- Enhancing efficacy of gemcitabine in pancreatic patient-derived xenograft mouse models
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Gemcitabine (Gem), a nucleoside analog, is a preferred choice of treatment for pancreatic cancer (PCa) and often used in combination therapy against wide range of solid tumors. It is known to be rapidly inactivated in blood by cytidine deaminase. The objective of the study was to improve the systemic stability and anticancer activity of modified Gem termed 4-N-stearoylGem (4NSG) In this study, the IC50 values of 4NSG treated MiaPaCa-2 and primary pancreatic cancer (PPCL-46) cultures were significantly lower when compared with gemcitabine hydrochloride (GemHCl) treated cultures. In acute toxicity study, liver enzyme level of aspartate aminotransferase (AST) of the control mice was not significantly different from AST levels of 4NSG and GemHCl treated mice. However, alanine aminotransferase (ALT) level of control mice (67 ± 5 mUnits/mL) was significantly lower compared with ALT levels of GemHCl (232 ± 28 mUnits/mL) and that of 4NSG (172 ± 22 mUnits/mL) (p a remarkable tumor growth inhibition and revealed significant antiangiogenic activity in 4GSN treated pancreatic PDX tumor.
- Affram, Kevin,Agyare, Edward,Han, Bo,Inkoom, Andriana,Krishnan, Sunil,Ndemazie, Nkafu,Ofori, Edward,Smith, Taylor,Trevino, Jose,Underwood, Patrick,Zhu, Xue
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Read Online
- Gemcitabine Lipid Prodrugs: The Key Role of the Lipid Moiety on the Self-Assembly into Nanoparticles
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A small library of amphiphilic prodrugs has been synthesized by conjugation of gemcitabine (Gem) (a hydrophilic nucleoside analogue) to a series of lipid moieties and investigated for their capacity to spontaneously self-assemble into nanosized objects by simple nanoprecipitation. Four of these conjugates formed stable nanoparticles (NPs), while with the others, immediate aggregation occurred, whatever the tested experimental conditions. Whether such capacity could have been predicted based on the prodrug physicochemical features was a matter of question. Among various parameters, the hydrophilic-lipophilic balance (HLB) value seemed to hold a predictive character. Indeed, we identified a threshold value which well correlated with the tendency (or not) of the synthesized prodrugs to form stable nanoparticles. Such a hypothesis was further confirmed by broadening the analysis to Gem and other nucleoside prodrugs already described in the literature. We also observed that, in the case of Gem prodrugs, the lipid moiety affected not only the colloidal properties but also the in vitro anticancer efficacy of the resulting nanoparticles. Overall, this study provides a useful demonstration of the predictive potential of the HLB value for lipid prodrug NP formulation and highlights the need of their opportune in vitro screening, as optimal drug loading does not always translate in an efficient biological activity.
- Coppens, Eleonore,Desma?le, Didier,Mougin, Julie,Tusseau-Nenez, Sandrine,Couvreur, Patrick,Mura, Simona
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Read Online
- Enhanced anti-tumor efficiency of gemcitabine prodrug by FAPα-mediated activation
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Gemcitabine (Gem) as an anti-cancer agent has been limited by its short circulation time and rapid metabolism that reflects in low tumor uptake and low therapeutic efficiency. To improve its anti-tumor activity, a novel FAPα enzyme-activated prodrug of Z-
- Sun, Jing,Yang, Dan,Cui, Shi-He,Zhang, Hai-Tao,Fu, Yu,Wang, Jian-Cheng,Zhang, Qiang
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Read Online
- Integrin-Targeting Knottin Peptide–Drug Conjugates Are Potent Inhibitors of Tumor Cell Proliferation
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Antibody–drug conjugates (ADCs) offer increased efficacy and reduced toxicity compared to systemic chemotherapy. Less attention has been paid to peptide–drug delivery, which has the potential for increased tumor penetration and facile synthesis. We report a knottin peptide–drug conjugate (KDC) and demonstrate that it can selectively deliver gemcitabine to malignant cells expressing tumor-associated integrins. This KDC binds to tumor cells with low-nanomolar affinity, is internalized by an integrin-mediated process, releases its payload intracellularly, and is a highly potent inhibitor of brain, breast, ovarian, and pancreatic cancer cell lines. Notably, these features enable this KDC to bypass a gemcitabine-resistance mechanism found in pancreatic cancer cells. This work expands the therapeutic relevance of knottin peptides to include targeted drug delivery, and further motivates efforts to expand the drug-conjugate toolkit to include non-antibody protein scaffolds.
