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    Methods and compositions for enhancing transport across biological membranes
    2.
    发明申请
    Methods and compositions for enhancing transport across biological membranes 审中-公开
    用于增强跨生物膜的转运的方法和组合物

    公开(公告)号：US20060111274A1

    公开(公告)日：2006-05-25

    申请号：US11335007

    申请日：2006-01-18

    申请人： Jonathan Rothbard ,  Paul Wender

    发明人： Jonathan Rothbard ,  Paul Wender

    IPC分类号： A61K48/00 ,  A61K38/17 ,  A61K31/785

    CPC分类号： C07D305/14 ,  A61K31/785 ,  A61K47/62 ,  A61K47/645 ,  A61K48/00 ,  C07B2200/11 ,  C40B40/00

    摘要： Methods and compositions for transporting drugs and macromolecules across biological membranes are disclosed. In one embodiment, the invention pertains to a method for enhancing transport of a selected compound across a biological membrane, wherein a biological membrane is contacted with a conjugate containing a biologically active agent that is covalently attached to a transport polymer. In a preferred embodiment, the polymer consists of from 6 to 25 subunits, at least 50% of which contain a guanidino or amidino sidechain moiety. The polymer is effective to impart to the attached agent a rate of trans-membrane transport across a biological membrane that is greater than the rate of trans-membrane transport of the agent in non-conjugated form.

    摘要翻译： 公开了在生物膜上运输药物和大分子的方法和组合物。 在一个实施方案中，本发明涉及一种用于增强所选化合物跨生物膜的转运的方法，其中生物膜与含有共价连接于转运聚合物的生物活性剂的缀合物接触。 在优选的实施方案中，聚合物由6至25个亚基组成，其中至少50％含有胍基或脒基侧链部分。 聚合物有效地赋予附着剂超过生物膜的跨膜转运速率，该速率大于非共轭形式的试剂的跨膜转运速率。

    Oligocarbonate molecular transporters
    3.
    发明授权
    Oligocarbonate molecular transporters 有权
    低聚碳酸酯分子转运蛋白

    公开(公告)号：US07939621B2

    公开(公告)日：2011-05-10

    申请号：US12433693

    申请日：2009-04-30

    申请人： Christina Cooley ,  James Lupton Hedrick ,  Matthew Kiesewetter ,  Fredrik Nederberg ,  Brian Trantow ,  Robert Waymouth ,  Paul Wender

    发明人： Christina Cooley ,  James Lupton Hedrick ,  Matthew Kiesewetter ,  Fredrik Nederberg ,  Brian Trantow ,  Robert Waymouth ,  Paul Wender

    IPC分类号： C08G64/00 ,  C08G63/02

    CPC分类号： C07D319/06 ,  A61K47/55 ,  C08G64/0225 ,  C08G64/30 ,  Y02P20/55

    摘要： A cyclic carbonate monomer, including: wherein R1, R2, and R3 are independently selected from the group consisting of H, linear or branched, substituted or unsubstituted alkyl; R10 is a connecting group selected from the group consisting of linear or branched, substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R4 is an optional bridging group selected from the group consisting of linear or branched, substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; Z is selected from the group consisting of O, NH, NR, and S; G is a guanidine group; and P is a protecting group. The cylic carbonate monomer can be reacted with an initiator including a drug, drug candidate, probe or other molecule of interest to form an oligomer with the molecule of interest attached to one end of a carbonate backbone and guanidine groups attached to the carbonate backbone.

