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As a part of our targeting program based on the affinity of the quaternary ammonium moiety for cartilage, our objective was to develop more selective anticancer drugs towards chondrosarcoma that would concentrate in this malignant cartilaginous tissue and so improve the therapeutic index through a reduction of side effects. For this purpose we have synthesized and labeled with 14C a quaternary ammonium (QA) derivative of chlorambucil. Biological studies performed in rats showed that [14C]-CQA and [ 14C]-chlorambucil exhibited different pharmacokinetic profiles. The blood elimination of [14C]-CQA was faster than that of parent compound. [14C]-CQA was principally excreted by the fecal way. However, until 15 min after administration, levels of radioactivity were measured in cartilaginous tissues of rats given [14C]-CQA which was not the case for the rats which had received [14C]-chlorambucil. Although rates of radioactivity were quantified only during 15 min, these results prove that the functionalization of chlorambucil by a quaternary ammonium group allows the molecule to be carried selectively to cartilaginous tissues.
- Rapp, Maryse,Giraud, Isabelle,Maurizis, Jean-Claude,Madelmont, Jean-Claude
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p. 5007 - 5012
(2007/10/03)
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- Prodrug derivatives of carboxylic acid drugs
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Novel ester derivatives of carboxylic acid medicaments of formula (I), wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integrer from 1 to 3, and R1 and R2 are the same or different and are selected from a group consisting of an alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may be unsubstituted or substituted, or R1 and R2 together with the N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which heterocyclic group may be substituted. These compounds are highly biolabile prodrug forms of the corresponding carboxylic acid compounds and are highly susceptible to undergoing enzymatic hydrolysis in vivo whereas they are highly stable in aqueous solution. The novel derivatives are less irritating to mucosa than the parent carboxylic acids and may provide an improved bio-availability of the drugs.
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- DNA-Directed Alkylating Agents. 3. Structure-Activity Relationships for Acridine-Linked Aniline Mustards: Consequences of Varying the Length of the Linker Chain
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Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability.The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons.Relationships were sought between chain length and biological properties.Within eachseries, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue.The in vivo antitumor activities of the compounds dependend to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive.However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not.Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation.
- Valu, Kisione K.,Gourdie, Trudi A.,Boritzki, Theodore J.,Gravatt, G. Lance,Baguley, Bruce C.,et al.
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p. 3014 - 3019
(2007/10/02)
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- Soluble phosphorylated glucan: methods and compositions for treatment of neoplastic diseases
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A new class of soluble phosphorylated glucans is described as well as the process for making the same. According to one embodiment, the soluble phosphorylated glucan is derived from the yeast Saccharomyces cerevisiae. The soluble phosphorylated glucans are useful for prophylactic and therapeutic applications against neoplastic, bacteria, viral, fungal and parasitic diseases. The soluble phosphorylated glucans are used either alone or in combination with a known antimicrobial agent for prophylactic and therapeutic antimicrobial applications. Additionally, they may be administered either alone or as a non-toxic adjuvant, in combination with chemotherapy. The soluble phosphorylated glucans are also useful for stimulating macrophage cells, either in vivo or in vitro, to produce a cytotoxic/cyctostatic factor effective against cancer cells.
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- High molecular weight prodrug derivatives of antiinflammatory drugs
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Compounds of the formula 1, PS - O - A - (CH2)n- B - D (1), wherein PS-O represents an alkoxide residue of any of the free hydroxy groups of a polysaccharide (PS-OH) compound with molecular weight (Mw) of from 40,000 to 5,000,000 selected from dextran, carboxymethyl dextran, diethylaminoethyl dextran, starch, hydroxyet-hyl starch, alginates, glycogen, pullullan, agarose, cellulose, chitosan, chitin and carrageenan,A is a carbonyl group or absent,n is zero or a positive integer from 1 to 14,B is oxygen, a carbonyl group, NR wherein R is hydrogen or lower alkyl, or B is absent, and, D is (i) a group of the formula:, R1 - CO - (11), wherein R1-CO- represents the acyl residue of a carboxylic acid drug (R1-COOH) used in the treatment of inflammatory disorders; or (ii) a group of the formula:, R2 - O - (12), wherein R2-O- refers to the C-21 alkoxide residue of a known antiinflammatory steroid (R2-OH) or an alkoxide residue of any other drug or medicament containing a hydroxy functional group used in the treatment of inflammatory disorders; with the proviso that when A is absent, n is 0, and B is absent, then R1-CO- is different from the acyl residue of acetylsalicylic acid;, and non-toxic pharmaceutically acceptable acid addition salts thereof;, and non-toxic pharmaceutically acceptable cation salts thereof. Such compounds are biolabile prodrugs providing controlled release and prolonged duration of action of the parent active antiinflamma-tory agents locally at the administration site after intra-articular, intra-muscular, subcutaneous or extra-dural application while at the same time being highly stable in aqueous solution in the pH range 3--5. After oral administration of such prodrugs the parent drug is liberated selectively in the terminal ileum and the colon over an extended period of time.
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