- Cox, Nick,Kintzing, James R.,Smith, Mark,Grant, Gerald A.,Cochran, Jennifer R.
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Read Online
- Single Diastereomers of the Clinical Anticancer ProTide Agents NUC-1031 and NUC-3373 Preferentially Target Cancer Stem CellsIn Vitro
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A 3′-protected route toward the synthesis of the diastereomers of clinically active ProTides, NUC-1031 and NUC-3373, is described. Thein vitrocytotoxic activities of the individual diastereomers were found to be similar to their diastereomeric mixtures. In the KG1a cell line, NUC-1031 and NUC-3373 have preferential cytotoxic effects on leukemic stem cells (LSCs). These effects were not diastereomer-specific and were not observed with the parental nucleoside analogues gemcitabine and FUDR, respectively. In addition, NUC-1031 preferentially targeted LSCs in primary AML samples and cancer stem cells in the prostate cancer cell line, LNCaP. Although the mechanism for this remains incompletely resolved, NUC-1031-treated cells showed increased levels of triphosphate in both LSC and bulk tumor fractions. As ProTides are not dependent on nucleoside transporters, it seems possible that the LSC targeting observed with ProTides may be caused, at least in part, by preferential accumulation of metabolized nucleos(t)ide analogues.
- Slusarczyk, Magdalena,Serpi, Michaela,Ghazaly, Essam,Kariuki, Benson M.,McGuigan, Christopher,Pepper, Chris
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p. 8179 - 8193
(2021/06/28)
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- A self-assembling prodrug nanosystem to enhance metabolic stability and anticancer activity of gemcitabine
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Self-assembly is a powerful approach in molecular engineering for biomedical applications, in particular for creating self-assembling prodrugs. Here, we report a self-assembling prodrug of the anticancer drug gemcitabine (Gem) based on amphiphilic dendrimer approach. The prodrug reported in this study demonstrates high drug loading (40%) and robust ability to self-assemble into small nanomicelles, which increase the metabolic stability of Gem and enable entry into cells via endocytosis, hence bypassing transport-mediated uptake. In addition, this prodrug nanosystem exhibited an effective pH- and enzyme-responsive release of Gem, resulting in enhanced anticancer activity and reduced toxicity. Harboring advantageous features of both prodrug- and nanotechnology-based drug delivery, this self-assembling Gem prodrug nanosystem constitutes a promising anticancer candidate. This study also offers new perspectives of the amphiphilic dendrimer nanoplatforms for the development of self-assembling prodrugs.
- Cong, Mei,Dhumal, Dinesh,Laurini, Erik,Peng, Ling,Pricl, Sabrina,Xia, Yi,Xu, Guangling,Yang, Shaoyou,Zhang, Jing,Zhang, Kaiyue,Zhang, Wenzheng,Zhao, Weidong
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supporting information
(2021/12/30)
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- Prodrug based on gemcitabine structure as well as preparation method and application of prodrug
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The invention discloses a prodrug based on a gemcitabine structure. The prodrug has a structure of general formula I. The prodrug has certain inhibitory activity on tumors. The invention further discloses a preparation method of the prodrug. According to the preparation method, lipid solubility of the prodrug is improved by modifying N4 site of the gemcitabine structure, and membrane permeabilityof the compound is improved. The invention further discloses application of the prodrug in antitumor drugs. The fat-soluble prodrug can enter tumors through passive diffusion and active transport, thereby inhibiting tumor growth, overcoming tumor drug resistance, and improving tumor targeting of gemcitabine. The invention further discloses a pharmaceutical composition containing the prodrug. The pharmaceutical composition is administrated in an oral administration mode, and after the prodrug is absorbed, the prodrug can be rapidly broken into gemcitabine in vivo, thereby exerting a therapeuticeffect in time and increasing oral bioavailability of gemcitabine.