    摘要翻译： 一种环状碳酸酯单体，包括：其中R1，R2和R3独立地选自H，直链或支链，取代或未取代的烷基; R10是选自直链或支链，取代或未取代的烷基，杂烷基，环烷基，杂环，芳基和杂芳基的连接基团; R4是选自直链或支链，取代或未取代的烷基，杂烷基，环烷基，杂环，芳基和杂芳基的任选的桥连基团; Z选自O，NH，NR和S; G是胍基; 而P是保护基。 环状碳酸酯单体可以与包括药物，候选药物，探针或其他目标分子的引发剂反应，以形成与目标分子连接在碳酸酯骨架的一端和与碳酸酯骨架连接的胍基的低聚物。

    OLIGOCARBONATE MOLECULAR TRANSPORTERS
    4.
    发明申请
    OLIGOCARBONATE MOLECULAR TRANSPORTERS 有权
    低分子量分子运输机

    公开(公告)号：US20100280219A1

    公开(公告)日：2010-11-04

    申请号：US12433693

    申请日：2009-04-30

    申请人： Christina Cooley ,  James L. Hedrick ,  Matthew Kiesewetter ,  Fredrik Nederberg ,  Brian Trantow ,  Robert Waymouth ,  Paul Wender

    发明人： Christina Cooley ,  James L. Hedrick ,  Matthew Kiesewetter ,  Fredrik Nederberg ,  Brian Trantow ,  Robert Waymouth ,  Paul Wender

    IPC分类号： C08G64/02 ,  C07D323/04 ,  C08G64/30

    CPC分类号： C07D319/06 ,  A61K47/55 ,  C08G64/0225 ,  C08G64/30 ,  Y02P20/55

    摘要： A cyclic carbonate monomer, including: wherein R1, R2, and R3 are independently selected from the group consisting of H, linear or branched, substituted or unsubstituted alkyl; R10 is a connecting group selected from the group consisting of linear or branched, substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R4 is an optional bridging group selected from the group consisting of linear or branched, substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; Z is selected from the group consisting of O, NH, NR, and S; G is a guanidine group; and P is a protecting group.The cylic carbonate monomer can be reacted with an initiator including a drug, drug candidate, probe or other molecule of interest to form an oligomer with the molecule of interest attached to one end of a carbonate backbone and guanidine groups attached to the carbonate backbone.

    摘要翻译： 一种环状碳酸酯单体，包括：其中R1，R2和R3独立地选自H，直链或支链，取代或未取代的烷基; R10是选自直链或支链，取代或未取代的烷基，杂烷基，环烷基，杂环，芳基和杂芳基的连接基团; R4是选自直链或支链，取代或未取代的烷基，杂烷基，环烷基，杂环，芳基和杂芳基的任选的桥连基团; Z选自O，NH，NR和S; G是胍基; 而P是保护基。 环状碳酸酯单体可以与包括药物，候选药物，探针或其他目标分子的引发剂反应，以形成与目标分子连接在碳酸酯骨架的一端和与碳酸酯骨架连接的胍基的低聚物。

    Amphipathic Co-Oligomers for the Delivery of SIRNA
    6.
    发明申请
    Amphipathic Co-Oligomers for the Delivery of SIRNA 有权
    用于输送SIRNA的两亲性共低聚物

    公开(公告)号：US20140350077A1

    公开(公告)日：2014-11-27

    申请号：US14342480

    申请日：2012-09-05

    申请人： Christina Barnes Cooley ,  Erika Geihe Stanzl ,  Robert M. Waymouth ,  Paul Wender

    发明人： Christina Barnes Cooley ,  Erika Geihe Stanzl ,  Robert M. Waymouth ,  Paul Wender

    IPC分类号： C12N15/113

    CPC分类号： C12N15/113 ,  A61K9/0019 ,  A61K47/593 ,  C12N2310/14 ,  C12N2320/32

    摘要： Co-oligomer compounds, complexes of the same with polyanions, such as siRNAs, and methods for using the same are provided. the delivery of polynucleotides, into a cell. The subject co-oligomers include at least a liphopilic monomer and at least a hydrophilic monomer (e.g., a guanidinium containing monomer). In some embodiments, the co-oligomer compounds are capable of complexing a siRNA of interest, thereby increasing the cell permeability of the siRNA, prior to release of the siRNA into the cell. In some embodiments, the subject method is a method of delivery a siRNA into a cell. In some embodiments, the subject method is a method of reducing expression of a protein target of a siRNA of interest. The subject co-oligomer/siRNA complexes may be formulated and administered to a subject to treat a condition resulting from expression of a protein target of the siRNA of interest.

