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hpma-docetaxel or gemcitabine conjugates and uses thereof

一种吉西他滨、多西他赛的技术，应用在HPMA-多西他赛或吉西他滨缀合物及其用途领域，能够解决肿瘤转移性疾病等问题

Inactive Publication Date: 2011-11-30
REXAHN PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chemotherapy and radiation therapy are largely ineffective, and metastatic disease occurs frequently even after potentially curative surgery

Method used

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  • hpma-docetaxel or gemcitabine conjugates and uses thereof
  • hpma-docetaxel or gemcitabine conjugates and uses thereof
  • hpma-docetaxel or gemcitabine conjugates and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Example 1: Synthesis of HPMA-gemcitabine or docetaxel conjugates for drug delivery

[0101] HPMA comonomer drug conjugates were synthesized by polymerization of HPMA monomer and activated MA-GFLG-drug (SEQ ID NO: 1 ) comonomer in different molar ratios.

[0102] 1) Synthesis of HPMA comonomer

[0103] The synthesis of HPMA monomer was carried out as previously described (Kopecek and Bazilova, Eur. Polym. J., 9: 7-14 (1973)), as figure 1 shown. The MA-GG-ONp comonomer was prepared by a modified multistep reaction (Kopecek et al., Ann. N Y Acad. Sci., 446:93-104 (1985)).

[0104] plan 1

[0105]

[0106] To a solution of 1-amino-2propanol (65.6ml, 0.84mol) in 250ml of acetonitrile was added dropwise freshly distilled methacryloyl chloride (MACl) (41ml, 0.42mol, in 20ml of acetonitrile) at -5°C with vigorous stirring . A small amount of the inhibitor tert-octylcatechol was added to the solution. The reaction mixture was stirred at room temperature for an additional ...

Embodiment 2

[0148] Embodiment 2: biological test

[0149] 1) Growth of cancer cell lines

[0150] Cancer cell lines used to assay the effects of HPMA-drug conjugates were obtained from the following sources: human MDA-MB-231 (breast), HCT116 (colon) and PANC-1 (pancreas) from the American Standard Culture Center (ATCC) ( Manassas, VA). UMRC2 (kidney) was from the National Cancer Institute (Bethesda, MD). Cells were maintained in Dulbecco's Modified Eagle's Medium ("DMEM", Invitrogen) supplemented with 10% FBS, P / S and 10 mM HEPES. All cells were incubated at 37°C in humidified 5% CO 2 incubate.

[0151] 2) In vitro cell proliferation assay for human tumor cell lines

[0152] Growth inhibition assays of HPMA-drug conjugates against human cancer cell lines were performed using the sulforhodamine B ("SRB") method (Skehan et al., J. National Cancer Institute, 82: 1107-1112 (1990)). Briefly, exponentially growing cancer cells were treated with 2-3x10 3 Cells / well were seeded in 96-well ...

Embodiment 3

[0159] Example 3: Xenotransplantation Studies

[0160] To observe tumor growth inhibition in animal models, HPMA-conjugated docetaxel or gemcitabine was used on nude mouse xenograft models as described below.

[0161] Mia-Paca human pancreatic cancer cell or HCT116 cell suspension (3x10 6 cells) were subcutaneously injected into the lower flank of six-week-old female FoxN1 nude mice. When the tumor reaches an appropriate size (eg, about 50-60mm 3 volume), the mice were injected intravenously with phosphate-buffered saline (PBS) alone or the drug conjugate of the invention every 4-5 days. Animals are monitored for several weeks until control tumors reach, eg, about 1 cm in diameter, at which point animals are euthanized. Tumor size and tumor composition were determined and reported as fold change in tumor size ( Figure 1-Figure 3 ).

[0162] Using the model described in this example, it was shown that drug conjugates of the invention, such as those described in Example 1,...

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Abstract

The present invention discloses gemcitabine and docetaxel water soluble compositions formed by conjugating gemcitabine or docetaxel to a water soluble polymer such as N-2-hydroxypropylmethacrylamide (HPMA). The invention also discloses a method of treating cancer using the composition of the invention.

Description

technical field [0001] The present invention relates to conjugations comprising anticancer agents (such as gemcitabine or docetaxel) and / or targeting ligands (such as RGDfK, EPPT1 peptide or folic acid) and N-(2-hydroxypropyl)methacrylamide (HPMA) Compositions of these conjugates, and methods of delivering these conjugates to cells using the compositions. Background technique [0002] Docetaxel (Taxotere) is one of the most important members of a new class of oncology drugs. However, its poor solubility presents pharmaceutical challenges, and emerging data suggest that specific tissue exposure profiles, such as low drug concentrations over prolonged periods, may enhance beneficial antitumor mechanisms. Since the main disadvantage of docetaxel is that it is highly lipophilic and practically insoluble in water, the considerations for formulating docetaxel formulations have been extensively studied. For clinical use, they are formulated and administered in a co-solvent system...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61P35/00
CPCA61K47/48176A61K47/48107B82Y5/00A61K47/48338A61K47/48246A61K31/337A61K47/65A61K47/551A61K47/58A61K47/64A61P35/00A61P35/02A61K38/07
Inventor 李永福安昌浩金德中哈米德雷扎·甘德哈里阿比西特·雷安贾·南
Owner REXAHN PHARMA INC
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