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Paragraph 0016; 0035-0037
(2021/01/25)
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- A PRODRUG PLATFORM USEFUL TO DELIVER AMINES, AMIDES AND PHENOLS
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Provided herein is a prodrug platform useful to deliver pharmaceutically active amines, amides and phenols and their use in the diagnosis, prevention and/or treatment of various diseases. Compared with the parent drug (e.g., Gemcitabine), the prodrugs show a significant overall safety improvement (therapeutic index (TI) improvement), especially in liver.
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Page/Page column 31
(2021/02/26)
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- LIVER SPECIFIC DELIVERY-BASED GEMCITABINE PRODRUG NUCLEOSIDE CYCLIC PHOSPHATE COMPOUND, AND APPLICATION THEREOF
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Provided are a liver specific delivery (LSD)-based anticancer prodrug nucleoside cyclic phosphate compound and an application thereof, and in particular, a compound represented by formula (I) as well as isomers, pharmaceutically acceptable salts, hydrates, and solvates thereof, and corresponding pharmaceutical compositions. Also provided is an application of the compound alone or in combination with other anticancer drugs in anticancer area, particularly the treatment of hepatocellular carcinoma (HHC).
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Paragraph 0072; 0073
(2020/11/26)
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- SONODYNAMIC THERAPY
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The invention provides a method of preparing a microbubble covalently attached to at least one therapeutic agent which comprises: (i) providing a lipid (e.g. a phospholipid) capable of forming a microbubble; covalently linking at least one therapeutic agent to said lipid to produce a functionalised lipid; and preparing a microbubble from said functionalised lipid. Microbubble-therapeutic agent complexes which comprise a microbubble shell formed from a plurality of lipids (e.g. phospholipids) in which at least a proportion of the lipids are covalently linked to at least one therapeutic agent are also provided. Examples of therapeutic agents which may be attached to the microbubble include chemotherapeutic agents and sonosensitising agents. The complexes find use in methods of sonodynamic therapy and, in particular, in methods of combined sonodynamic therapy and chemotherapy.
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Paragraph 43-44
(2020/12/30)
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- Selective Activation of a Prodrug by Thioredoxin Reductase Providing a Strategy to Target Cancer Cells
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Elevated reactive oxygen species and antioxidant defense systems have been recognized as one of the hallmarks of cancer cells. As a major regulator of the cellular redox homeostasis, the selenoprotein thioredoxin reductase (TrxR) is increasingly considered as a promising target for anticancer drug development. The current approach to inhibit TrxR predominantly relies on the modification of the selenocysteine residue in the C-terminal active site of the enzyme, in which it is hard to avoid the off-target effects. By conjugating the anticancer drug gemcitabine with a 1,2-dithiolane scaffold, an unprecedented prodrug strategy is disclosed that achieves a specific release of gemcitabine by TrxR in cells. As overexpression of TrxR is frequently found in different types of tumors, the TrxR-dependent prodrugs are promising for further development as cancer chemotherapeutic agents.
- Li, Xinming,Hou, Yanan,Meng, Xianke,Ge, Chunpo,Ma, Huilong,Li, Jin,Fang, Jianguo
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p. 6141 - 6145
(2018/04/30)
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- Striking a Balance between Carbonate/Carbamate Linkage Bond- and Reduction-Sensitive Disulfide Bond-Bearing Linker for Tailored Controlled Release: In Situ Covalent-Albumin-Binding Gemcitabine Prodrugs Promote Bioavailability and Tumor Accumulation
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To address the challenges of rapid enzyme inactivation, poor tumor targeting, and acquired drug resistance in gemcitabine (GEM) application, we report two groups of maleimide-functionalized GEM prodrugs conjugating covalently in situ with Cys-34 of blood-circulating albumin and then resulting in macromolecular prodrugs after intravenous administration. Tailored and accurate controlled release was achieved through different combinations of linkage bonds, relatively stable and labile (carbamate and carbonate, respectively), and linkers with or without insertion of a disulfide bond. Interestingly, we found that the overall advantages or disadvantages brought by a disulfide bond varied with the stability of the linkage bond. Finally, the carbonate linkage bond-bearing group, especially the one with a linker lacking a disulfide bond, stood out with remarkably increased bioavailability (21-fold greater than GEM) and efficient tumor free-GEM accumulation (8-fold of GEM), which consequently contributed to excellent in vivo antitumor efficacy.