    摘要翻译： 提供了共低聚物化合物，与聚阴离子的复合物，如siRNAs，以及使用它们的方法。 将多核苷酸递送到细胞中。 本发明共低聚物包括至少一种亲脂单体和至少一种亲水单体（例如含有胍基的单体）。 在一些实施方案中，在将siRNA释放到细胞之前，共低聚物化合物能够络合感兴趣的siRNA，从而增加siRNA的细胞通透性。 在一些实施方案中，本发明方法是将siRNA递送至细胞的方法。 在一些实施方案中，本发明方法是减少感兴趣的siRNA的蛋白质靶标的表达的方法。 可以将受试者共同寡聚体/ siRNA复合物配制并施用于受试者以治疗由感兴趣的siRNA的蛋白质靶标表达产生的病症。

    Conjungation of Small Molecules to Octaarginine Transporters for Overcoming Multi-Drug Resistance
    7.
    发明申请
    Conjungation of Small Molecules to Octaarginine Transporters for Overcoming Multi-Drug Resistance 审中-公开
    将小分子与八氢精氨酸转运蛋白结合以克服多药耐药

    公开(公告)号：US20110160146A1

    公开(公告)日：2011-06-30

    申请号：US12865692

    申请日：2009-02-05

    申请人： Paul Wender ,  Elena A. Dibikovskaya ,  Stephen H. Thorne ,  Christopher H. Contag

    发明人： Paul Wender ,  Elena A. Dibikovskaya ,  Stephen H. Thorne ,  Christopher H. Contag

    IPC分类号： A61K47/48 ,  C12N5/09 ,  C12N5/095 ,  C07K2/00 ,  C07K7/06 ,  C07K7/08 ,  A61P35/00

    CPC分类号： A61K31/7048 ,  A61K31/337 ,  A61K47/645

    摘要： Many cancer therapeutic agents elicit resistance that renders them ineffective and often produces cross resistance to other drugs. One of the most common mechanisms of resistance involves P-glycoprotein (Pgp) mediated drug efflux. Here we provide compositions and methods that restore the efficacy of a therapeutic agent reduced by resistance by conjugation of the same agent to an oligoarginine transporter comprising from about 5 to about 25 guanidino or amidino moieties. We specifically show that the widely used chemotherapeutic agent taxol, ineffective against taxol-resistant human ovarian cancer cell lines, can be incorporated into an octaarginine conjugate that is effective against the same taxol-resistant cell lines. Significantly, the ability of the taxol conjugates to overcome taxol resistance is observed both in cell culture and in animal models of ovarian cancer. The generality and mechanistic basis for this effect were also explored with other Pgp substrate. This approach shows generality for overcoming the multidrug resistance elicited by small molecule cancer chemotherapeutics and could improve the prognosis for many cancer patients and fundamentally alter search strategies for novel therapeutic agents effective against resistant disease.

    摘要翻译： 许多癌症治疗剂引起抗性，使其无效，并且经常产生与其它药物的交叉耐药性。 最常见的机制之一涉及P-糖蛋白（Pgp）介导的药物流出。 在这里，我们提供了通过将相同试剂与包含约5至约25个胍基或脒基部分的寡精氨酸转运蛋白缀合来恢复通过抗性降低的治疗剂的功效的组合物和方法。 我们具体表明，广泛使用的化疗药物紫杉醇对紫杉醇耐药的人类卵巢癌细胞系无效，可以掺入对抗相同抗紫杉醇细胞系有效的八氮精氨酸缀合物。 显着地，在细胞培养和卵巢癌的动物模型中观察到紫杉醇缀合物克服紫杉醇耐药性的能力。 还对其他Pgp底物进行了研究。 这种方法显示了克服小分子癌化学治疗引发的多药耐药性的一般性，并且可以改善许多癌症患者的预后，从根本上改变对抗性疾病有效的新型治疗剂的搜索策略。