- Zhang, Huicong,Wang, Kuanglei,Na, Kexin,Li, Dan,Li, Zhenbao,Zhao, Dongyang,Zhong, Lu,Wang, Menglin,Kou, Longfa,Luo, Cong,Zhang, Haotian,Kan, Qiming,Ding, Huaiwei,He, Zhonggui,Sun, Jin
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p. 4904 - 4917
(2018/05/29)
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- Gemcitabine-aromatic chlormethine conjugate targeting at high-level ROS (reactive oxygen species) of cancer cells and preparation method and pharmaceutical application thereof
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The invention discloses gemcitabine-aromatic chlormethine conjugate targeting at high-level ROS (reactive oxygen species) of cancer cells and its pharmaceutically acceptable salts, having a structureshown in the general formula I that is shown in the desc
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Paragraph 0050; 0051; 0052; 0053
(2018/07/15)
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- Multifunctional Tumor-Targeting Cathepsin B-Sensitive Gemcitabine Prodrug Covalently Targets Albumin in Situ and Improves Cancer Therapy
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We report a new type of amide bond-bearing cathepsin B-sensitive gemcitabine (GEM) prodrugs, capable of in situ covalently targeting circulating albumin and then making a hitchhike to the tumor. Specially, less plasma-enzyme deactivation, long plasma half-life, independence on nucleoside transporters, outstanding tumor targeting, and site-specific drug release are achieved, and as such these multifunctional advantages contribute to the dramatically increased in vivo antitumor efficacy.
- Zhang, Huicong,Sun, Zhisu,Wang, Kuanglei,Li, Na,Chen, Hongxiang,Tan, Xiao,Li, Lingxiao,He, Zhonggui,Sun, Jin
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p. 1852 - 1858
(2018/05/29)
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- Albumin conjunction-type gemcitabine prodrug as well as synthetic method and application thereof
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The invention relates to an albumin conjunction-type maleimide functionalized gemcitabine prodrug as well as application thereof in transferring an antitumor prodrug. The albumin conjunction-type maleimide functionalized gemcitabine prodrug is a compound consisting of gemcitabine and maleimide connected by virtue of an amido bond, a carbonate bond or an amino formate bond, and a maleimide group isused as an albumin 34-site cysteine free mercapto group jointed target. The prodrug compound can be rapidly specifically bonded with albumin in blood to form an albumin prodrug compound, thereby lowering the drug metabolism speed, significantly prolonging a half-life period of the drug, and realizing the long cycling effect. In addition, under the EPR effect and the albumin receptor mediation, the tumor targeting can be realized, and the antitumor effect can be improved. The gemcitabine precursor drug is used for intravenous injection and larger in market application prospect.
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Paragraph 0036; 0038; 0042
(2018/08/28)
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- Anticancer prodrug molecule and its preparation method and target compound
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The invention discloses an anticancer prodrug molecule and its preparation method and a target compound, and relates to the field of organic synthesis and molecular medicine. The target compound of the anticancer prodrug molecule can be selectively identified by protein which is excessively expressed in a cancer cell; the preparation method of the anticancer prodrug molecule includes steps of connecting the target compound to amino acid or hydroxyl of the anticancer active molecule; through the method, the target compound is connected with the anticancer active molecule, thus the anticancer prodrug molecule is prepared; after the target compound is identified by the protein specificity which is highly expressed in the cancer cell, the anticancer prodrug molecule is released and directly acted on the cancer cells, thereby reaching the purpose of targeted treatment.
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Paragraph 0063; 0067; 0069; 0088
(2017/12/30)
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- Crystal form of gemcitabine predrug, preparation method and use of crystal form and pharmaceutical composition
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The invention relates to a compound crystal form, a preparation method and use thereof and a pharmaceutical composition and particularly relates to a crystal form of a gemcitabine predrug, a preparation method and use of the crystal form and an anti-cance
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Paragraph 0047-0048
(2017/09/01)
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- NO donor-type of gemcitabine/FTA/furazane conjugate and preparation method and use thereof
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The invention discloses a gemcitabine/FTA/furazan conjugate in a NO-donor type, a preparation method and an application. A product in the invention is the novel gemcitabine/FTA/furazan conjugate in the NO-donor type or a pharmaceutically-acceptable salt t
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Paragraph 0065-0067
(2017/08/26)
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- N4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO
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This disclosure relates to certain N4-hydroxycytidine derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of a Zika virus infection.
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Page/Page column 59; 77; 78
(2017/10/06)
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- Discovery of a novel chimeric ubenimex–gemcitabine with potent oral antitumor activity
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Herein, a novel mutual prodrug BC-A1 was discovered by integrating ubenimex and gemcitabine into one molecule. Biological characterization revealed that compound BC-A1 could maintain both the anti-CD13 activity of ubenimex and the cytotoxic activity of ge
- Jiang, Yuqi,Hou, Jinning,Li, Xiaoyang,Huang, Yongxue,Wang, Xuejian,Wu, Jingde,Zhang, Jian,Xu, Wenfang,Zhang, Yingjie
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p. 5787 - 5795
(2016/11/09)
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- N4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO
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This disclosure relates to N4-hydroxycytidine derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to the treatment and prophylaxis of viral infections.
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Page/Page column 72; 73
(2016/07/27)
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- Synthesis and biological evaluation of nitric oxide-releasing hybrids from gemcitabine and phenylsulfonyl furoxans as anti-tumor agents
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A series of novel hybrids 10a-m were designed and synthesized by coupling phenylsulfonyl furoxans with gemcitabine through various diols or alcohol amine linkers, and their biological activities were evaluated in vitro. Most of the hybrids exhibited good to moderate anti-tumor activities, which are associated with NO release. In particular, hybrid 10e showed excellent anticancer activities which were more potent than or comparable to gemcitabine. However, inhibition of nucleoside transport only significantly decreased the inhibitory rates of gemcitabine against HepG2 cells but not 10e, and the inhibitory rates of 10e were partially reduced by pre-treatment with hemoglobin, demonstrating that the anti-tumor activity of 10e might result from the synergic effect of high levels of NO production and gemcitabine fragment. In addition, compound 10ecould apparently induce cell apoptosis by regulating apoptotic relative proteins. Therefore, our novel findings provide a proof of principle in the design of new furoxan/gemcitabine hybrids for the intervention of human cancers.
- Li, Xianghua,Wang, Xuemin,Xu, Chenjun,Huang, Junkai,Wang, Chengniu,Wang, Xinyang,He, Liqin,Ling, Yong
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supporting information
p. 1130 - 1136
(2015/06/25)
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- TARGETED THERAPEUTICS
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The present invention provides pharmacological compounds including an effector moiety conjugated to a binding moiety that directs the effector moiety to a biological target of interest. Likewise, the present invention provides compositions, kits, and meth
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Paragraph 00493; 00494
(2015/05/19)
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- Polymer prodrug nanoparticles based on naturally occurring isoprenoid for anticancer therapy
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The synthesis of a novel class of polymer prodrug nanoparticles with anticancer activity is reported by using squalene, a naturally occurring isoprenoid, as a building block by the reversible addition-fragmentation (RAFT) technique. The RAFT agent was functionalized by gemcitabine (Gem) as anticancer drug, and the polymerization of squalenyl-methacrylate (SqMA) led to well-defined macromolecular prodrugs comprising one Gem at the extremity of each polymer chain. The amphiphilic nature of the resulting Gem-PSqMA conjugates allowed them to self-assemble into long-term stable and narrowly dispersed nanoparticles with significant anticancer activity in vitro on various cancer cell lines. To confer stealth properties on these nanoparticles, their PEGylation was successfully performed, as confirmed by X-ray photoelectron spectroscopy (XPS) and complement activation assay. It was also shown that the PEGylated nanoparticles could be internalized in cancer cells to a greater extent than their non-PEGylated counterparts.
- Trung Bui, Duc,Maksimenko, Andrei,Desmaele, Didier,Harrisson, Simon,Vauthier, Christine,Couvreur, Patrick,Nicolas, Julien
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p. 2837 - 2847
(2013/09/02)
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